Psychiatric Disorders in Dementia

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, a neurodegenerative disorder which is characterized not only by cognitive deterioration but also by a diversity of Behavioral and Psychological Signs and Symptoms of Dementia (BPSD). BPSD in AD or other dementia subtypes such as frontotemporal dementia (FTD) or dementia with Lewy bodies (DLB) consist of delusions, hallucinations, activity disturbances, aggression/agitation, diurnal rhythm disturbances, mood disorders, apathy, and anxieties/phobias. Neuroimaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are very essential and useful imaging tools to differentially diagnose between AD and non-AD or healthy control subjects or between different dementia subtypes, such as AD and DLB or FTD. Besides their diagnostic characteristics, PET and SPECT are also useful tools to investigate the cerebral pathophysiology of BPSD in AD, FTD, and DLB among others.

Below, PET- and SPECT-related neuroimaging in dementia spanning the last two decades has been reviewed. The common use of different PET and SPECT radioligands and other compounds which target different and unique aspects of neurodegeneration in the differential diagnosis of dementia is described. Furthermore, PET and SPECT research in BPSD with a main focus on depression, apathy, and psychosis in AD, DLB, and FTD are illustrated as well. On the whole, both PET and SPECT imaging of neuropsychiatric disturbances in dementia have demonstrated that depending on the behavioral phenomenon and dementia subtype, BPSD are the fundamental expression of very regional cerebral pathological events rather than a diffuse brain illness.

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1 Dementia: Definition and Epidemiology

1.1 Definition

According to the Diagnostic and Statistical Manual for Mental Disorders IV (DSM-IV-TR), dementia is a clinical syndrome characterized by a gradual loss of function in multiple cognitive domains leading to a significant impairment in social and occupational functioning (American Psychiatric Association 2000) (Table 11.1).

Table 11.1 Criteria of the dementia syndrome according to DSM-IV-TR

Besides the cognitive aspects, dementia is also characterized by numerous behavioral symptoms entitled Behavioral and Psychological Signs and Symptoms of Dementia (BPSD) (Reisberg et al. 1987). BPSD consist of delusional ideation, hallucinations, activity disturbances, agitation/aggression, circadian rhythm disturbances, affective disturbances, and anxiety disorders and are considered a major component of the dementia syndrome. Lastly, basic (BADL) and instrumental activities of daily living (IADL) complete the definition of dementia. BADL refer to daily self-care activities such as personal hygiene, getting dressed, eating, and general mobility, whereas IADL require more complex abilities such as driving a car, utilizing a phone, taking medication, doing groceries, and managing finances (Lawton and Brody 1969). During the course of dementia, IADL are firstly affected and are later followed by BADL (Gauthier et al. 1997). Several studies also showed a direct association between cognitive decline and worsening of BADL and IADL in dementia patients and non-demented elderly (Mitnitski et al. 1999).

The definition above emphasizes that the term “dementia” is a syndrome (i.e., association of several clinically recognizable features, signs, and symptoms) rather than only a cognitive disorder and is completed by important behavioral and functional shortcomings as well (Fig. 11.1).

Fig. 11.1

The dementia syndrome consists of cognitive and noncognitive symptomatology. Worsening of BADL and IADL completes the definition. BPSD examples are delusional ideation and hallucinations, activity disturbances, aggression and agitation, sleep disturbances, mood disorders, and anxiety. Abbreviations: BADL basic activities of daily living, BPSD Behavioral and Psychological Signs and Symptoms of Dementia, IADL instrumental activities of daily living

1.2 Prevalence and Incidence

Although dementia strikes irrespective of age, the prevalence of dementia generally rises with it. Women seem to be more frequently affected by dementia than men (Breteler et al. 1992) although this observation might be attributed to a slower progression rate of the disease in women combined with a proportionally longer life expectancy (Bachman et al. 1993). Prevalence estimates of dementia in the aged population show distinct variation due to differences in population selection, case ascertainment procedures, and diagnostic criteria, which often results in over- or underestimation of dementia occurrence (De Deyn et al. 2011). In general, however, the prevalence of moderate to severe dementia approximately doubles every 5 years starting at a rate of 2 % between the age of 65 and 69, augmenting to 4 % in people aged between 70 and 74 up to 16 % in octogenarians (Henderson 1990; Morris 1994). These numbers correspond to a prevalence of 5 up to 10 % in the elderly aged 65 and older. In Europe, the prevalence of dementia varies between 1 % at the age of 60–64 rising up to 34.7 % in elderly aged 95–99 (Hofman et al. 1991). In the Netherlands, prevalence of dementia in people aged 75–79 was estimated to be 5.2 % in 1992 (in a rural area near Zwolle) (Boersma et al. 1998) and 6.1 % in 1993 (in the Rotterdam suburb of Ommoord) (Ott et al. 1995; Breteler et al. 1998), while in Belgium, it was estimated to be 7.6 % in 1993 (in the semirural area of Heist-op-den-Berg) (Roelands et al. 1994). More recent figures of Belgian dementia prevalence estimates came from the Antwerp Cognition (ANCOG) study. This longitudinal cohort study of 825 community-dwelling elderly aged between 75 and 80, living in 6 different districts of Antwerp, with a 3-year follow-up period (n = 363) resulted in an overall prevalence rate of 8.7 % (De Deyn et al. 2011).

To give exact numbers, Wimo et al. (2003) assessed the worldwide occurrence of dementia from 1950 until 2000 and also estimated its progression until 2050. The worldwide number of persons with dementia in 2000 was estimated at about 25 million persons. Almost half of the demented individuals lived in Asia (46 %), 30 % in Europe, and 12 % in North America. Fifty-two percent lived in developing regions. About 6.1 % of the population aged 65 years and older suffered from dementia (about 0.5 % of the worldwide population) and 59 % were female. The number of new cases of dementia in 2000 was calculated to be approximately 4.6 million. The forecast indicated a considerable increase in the number of demented elderly from 25 million in the year 2000 to 63 million in 2030 (41 million in less developed regions) and to 114 million in 2050 (84 million in developing regions).

It thus becomes clear that due to progressive aging of the general population, a further increase of dementia prevalence during the next decades is expected. Moreover, the majority of demented elders live in less developed countries and this proportion will increase considerably in the future.

Less data is available regarding dementia incidence estimates (i.e., a measure of the risk to develop dementia within a specific period of time). Versporten et al. (2005) reported an overall incidence rate of dementia of 41 per 1,000 person years (Py) for men and 33 per 1,000 Py for women (i.e., 41 or 33 persons out of 1,000 that were observed for 1 year). This Epidemiology Research on Dementia in Antwerp (ERDA) study started in 1990 and consisted of 937 non-demented elderly aged 65 and older. Moreover, individuals with less than 7 years of education in this study population were – independently of gender – at higher risk of developing dementia compared with those receiving higher education (Versporten et al. 2005). Accordingly with the ERDA study, the ANCOG study resulted in a cumulative incidence rate of 36.60 per 1,000 Py with annual incidence rates ranging from 34.39 over 35.16 to 49.09 per 1,000 Py. In America, the average incidence rate varies between 3 per 1,000 Py in people aged 65 up to 69 years old and a maximum of 56 per 1,000 Py in 90-year-olds (Kukull et al. 2002). These figures are consistent with a previously executed large-scale European study (Launer et al. 1999).

1.3 Alzheimer’s Disease (AD) and Specific Dementia Syndromes

Dementia syndromes are commonly subdivided according to their reversible or irreversible characteristics (Katzman et al. 1988).

Primary dementia syndromes are irreversible neurodegenerative disorders such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), Huntington’s disease, and Creutzfeldt-Jakob disease.

On the contrary, secondary dementia syndromes are “potentially” reversible and originate from a specific acquired central nervous system disorder which led to “dementia-like deficits” (i.e., cognitive dysfunction, behavioral phenomenology). Some examples are brain tumors, cerebrovascular accidents (vascular dementia (VAD)), infections (meningitis, AIDS dementia complex), head traumas (subdural hematoma), alcohol abuse (Korsakoff syndrome), or normal pressure hydrocephalus.

Lastly, pseudodementias are “completely” reversible dementia subtypes that very much resemble primary dementia syndromes although the aspect of abundant neurodegeneration itself is absent. Examples are psychiatric disturbances (depression, schizophrenia), endocrine/metabolic disorders (hypothyroidism), malnutrition/vitamin deficiency (vitamin B12 or folic acid deficiency), or toxicological-/pharmacological-/substance-related conditions (certain sleep medication, anxiolytic, or sedatives) (Katzman et al. 1988).

For this chapter, we will be exclusively focusing on primary dementias such as AD, FTD, and DLB. Secondary dementia syndromes and pseudodementias will not be considered in the further discussion of this chapter.

1.3.1 Alzheimer’s Disease (AD)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is named after Dr. Alois Alzheimer, who first described this syndrome in 1907 in a 51-year-old patient who suffered from a progressive cognitive impairment associated with behavioral changes and brain atrophy. AD (code 294.1x) applies with the DSM-IV-TR criteria for the dementia syndrome described above (Table 11.1) (American Psychiatric Association 2000) and is manifested by multiple cognitive deficits such as memory impairment but also aphasia, apraxia, agnosia, and/or executive dysfunctioning. Additionally, AD is encoded based on the presence (294.11) or absence (294.10) of an associated clinically significant behavioral disturbance.

1.3.1.1 Diagnosis

The National Institute on Aging and the Alzheimer’s Association workgroups (McKhann et al. 2011) recently updated the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders (ADRDA) criteria of 1984 (McKhann et al. 1984) which subdivided AD into probable, possible, and definite AD. Probable AD is characterized by cognitive deficits in at least 2 cognitive domains with an insidious onset and a progressive worsening over time, a clear-cut history of cognitive worsening by report or observation and the most prominent cognitive deficits are evident on history or clinical examination in an amnestic (e.g., impairment in learning recall and at least 1 other cognitive domain) or nonamnestic (aphasia/apraxia/agnosia/executive dysfunctioning) manner (core criteria) (McKhann et al. 2011). Supportive criteria are among others: a family history of AD, associated BPSD, disturbed ADL, and a CT scan not displaying central nervous system pathology which may underlie the dementia syndrome (McKhann et al. 1984). A new subcategory of probable AD, compared to the 1984 criteria, is the probable AD with evidence of the AD pathophysiological process category. In this new diagnostic entity, biomarker evidence of cerebrospinal fluid (CSF) amyloid beta (Aβ), total and phosphorylated tau levels, positive PET amyloid imaging, or a decreased ¹⁸F-fluorodeoxyglucose (FDG) uptake on PET in the temporoparietal cortex may increase the certainty of an active AD pathophysiological process in persons who meet the core clinical criteria for probable AD (McKhann et al. 2011). Patients who met the 1984 NINCDS-ADRDA criteria for probable AD would also correspond with the more recent 2011 criteria described above.

Possible AD differs from probable AD as it is manifested by a somewhat atypical course and heterogeneity of symptoms with an either sudden onset of cognitive impairment or an etiologically mixed presentation, such as concomitant cerebrovascular disease. The core criteria of AD, however, remain present (McKhann et al. 2011).

Finally, definite AD (McKhann et al. 1984) or pathophysiologically proved AD dementia (McKhann et al. 2011) is applicable if the core criteria for probable AD were met and, in addition, a (postmortem) neuropathological examination demonstrated the presence of AD pathology.

1.3.1.2 Pathophysiological Mechanisms

AD and other dementia subtypes are all proteinopathies. The histopathological hallmarks of the AD brain are extracellular deposits of Aβ plaques and intracellular neurofibrillary tangles (NFT) which lead to a widespread synaptic loss and neurodegeneration with a consequent neurotransmission failure, especially of the cholinergic neurotransmitter system (Van Dam and De Deyn 2006). Familial AD is an autosomal dominant disorder with an onset before the age of 65 (Blennow et al. 2006). A mutation in the amyloid precursor protein (APP) gene on chromosome 21 or in the presenilin 1 (PSEN1) or presenilin 2 (PSEN2) genes accounts for most of the familial cases. However, the familial form is rare with a prevalence of approximately 1 % (Harvey et al. 2003). In most sporadic AD cases (>95 %) with an age of onset above 65, the etiology is not entirely known. So far, only risk genes have been identified such as the apolipoprotein E (APOE) ε4 allele which increases the risk of the disease by three times in heterozygotes and 15 times in homozygotes (Farrer et al. 1997).

The amyloid cascade hypothesis is the most dominant etiological AD hypothesis and states that Aβ accumulation results from an imbalance between Aβ production and clearance (Blennow et al. 2006). Physiologically, APP is a cell membrane expressed protein not only in neurons but also in many other tissues and is likely to be involved in maintenance and modulation of neuronal networks (Loo et al. 1993). Posttranslational cleavage of APP by consecutive α- and ɣ-secretases releases a p3 fragment (non-amyloidogenic pathway), whereas the combined effect of β- and ɣ-secretases releases non-soluble Aβ peptides of various lengths, i.e., Aβ_1-40 or Aβ_1-42 (amyloidogenic pathway). In normal situations, the non-amyloidogenic pathway is mostly active. In familial AD, however, a mutation in PSEN1/PSEN2 (which form the catalytic subunits of the secretases) or around the cleavage site of APP causes an overproduction of the hydrophobic Aβ_1-42 and consequently leads to a shifted Aβ_1-40/Aβ_1-42 balance. As a result, enormous amounts of Aβ_1-42 fragments aggregate and form extracellular “senile plaques” (Hardy and Selkoe 2002) (Fig. 11.2). Whereas in familial AD, there is an overproduction of Aβ_1-42 due to certain mutations, sporadic AD cases seem to fail sufficient Aβ clearance which leads to gradually increasing and accumulating Aβ levels in the brain. As mentioned above, genetic risk factors such as APOE ε4 but also aging and certain environmental risk factors were proven to be strongly associated with sporadic AD (Blennow et al. 2006).

Fig. 11.2

The amyloid cascade hypothesis in AD. Amyloid precursor protein (APP) is a large transmembrane protein which is consecutively cleaved by α- and ɣ-secretases (non-amyloidogenic pathway) so that soluble p3 fragments are formed. In familial Alzheimer’s disease (AD), however, dysfunctional cleavage of APP by β- and ɣ-secretases (amyloidogenic pathway) releases larger amyloid beta (Aβ) 1–40 and 1–42 fragments which leads to an overproduction of specifically Aβ1-42. Aβ_1-42 are hydrophobic, insoluble filaments that will aggregate and form amyloid “senile” plaques, the hallmark of AD pathology. In sporadic AD, Aβ aggregates are formed as well but this time due to a failed Aβ clearance. It has been suggested that an imbalance between Aβ production and clearance lies at the basis of AD pathogenesis as such. AICD APP intracellular domain, CTF C-terminal fragment, KPI Kunitz-type protease inhibitor, sAPP soluble APP (Reprinted from Blennow et al. (2006), with permission. Copyright@2006 Elsevier)

The second hallmark of AD pathology is the presence of intracellular NFT, which results from the hyperphosphorylation and aggregation of the axonal tau proteins, a group of microtubule-associated proteins that contribute to the assembly and stabilization of microtubules in neurons among others (Grundke-Iqbal et al. 1986). Tau phosphorylation is regulated by the balance between multiple kinases (e.g., GSK-3β and CDK5) and phosphatases (e.g., PP-1 and PP-2A) (Iqbal et al. 2005). An imbalance between the protein kinases and phosphatases causes tau to be hyperphosphorylated into insoluble fibrils, also called “paired helical filaments.” Tau hyperphosphorylation starts intracellularly and leads to sequestration of normal tau and other microtubule-associated proteins, which causes disassembly of microtubules and thus impaired axonal transport, compromising neuronal and synaptic function (Iqbal et al. 2005). Tau pathology starts early in the disease process in neurons of the transentorhinal region, from where it further spreads to the hippocampus and amygdala and finally to other cortical and neocortical association areas (Braak et al. 1999; Smith 2002) (Fig. 11.3).

Fig. 11.3

Progressive expansion of neurofibrillary tangles (NFT) in an AD brain, showing the medial aspect of the cerebral cortex. The depth of the red color is in proportion to the density of tangles (Reprinted from Smith (2002), with permission. Copyright@2002 National Academy of Sciences, USA)

Besides Aβ deposits and NFT, oxidative stress and inflammation are two key factors in the etiological hypotheses of AD as well.

Oxidative damage to different classes of biological molecules such as sugars, lipids, proteins, and DNA is a common aspect of both normal aging and most neurodegenerative disorders (Moreira et al. 2005). In early AD, oxidative stress might have an important pathogenic role as neurons themselves use different antioxidant defense systems in case of increased oxidative stress. Evidence demonstrates that Aβ depositions and hyperphosphorylation of tau form two primary defense lines against oxidative stress. With disease progression, both Aβ and tau transform into prooxidants due to a profound redox imbalance (Smith et al. 2002).

With regard to inflammation, it has been proven that many neuroinflammatory mediators are upregulated in affected areas of the AD brain, including prostaglandins, complement components, anaphylatoxins, cytokines, chemokines, proteases, protease inhibitors, adhesion molecules, and free radicals (Akiyama et al. 2000). Côté et al. (2012) recently established a direct association between the prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs), which target cyclooxygenase (COX), and a decreased risk of subsequently developing AD even though several other clinical studies using NSAIDs in AD patients yielded a negative outcome (ADAPT Research Group et al. 2008; Breitner et al. 2011). Initially, the effect of NSAIDs in AD was thought to be attributed to a reduction of inflammation (Van Dam and De Deyn 2006). In 2001, however, it was reported that a subset of NSAIDs reduced Aβ_1-42 production in cultured cells and mouse brain through a mode of action different from COX inhibition (Weggen 2001). On the other hand, the initial assumption of possible underlying anti-inflammatory mechanisms of NSAIDs in AD should not be completely abandoned (Van Dam and De Deyn 2006).

Interestingly, the induced neuroinflammation in AD might also lie at the basis of some BPSD, such as depression. For example, the enzyme indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan, the precursor of serotonin (5HT), into kynurenine. Due to neuroinflammation, the IDO activity becomes upregulated and eventually the kynurenine catabolization further leads to an overproduction of quinolinic acid, the neurotoxic end product of the tryptophan pathway which also contributes to the excitotoxic effects in an AD brain. The altered tryptophan levels consequently affect 5HT synthesis, which is a neurochemical hallmark in the etiology of depression. Neuroinflammation by upregulating IDO and consequently lowering tryptophan levels has therefore been linked with major depressive disorder in AD patients (Dobos et al. 2010).

1.3.2 Other Dementia Subtypes

Except for AD which is the most prevalent dementia syndrome (65 % approximately), AD with cerebrovascular disease (AD + CVD), vascular dementia (VAD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and frontotemporal dementia (FTD) together roughly account for the other 35 % (Fig. 11.4) (Small et al. 1997).

Fig. 11.4

Different etiological diagnoses of dementia. Alzheimer’s disease is the most prevalent dementia subtype (64 %), followed by Alzheimer’s disease + cerebrovascular disease (AD + CVD) (11 %), dementia with Lewy bodies (DLB)/Parkinson’s disease dementia (PDD) (7 %), vascular dementia (VAD) (5 %), dementia with Lewy bodies and Alzheimer’s disease (DLB + AD) (5 %), and finally other types of dementia (8 %), such as frontotemporal dementia (FTD) (Based upon Small et al. (1997))

Below, DLB and FTD are briefly described as they significantly differ from AD concerning their diagnostic criteria, pathogenesis, disease course, and behavioral profiles.

1.3.2.1 Dementia with Lewy Bodies (DLB)

Dementia with Lewy bodies (DLB) is the third most prevalent dementia subtype and is diagnosed according to McKeith et al. (2005). Comparable with AD, several core and supportive criteria need to be present in order to establish a clinically acceptable DLB diagnosis. The three core criteria are a fluctuating cognition, recurrent and well-described visual hallucinations, and clinical sings of parkinsonism (extrapyramidal symptoms (EPS): tremor, rigidity, and hypokinesia). The presence of only two core criteria is sufficient to diagnose “probable” DLB. Some other supportive criteria are a disturbed REM sleep behavior, a low dopamine transporter reuptake in the basal ganglia proven on SPECT or PET imaging, autonomic dysfunction, depression, and concurrent delusional ideation. Furthermore, DLB patients suffer from neuroleptic sensitivity which severely worsens EPS when classical neuroleptics (antipsychotic medication) are administered (McKeith et al. 2005). The difference between DLB and PDD is solely based upon the temporal sequence of appearance of the extrapyramidal symptoms: DLB should be diagnosed when dementia occurs before (at least 1 year in research studies) or concurrently with parkinsonism (if it is present). The term PDD should be used to describe dementia that occurs in the context of well-established Parkinson’s disease (PD) (Geser et al. 2005; McKeith et al. 2005).

The main pathological characteristic of DLB is the presence of cytoplasmatic aggregated inclusions of α-synucleins, generally known as “Lewy bodies” (Vladimir 2007). Synucleinopathies form a group of neurodegenerative disorders that share common pathologic proteinaceous lesions containing aggregated α-synuclein molecules which are deposited in vulnerable positions of neurons and glia (Goedert 1999;2001). Specifically in DLB, Lewy body aggregates precipitate in the substantia nigra (pars compacta) of the basal ganglia and also in the neocortex and hippocampus (McKeith et al. 2005). Only when a loss of dopaminergic neurons of 80 % or more in the substantia nigra is reached, EPS will set off. Several case studies demonstrated the occurrence of familial DLB cases (Gwinn-Hardy and Singleton 2002) and that Lewy bodies are commonly seen in familial cases of AD as well (Trembath et al. 2003). There are reports of triplications of the α-synuclein (SNCA) gene in DLB, PD, and PDD patients, whereas SNCA gene duplications only seem to be associated with motor PD, suggesting a possible gene dose effect (Singleton and Gwinn-Hardy 2004). However, SNCA gene multiplications were not found in most sporadic DLB cases (Johnson et al. 2004).

1.3.2.2 Frontotemporal Dementia (FTD)

A less frequent neurodegenerative disorder is frontotemporal dementia (FTD). Neary et al. (1998) established the diagnostic criteria of among others FTD, which forms one of the three diagnostic entities of “frontotemporal lobar degeneration (FTLD)” together with primary progressive aphasia and semantic dementia (SD). Typical for FTD patients is the very early disease onset compared to AD or DLB, namely, between the age of 45 and 70. At onset of the syndrome, there may typically be a neglect of personal hygiene, disinhibition, loss of insight and judgement, social neglect, and emotional disturbance (i.e., emotional bluntness, impaired control of emotions) in contrast to a comparatively spared memory and spatial abilities (core criteria). A subsequent cognitive impairment is inevitable although in the beginning amnesia remains surprisingly absent. FTD thus initially manifests itself by subtle changes in behavior and character (De Deyn et al. 2005; Neary et al. 1998). Some other typical behavioral characteristics are the expression of stereotypes and changes in sexual behavior, dietary hyperactivity, speech disturbances (echolalia, mutism, logorrhea), and restlessness. From a clinical point of view, FTD is also likely to be recognized and distinguished from AD solely due to this distinctive behavioral pattern (De Deyn et al. 2005).

Similarly as with AD, FTD can be subdivided into familial (±30 %) and sporadic (±70 %) variants. For familial FTD, a distinction must be made between tauopathies and non-tauopathies. Tauopathies are caused by a mutation in the microtubule-associated protein tau (MAPT) gene (Bancher et al. 1987; Sieben et al. 2012), whereas non-tauopathies can be etiologically defined by mutations in the progranulin (PGRN) (Cruts et al. 2006) and TAR DNA-binding protein 43 (TDP-43) gene (Arai et al. 2006; Neumann et al. 2006). Mutations in the MAPT gene cause cytoplasmatic tau to aggregate which leads to the formation of tangles and eventually to neuronal death, especially in frontotemporal cortical areas. Neuropathologically, this degenerative phenomenon is known as “Pick’s disease,” but supranuclear palsy and corticobasal degeneration are also classified as tauopathies (Keith 2008). On the other hand, mutations in both TDP-43 and PGRN genes (non-tauopathies) cause TDP-43 and PGRN aggregates, again leading to a consequent neuronal degradation (Sieben et al. 2012). Histopathologically, these aggregates are visible as tau-negative but ubiquitin (U)-positive inclusions so that non-tauopathies are generally categorized as FTLD-U. Noteworthy, the frontotemporal localization of tau and ubiquitin lesions in FTLD patients is pathophysiologically crucial to cause the frontal behavioral phenotype clarified above.

Recently, Gijselinck et al. (2012) identified a pathogenic GGGGCC repeat expansion in the C9orf72 promoter region on chromosome 9p21 in FTLD and amyotrophic lateral sclerosis (ALS) patients of a Flanders-Belgian cohort. FTLD and ALS are both clinically, pathologically, and genetically overlapping degenerative diseases. This genetic linkage and association study was performed in 337 FTLD, 23 FTLD-ALS, 141 ALS, and 859 control subjects. The GGGGCC repeat expansion showed to be highly penetrant, explaining all of the contribution of chromosome 9p21 to FTLD and ALS in this cohort. As for now, the function of the C9orf72 gene remains unknown, although it is highly conserved in all vertebrates. Further research of its function might eventually lead to a better insight into the common pathophysiological mechanisms of FTLD and ALS.

2 Behavioral and Psychological Signs and Symptoms of Dementia (BPSD)

Besides cognitive disturbances, dementia is characterized by numerous behavioral disturbances as well, categorized as Behavioral and Psychological Signs and Symptoms of Dementia (BPSD) (Finkel et al. 1996; Reisberg et al. 1987). BPSD are a heterogeneous group of behavioral, psychological, and psychiatric disturbances occurring in 50–80 % of dementia patients of any etiology (Finkel et al. 1996). These behavioral and psychological symptoms are generally classified into seven main subtypes: paranoid and delusional ideation, hallucinations, activity disturbances, aggressiveness, diurnal rhythm disturbances, affective disturbances, and anxieties/phobias (Reisberg et al. 1987). BPSD often lead to a greater amount of caregiver distress, diminished quality of life for both patient and caregiver, greater cognitive impairment (Weamer et al. 2009), premature institutionalization, frequent (re)hospitalizations, and increased secondary morbidity and mortality (Finkel 2000). Last but not least, BPSD also have a significant and increasing socioeconomic impact (Beeri et al. 2002) (Fig. 11.1).

From an etiological point of view, research has repeatedly suggested that there is a neurochemical basis underlying BPSD although its pathophysiological mechanisms are still not well understood (Engelborghs et al. 2008). Alterations in central noradrenergic (Engelborghs et al. 2008; Herrmann et al. 2004; Lanari et al. 2006; Matthews et al. 2002), serotonergic (Engelborghs et al. 2008; Garcia-Alloza et al. 2005; Lanctôt et al. 2001), and dopaminergic (Engelborghs et al. 2008; Lanari et al. 2006) neurotransmitter systems and associated receptors proved to play a critical role in BPSD manifestation, irrespective of the dementia subtype (Vermeiren et al. 2012). Particularly the balance between those different neurotransmitter systems seems to be of importance as it is conceivable, due to the neurochemical complexity and diversity of BPSD, that more than one neurotransmitter system contributes to a particular behavioral syndrome (Lanari et al. 2006). Studying neurotransmitter systems in isolation cannot fully explain changes in behavior, given that many neurotransmitter systems work in conjunction with each other. In spite of this difficulty, the neurochemical mechanisms underlying BPSD are proven to be both BPSD- and dementia-specific (Engelborghs et al. 2008; Vermeiren et al. 2012), so that dementia-specific neurochemical alterations might be found. There is also supportive evidence for amino acids playing a functional role in the neurochemical pathophysiology of BPSD (Engelborghs et al. 2003; Fekkes et al. 1998; Francis 2009; Garcia-Alloza et al. 2006), with, e.g., significantly high correlations between CSF taurine levels and depression in AD and CSF glutamate levels and agitation in FTD (Vermeiren et al. 2012).

Engelborghs et al. (2005) showed that different behavioral patterns can be observed depending on the dementia subtype, thereby further stressing that behavioral assessment itself may help in differentiating between different forms of dementia (Fig. 11.5).

Fig. 11.5

Frequency of dementia-specific BPSD items. This figure shows that, e.g., apathy is much more frequent in FTD as compared to AD/MXD/DLB whereas delusions, hallucinations, and anxieties are less frequently present in FTD compared to DLB. Abbreviations: AD Alzheimer’s disease, BPSD Behavioral and Psychological Signs and Symptoms of Dementia, DLB dementia with Lewy bodies, FTD frontotemporal dementia, MXD mixed dementia (Based upon Engelborghs et al. (2005))

In 1996, Jost and Grossberg examined the frequency of BPSD in temporal relationship with the diagnostic progression of AD patients, as is demonstrated in Fig. 11.6. In contrast to the cognitive symptoms in AD which progressively worsen during its course, BPSD are different as some behavioral symptoms are severely present during the early disease stages (e.g., depression) although later on these symptoms might gradually diminish or even completely disappear, to be eventually replaced by other BPSD items (e.g., aggression).

Fig. 11.6

Frequency of BPSD in temporal relationship with the progression of AD diagnosis. The evolution of Behavioral and Psychological Signs and Symptoms of Dementia (BPSD) in 100 autopsy-confirmed Alzheimer’s disease (AD) patients before and after their initially established diagnosis is shown above. Especially depression and diurnal rhythm disturbances seem to be significantly present roughly 25 and 9 months before AD diagnosis whereas aggression, agitation, and hallucinations are symptoms that are characteristically manifested approximately 2–3 years later (Based upon Jost and Grossberg (1996))

2.1 Delusional Ideation and Hallucinations: The Psychotic Syndrome

Approximately more than 40 % of dementia patients of any etiology and up to 73 % of AD patients suffer from delusional ideation during the disease course (Finkel 2001). The most prominent delusion according to Reisberg et al. (1987) is suspiciousness/paranoia, i.e., the conviction that people are stealing things from the patient. Other frequently occurring delusions are the “one’s house is not one’s home delusion” or the accusation of infidelity towards their spouse or caregiver. Delusions are frequently associated with verbal and physical aggression which in most cases leads to an untenable situation at home and premature institutionalization (Deutsch et al. 1991). Deutsch et al. (1991) suggest delusions to be risk factors in patients with probable AD who have moderate to severe cognitive impairment.

In patients with AD, psychosis occurs more frequently in women than in men. Some other predisposing factors besides gender for psychotic symptoms are age, severity of illness, and cognitive deterioration (Hirono et al. 1998). Weamer et al. (2009) found that the severity of cognitive impairment was a strong predictor of psychosis in AD patients up to 2 years prior to psychosis onset.

Hallucinations in dementia patients are less frequent than delusions, with a prevalence rate of 12 up to 49 % (Swearer 1994). Hallucinations as well as delusions are characteristic for specifically DLB patients, as is shown in Fig. 11.5 (Engelborghs et al. 2005). A hallucination is the patient’s strict conviction of a sensory perception in the absence of sensorial stimulation. Reisberg et al. (1987) made a distinction between visual, auditory, olfactory (smell), and haptic (touch) hallucinations. It is noticeable that hallucinations are more likely to occur in patients with more severe cognitive deterioration compared to patients with mild forms of dementia (Devenand et al. 1997). Moreover, hallucinations are less stressful for dementia patients than delusions so that pharmacological treatment is less mandatory (De Deyn 2004).

AD patients with psychosis have been reported to deteriorate twice as fast as patients without psychotic symptoms (Rosen and Zubenko 1991). Similarly, Scarmeas et al. (2005) studied whether the presence of delusions and hallucinations has predictive value for important outcomes in AD patients, such as cognitive and functional decline. Their results confirmed that the presence of delusions and hallucinations was associated with an increased risk for cognitive and functional decline, institutionalization, and even death.

It is noteworthy that psychosis of AD is a distinct syndrome that is markedly different from, e.g., schizophrenia in elderly patients. Numerous research groups have reported potentially relevant clinical, neuropsychological, neurochemical, neurobiological, and neuropathological differences between AD patients with and without psychosis (Jeste and Finkel 2000). In the past, there have been no specific criteria for diagnosing psychosis of AD as a distinct entity. Therefore, Jeste and Finkel have proposed several core criteria in 2000 in order to correctly diagnose the psychotic syndrome in AD. Characteristic symptoms are the presence of one (or more) visual/auditory hallucination(s) and/or delusion(s). Secondly, there has to be evidence from the patient’s history that these symptoms have not been continuously present prior to dementia onset. The symptoms also must have been present for at least 1 month or longer and have to cause some disruption in the patient’s functioning. Moreover, schizophrenia and related psychotic disorders as well as a delirium or other causes (e.g., substance-related) that might have initiated the psychosis need to be excluded. Finally, associated behavioral features such as agitation, negative symptoms, and/or depression might be present as well.

All criteria may also apply to a similar psychotic syndrome associated with other dementias such as DLB, VAD, and MXD.

2.2 Agitation and Aggression

Agitation includes inappropriate verbal, vocal, or motor behaviors that, in the opinion of an observer, do not result directly from the needs or confusion of the agitated individual (Cohen-Mansfield and Deutsch 1996). Approximately 80 % of dementia patients will suffer from agitation during the disease course. Agitation therefore is one of the most frequently (re)occurring BPSD (Allen and Burns 1995). In 2000, Lyketsos et al. reported the prevalence of agitation and other BPSD in 329 participants with dementia (the Cache County Study on Memory in Aging, Utah), of which 65 % had AD, and concluded that agitation and aggression were present in approximately 24 % of dementia patients. Given that the estimates were only considered over 1 month before behavioral assessments and due to the episodic course of this behavioral symptom, Lyketsos et al. (2000) mentioned that these prevalence numbers were an underestimation of the cumulative prevalence which may approach 70–80 %. Subsequently, the Cache County Study was resumed in 2003 (Steinberg et al. 2008) in which an incident sample of 408 dementia participants was behaviorally assessed during a 5-year follow-up period. At the end, 42 % of dementia participants developed agitation.

In general, agitation mostly occurs in the moderate stages of dementia and less in mild or severe dementia stages (Cohen-Mansfield et al. 1989; Lyketsos et al. 2000). Cohen-Mansfield et al. (1989) make a distinction between physically non-agitated behavior (e.g., restlessness, pacing, cognitive abulia, wandering, inappropriate (dis)robing) and verbally agitated behavior (e.g., negativism, complaining, repetitive sentences or questions, strange noises, unwarranted request for attention).

Aggression has a frequency between 20 and 30 % (Allen and Burns 1995) and can be divided into physically aggressive behavior (e.g., hitting, kicking, pushing, scratching, biting) and verbally aggressive behavior (e.g., screaming, cursing) (De Deyn 2004). In general, physically aggressive behavior is more common in male dementia patients compared to females (Cohen-Mansfield and Deutsch 1996). Furthermore, aggression in dementia patients is associated with depression according to Lyketsos et al. (1999).

2.3 Diurnal Rhythm Disturbances

Sleep disturbances can be subdivided into difficulties falling asleep, multiple awakenings during sleep, early morning awakenings, or a completely inversed sleep-wake pattern (Prinz et al. 1982). Insomnia in dementia also seems to be the most prominent reason for an eventual institutionalization according to Harper et al. (2001). One specific diurnal rhythm disturbance is sundowning, a situation in which patients are relatively calm during the day but as evening falls show an exacerbation of behavioral symptoms, such as pacing, wandering, and repetitive, purposeless activities (cognitive abulia) (Little et al. 1995).

2.4 Depression

In AD, depression has a prevalence of 20 (Castilla-Puentes and Habeych 2010) up to 50 % (Starkstein et al. 2005). As shown in Fig. 11.6, depression is mostly present in mild to moderate AD or even 2 years before the established AD diagnosis (Alexopoulos et al. 1988; Jost and Grossberg 1996). A major depressive episode in dementia is characterized by mood-related signs (anxiety, lack of reactivity to pleasant events, irritability), behavioral symptoms (agitation, retardation (slow movements and speech), loss of interest, physical complaints), physical signs (appetite and weight loss, lack of energy), sleep rhythm disturbances, and ideational disturbances (pessimism, suicidal wishes, poor self-esteem) (Alexopoulos et al. 1988). Besides the behavioral aspects, depression is also characterized by deficits in verbal and visual memory, concentration, and executive functioning (Sierksma et al. 2010). Several research groups have even suggested that depression in general might be a prodrome (i.e., a premonitory symptom indicating the onset of a disease; risk factor) of developing AD (Caraci et al. 2010; Korczyn and Halperin 2009), given the fact that the pathophysiological properties of depression and some etiological hallmarks of AD are related (e.g., increased neuroinflammation, monoaminergic deficiency, increased synaptic neurodegeneration, and altered neurotrophic factors) (Sierksma et al. 2010). Depressed dementia patients also have a higher mortality rate compared to their nondepressed counterparts (Rovner et al. 1991).

2.5 Activity Disturbances

According to Reisberg et al. (1987), activity disturbances form a separate entity in the behavioral phenomenology of AD patients among others. Approximately 80 % of AD patients suffer from activity disturbances (Engelborghs et al. 2005), which can be best described as a form of physical agitation. Some examples are wandering, purposeless activities (e.g., cognitive abulia, such as repetitive (dis)robing, pacing), and inappropriate activities (inappropriate physical sexual advances, hiding objects, hoarding) (Reisberg et al. 1987). In some cases, activity disturbances are severe enough to require restraint or even result in abrasions (e.g., pacing) or physical harm. Besides AD, FTD patients characteristically suffer from certain types of activity disturbances as well, mainly stereotype movements (e.g., tapping, hand clapping, patting, hand rubbing, wandering a fixed route) and general restlessness (aimless wandering, pacing, fidgeting, inability to sit still) (De Deyn et al. 2005).

2.6 Anxieties and Phobias

Although less frequent, anxiety is a psychological symptom in dementia patients which is present in different variants (De Deyn 2004). The anxiety or fear of being left alone as well as the Godot syndrome are two frequent types of anxiety in AD patients (Reisberg et al. 1987). In case of Godot syndrome, patients repeatedly and constantly ask questions concerning a completely normal but approaching event such as a meeting with the family doctor (Reisberg et al. 1986). This term was firstly described in the late 80s by Reisberg et al. (1986) and is an extreme form of anxiety in dementia patients and sometimes requires the patient to be accompanied at all times. On the other hand, pacing, stereotype behavior, and restlessness might be physical reflections of a rooted anxiety residing within the patient. A phobia is an anxiety disorder which is disproportional to the actual danger, often being irrational. Examples are fear of traveling, bathing, darkness, and overcrowded places (De Deyn 2004).

2.7 Apathy

In the context of dementia, apathy has been recently defined as a disorder of diminished motivation that persists over time for at least 4 weeks with an additional reduced goal-directed behavior, cognitive activity, and emotions (Robert et al. 2009). These relatively new criteria have been established due to the overlap between apathy and depression among others. Apathy is a common behavioral disorder not only in AD but also in PD, FTD, and stroke (Levy et al. 1998). Results from the European Alzheimer’s Disease Consortium study in 2007 showed that apathy is the most prominent and persistent neuropsychiatric syndrome in dementia as it occurred in 65 % of the total 2,354 AD patients (Aalten et al. 2007). Additionally, it is also present during all stages of the disease (Lyketsos et al. 2011; Robert et al. 2009), and there is a growing body of evidence that it might be indicative of a pre-dementia state (Ready et al. 2003; Robert et al. 2009).

3 Behavioral Assessment Scales

In order to evaluate this large group of behavioral and neuropsychiatric symptoms in dementia patients, different behavioral assessment scales have been developed throughout the years. The most common are described below, i.e., Middelheim Frontality Score (MFS), Behavioral Pathology in Alzheimer’s Disease Rating Scale (Behave-AD), Cohen-Mansfield Agitation Inventory (CMAI), Geriatric Depression Scale (GDS), Cornell Scale for Depression in Dementia (CSDD), and Neuropsychiatric Inventory (NPI). All these scales are very useful assessment tools to identify the behavioral profile of dementia patients or even to distinguish between different types of dementia (De Deyn et al. 2005). The efficacy of novel psychotropic medication in the treatment of BPSD can also be demonstrated by the use of these well-validated and drug-sensitive behavioral scales mentioned above, such as Behave-AD, CMAI, and NPI (De Deyn and Wirshing 2001). Moreover, these behavioral assessment scales are widely used to study the neuroanatomical and pathophysiological etiology of different behavioral phenotypes in dementia in combination with neuroimaging data.

3.1 Middelheim Frontality Score (MFS)

The Middelheim Frontality Score (MFS) is a clinical and behavioral assessment tool which measures frontal lobe features and secondly, in contrast to classical behavioral scales, reliably discriminates FTD from AD patients (De Deyn et al. 2005). The MFS is rated by a clinician and is obtained by summating the scores in a standardized fashion on ten different items. Each item is scored either zero (absent) or one (present), yielding a total maximal score of 10. Information is obtained through an interview of the patient and her/his professional and/or main caregiver, clinical files, and behavioral observation. The ten items are (item 1) initially comparatively spared memory and spatial abilities that reflect the neurobehavioral onset of the disease; frequently occurring personality and behavioral changes like (item 2) loss of insight and judgement; (item 3) disinhibition; (item 4) dietary hyperactivity (referring to overeating); (item 5) changes in sexual behavior (hypersexuality as well as the more frequently occurring hyposexuality); (item 6) stereotyped behavior (encompasses all kinds of stereotyped behavior, both simple repetitive behaviors (can also be oral) and complex behavioral routines such as wandering); (item 7) impaired control of emotions, euphoria, or emotional bluntness; (item 8) aspontaneity; (item 9) speech disturbances such as stereotyped phrases, logorrhoea, echolalia, and mutism; and finally, (item 10) restlessness. Although the NPI is able to correctly classify 77 % of AD and FTD patients (Levy et al. 1996), the frequently used Behave-AD and CMAI lack sensitivity for FTD as they have been specifically developed for AD patients. The Behave-AD even underestimates BPSD in FTD patients as was shown by Engelborghs et al. (2004): 28 FTD patients had significantly lower Behave-AD total scores compared to 152 AD patients, whereas the Behave-AD global scores (reflecting caregiver burden) were not different between both patient groups. Moreover, Pickut et al. (1997) previously showed that the total MFS scores correlated with severity of bifrontal hyperperfusion on SPECT in FTD.

The discriminatory cutoff score of the MFS is set at a total score of 5 as, respectively, 85.9 and 76.6 % of clinically diagnosed FTD and AD patients were correctly classified (De Deyn et al. 2005).

3.2 Behavioral Pathology in Alzheimer’s Disease Rating Scale (Behave-AD)

In 1987, the Behavioral Pathology in Alzheimer’s Disease Rating Scale (Behave-AD) was developed to correctly assess and categorize frequently occurring behavioral symptoms of AD patients (Reisberg et al. 1987). The first part of the Behave-AD comprises 25 items of which each item can be rated from zero (absent) to three (severely present, with emotional and physical component, possibly requiring restricting) with a total maximum score of 75. The second part is the Behave-AD global score which assesses caregiver burden: 0 (not at all troubling to the caregiver or dangerous to the patient), 1 (mildly troubling to the caregiver or dangerous to the patient), 2 (moderately troubling to the caregiver or dangerous to the patient), and 3 (severely troubling to the caregiver or dangerous to the patient). The first 25 items are categorized into 7 behavioral clusters: cluster A (paranoid and delusional ideation, items 1–7), cluster B (hallucinations, items 8–12), cluster C (activity disturbances, items 13–15), cluster D (agitation and aggression, items 16–18), cluster E (diurnal rhythm disturbances, item 19), cluster F (affective disturbances, items 20–21), and cluster G (anxieties and phobias, items 22–25).

The Behave-AD is a very detailed and relatively simple scale which allows an assessment within a short amount of time (De Deyn 2004). Several studies (Sclan et al. 1996; Patterson et al. 1990) showed that the reliability of the Behave-AD is comparable with those of several widely used cognitive assessment scales, such as the Mini-Mental State Examination (MMSE) (Folstein et al. 1975). However, one disadvantage of the Behave-AD is its specificity for and usage in exclusively AD patients. Furthermore, only the intensity of the 25 BPSD items is rated (scores 0–3) and not the frequency (De Deyn 2004).

3.3 Cohen-Mansfield Agitation Inventory (CMAI)

The Cohen-Mansfield Agitation Inventory (CMAI) was originally designed for the staff of nursing homes to rate the frequency of agitation and related behaviors in the elderly with cognitive deterioration. This scale assesses 29 types of agitated behavior which are subdivided into 3 main categories: items 1–10 comprise “aggressive behavior,” items 11–21 consist of “physically nonaggressive behavior,” and finally items 22–29 are clustered into the category “verbally agitated behavior.” Each item is scored depending on its frequency, i.e., from 1 (never) to 7 (several times an hour) (Cohen-Mansfield et al. 1989).

3.4 Geriatric Depression Scale (GDS)

The Geriatric Depression Scale (GDS) is the oldest scale so far and was designed to estimate depression in non-demented elderly (Yesavage et al. 1983). It takes little or no experience for the investigator to use this scale which consists of 30 questions that are related to depression in the elderly. Each question should be answered with a simple “yes” or “no.” A score of 12 or more is indicative of a “light” depression whereas 18 or more point to moderate depression. Debruyne et al. (2009), using the CSDD as the golden standard, concluded that the GDS-30, is not a reliable screening tool when assessing depressive symptoms in dementia patients but only in patients with mild cognitive impairment (MCI) and non-demented elderly.

3.5 Cornell Scale for Depression in Dementia (CSDD)

The Cornell Scale for Depression in Dementia (CSDD) dates from 1988 and is a very useful assessment tool to diagnose depression in dementia (Alexopoulos et al. 1988). The scale is a 19-item clinician-administered instrument that uses information from interviews with both the patient and nursing staff members, a method suitable for dementia patients. Each item is scored based on a three-point scale, i.e., 0 (absent), 1 (mild or intermittent), and 2 (severely present). If it is impossible to rate one of the items, a score remains absent (A: unable to evaluate). All 19 items are subdivided into 5 main categories:

• A. Mood-related signs (anxiety, sadness, lack of reactivity to pleasant events, irritability)

• B. Behavioral disturbances (agitation, retardation (slow movements and speech), multiple physical complaints, loss of interest)

• C. Physical signs (appetite loss, weight loss, lack of energy)

• D. Cyclic functions (diurnal variation of mood, diurnal rhythm disturbances)

• E. Ideational disturbances (suicidal ideation, poor self-esteem, pessimism, mood-congruent delusions).

A score of 8 or more is suggestive for the presence of depression (Burns et al. 2004).

3.6 Neuropsychiatric Inventory (NPI)

The Neuropsychiatric Inventory (NPI) evaluates 12 types of behavioral disturbances that are dementia-specific, i.e., delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, euphoria, apathy/indifference, disinhibition, irritability/lability, repetitive purposeless behavior, insomnia/diurnal rhythm disturbances, and appetite or a change in dietary activity (Cummings et al. 1994). The severity and the frequency of these symptoms are rated by a series of questions which are intended for the main caregiver of the patient. The severity score is based on a three-point scale ranging from 1 (mild) to 3 (severe), and the frequency score can vary between 1 (occasionally, less than once a week) and 4 (very frequent, multiple times a day). The scores of each of these 12 behavioral symptoms need to be summed up to obtain a total NPI score. Besides the severity and frequency scores, the level of caregiver distress (emotional burden) of each of the 12 behavioral symptoms requires rating as well. In this case, a scale ranging from 0 (no distress) to 5 (severe and extreme distress) is provided (Kaufer et al. 1998). The total score of “caregiver distress” is yielded by summing up the 12 individual distress subscores.

Because the NPI consists of a gross variety of behavioral symptoms, it is a useful instrument to discriminate between different types of dementia as well as to evaluate the behavioral outcome due to pharmacological interventions (De Deyn 2004; De Deyn and Wirshing 2001). In 2001, a shortened version of the NPI, namely, NPI-Q (questionnaire), was developed by Kaufer et al. (2000) which facilitates its daily use in a clinical setting. Several other forms of the NPI have also been proposed depending on the informant, such as clinicians (NPI-C) (de Medeiros et al. 2010), or the institutional setting, such as nursing homes (NPI-NH) (Wood et al. 2000).

4 PET in the Differential Diagnosis of Dementia

Neuroimaging has played an important role in the study and differential diagnosis of dementia over the last 40 years. More recently, positron emission tomography (PET) studies of cerebral metabolism with ¹⁸F-fluorodeoxyglucose (FDG) and amyloid tracers such as the Pittsburgh Compound-B (PiB) have provided invaluable information regarding specific AD-like brain changes (Johnson et al. 2012). Even in prodromal and presymptomatic states, PET imaging has emerged as a robust biomarker of neurodegeneration in individuals who were later found to progress to AD (de Leon et al. 2001; Bateman et al. 2012). Bateman et al. (2012), for example, detected early Aβ-deposition in the precuneus of 128 autosomal dominant AD patients measured by PET-PiB nearly 15 years before expected symptom onset, indicating PET imaging to be an essential and reliable imaging tool not only in the differential diagnosis between AD and non-AD but even in asymptomatic states.

Some of the most important PET radioligands and compounds which are widely used in the differential diagnosis of dementia are described below.

4.1 Radioligands and Compounds

Brain FDG-PET primarily indicates synaptic activity. Because the brain relies almost exclusively on glucose as its main energy resource, the glucose analog FDG is suitable as an indicator of brain metabolism and, when labeled with fluorine-18 (¹⁸F) (half-life 110 min), is detected with PET. Especially, the glutamatergic synaptic signaling is responsible for the maintenance of intrinsic, resting (task-independent) activity of the cerebral cortex which, most of the time, is the brains main task (Johnson et al. 2012; Sibson et al. 1997). Therefore, [¹⁸F]-FDG-PET is widely accepted to be a valid biomarker of the overall brain metabolism to which ionic gradient maintenance for synaptic activity is the most principal contributor (Schwartz et al. 1979; Magistretti 2006). The characteristic pattern found in AD generally is a hypometabolism of the temporoparietal cortex (Herholz et al. 2002; Ferreira and Busatto 2011) and specific limbic and association areas, such as the precuneus, posterior cingulate gyri, inferior parietal lobes, and posterolateral portions of the temporal lobe as well as the hippocampus and medial temporal cortices (Foster et al. 1983; Minoshima et al. 1997; Reiman et al. 2005). An asymmetry between both hemispheres is commonly seen in the early stages of AD whereas in a more advanced stage of the disease, usually the prefrontal association areas become affected (Johnson et al. 2012).

Recently, a meta-analysis showed that hypometabolism of the inferior parietal lobes and precuneus are the most striking neurological findings on FDG-PET imaging in AD patients compared to non-demented elderly (Schroeter et al. 2009). Moreover, longitudinal neurofunctional imaging studies have demonstrated hypometabolism in the parietal lobe of MCI converters in comparison with those who did not convert to AD (Schroeter et al. 2009). In conclusion, FDG-PET can be useful in cases of diagnostic uncertainty and has even shown to be valuable in distinguishing AD from FTD (Foster et al. 2007). However, it is advisable to always combine FDG-PET findings with imaging data of other neuroimaging techniques as FDG-PEt alone does not allow an adequate evaluation of the brain structure (Waldemar et al. 2007).

The pathological hallmark of the AD brain is the extracellular deposition of Aβ-plaques. Consequently, a second strategy to visualize AD pathology is not based on glucose metabolism, but on a synthesized derivate which in vivo binds Aβ, such as the N-methyl[¹¹C]2-(4′methylaminophenyl)-6-hydroxybenzothiazole, also known as Pittsburgh Compound-B (PiB) (Mathis et al. 2002), [¹²⁵I]-6 (Wang et al. 2002), and [³H]-BTA-1 (Klunk et al. 2003). All compounds have binding properties for Aβ in the nanomolar range and are based on thioflavin, a well-known chemical dye that stains a wide range of amyloid pathologies (Suhara et al. 2008). PET studies using PiB labeled with carbon 11 (¹¹C) showed that amyloid deposition already occurs years before the clinical diagnosis of dementia (Chetelat et al. 2010), is related to cortical atrophy rate as well as cognitive decline (Braskie et al. 2010), and is more present in MCI converters compared to non-converters (Forsberg et al. 2008). One concern however is the short half-life of PiB labeled with ¹¹C, which renders its use in some diagnostic clinical settings more difficult. Consequently the interest has raised to develop an amyloid-sensitive, radioactive-labeled PiB with longer half-life, such as PiB labeled with ¹⁸F (Wong et al. 2010). A very promising ¹⁸F-labeled amyloid imaging tracer which has recently been FDA-approved (April 6, 2012) is ¹⁸F-florbetapir (¹⁸F-AV-45) (Choi et al. 2009). Recent studies have compared the diagnostic utility of [¹⁸F]-florbetapir-PET compared to [¹¹C]-PiB-PET (Wolk et al. 2012) and the commonly used [¹⁸F]-FDG-PET (Newberg et al. 2012), concluding that [¹⁸F]-florbetapir-PET produced comparable results in discriminating AD patients from cognitively normal adults. Doraiswamy et al. (2012) even proved that [¹⁸F]-florbetapir-PET may help in identifying individuals who are at increased risk for progressive cognitive decline. The same goes for florbetaben (BAY 94–9172), another valuable ¹⁸F-PET marker for Aβ imaging which is currently in phase III clinical development with a sensitivity and specificity of 80 and 91 % in an AD versus control comparison (Barthel and Sabri 2011). Last in the series of ¹⁸F-labeled amyloid PET imaging tracers is ¹⁸F-flutemetamol (phase III trial). Recent work demonstrated similar findings of ¹⁸F-flutemetamol in probable AD and MCI patients relatively to healthy controls with a similar performance as ¹¹C-PiB within the same subjects (Vandenberghe et al. 2010). Additionally, Wolk et al. (2011) demonstrated a high correspondence between immunohistochemical estimates of Aβ levels in brain tissue of 7 AD patients who underwent previous biopsy and in vivo quantitative measures of ¹⁸F-flutemetamol uptake at the location contralateral to the biopsy site (i.e., right frontal), supporting its sensitivity to detect Aβ and its use in the study and early detection of AD.

Amyloid in vivo imaging is a very promising approach but is currently restricted to specialized centers around the world, although in the future it is likely that amyloid imaging techniques will be routinely used in the clinical evaluation of AD patients (Ferreira and Busatto 2011).

Besides amyloid deposits, intracellular NFT consisting of tau protein is a pathological feature of AD as well. The development of PET probes for in vivo imaging of NFT is presently an active research field (Ono and Saji 2012). The first ¹⁸F-labeled compound that was synthesized in order to bind NFT was [¹⁸F]-2-(1-(2-(N-(2-fluoroethyl)-N-methylamino)naphthalene-6-yl)ethylidene)malononitrile, abbreviated as FDDNP (Agdeppa et al. 2001; Barrio et al. 1999). Unfortunately, FDDNP does not exclusively bind NFT but also Aβ plaques. So, for the moment, no existing PET imaging agents allow an exclusive in vivo evaluation of tau pathology in AD brains (Ono and Saji 2012).

Finally, one last approach to visualize AD pathology using PET as an imaging tool is the in vivo mapping of altered neurochemical processes which are typical in the AD brain, such as cholinergic denervation (Van Dam and De Deyn 2006). One example is N-[¹¹C]-methylpiperidin-4-yl propionate, known as [¹¹C]-PMP (Kuhl et al. 1999). This novel radiopharmaceutical is used in PET imaging to determine the activity of the acetylcholinergic neurotransmitter system by acting as a substrate for acetylcholinesterase. Besides the cholinergic neurotransmission, PET imaging with radioligands that are involved with several other neurotransmitter systems or receptors, such as substrates for dopamine (DA) or serotonin (5HT) signaling, has provided important insights into several neurodegenerative disorders (Bohnen and Frey 2007) and has even helped in distinguishing AD from DLB and PD (Tatsch 2008).

Please visit http://www.clinicaltrials.gov/ to see ongoing clinical trials concerning the development of novel PET probes related to amyloid and tau imaging or other neurodegenerative-specific disease markers in the differential diagnosis of dementia.

5 PET Imaging in Neuropsychiatric Disturbances of Dementia

5.1 Alzheimer’s Disease

5.1.1 Depression and Apathy

Loss of neurons in the serotonergic raphe nuclei and dysfunction of its nerve terminals in the neocortex have been reported in AD (Mann and Yates 1983; Palmer et al. 1987). Many lines of evidence suggest this serotonin (5HT) deficiency theory to be strongly related with mood disorders in dementia patients and non-dementing elderly (Sierksma et al. 2010). In vivo imaging studies that used PET have so far focused on 5HT receptors in the limbic brain regions associated with cognitive impairment in AD (Kepe et al. 2006; Meltzer et al. 1998). Ouchi et al. (2009) more recently used a set of 2 different biomarkers in mild- to moderate-stage AD patients with and without depression to investigate the levels of presynaptic serotonergic function and cortical neuronal activity using PET with [¹¹C]-DASB ([¹¹C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile), a specific 5HT-transporter marker, and the more common [¹⁸F]-FDG-PET. Because the 5HT transporter is located on presynaptic 5HT terminals and regulates 5HT signaling, levels of [¹¹C]-DASB binding in these regions thus reflect the activity of presynaptic 5HT neurons in the dorsal raphe nuclei. Thomas et al. (2006) previously found a marked reduction in the binding of 5HT-transporter levels in the prefrontal cortex of AD patients (n = 14) compared to control subjects (n = 10) and non-demented depressed subjects (n = 8), but not between depressed (n = 9) and nondepressed (n = 5) AD patients. Contrastingly, Ouchi et al. (2009) observed a negative correlation between [¹¹C]-DASB binding potential levels in the subcortical serotonergic projection region (striatum) and GDS scores (n = 15) (Spearman Rank Order correlation, P < 0.01) as well as significantly lower [¹¹C]-DASB binding potential levels in AD patients, irrespective of depression, compared to healthy controls (n = 10) in putamen, thalamus, and midbrain (P < 0.05). Consequently, Ouchi et al. (2009) suggested that a certain degree of presynaptic 5HT function in the subcortical 5HT-projection region is compromised in AD patients even before the development of depression. Secondly, statistical parametric mapping (SPM) correlation analysis showed that glucose metabolism in the right dorsolateral prefrontal cortex was positively associated with the levels of striatal [¹¹C]-DASB binding, suggesting that right dorsolateral prefrontal dysfunction in parallel with 5HT inactivation is also implicated in the progression of emotional and cognitive deterioration in AD.

Holthoff et al. (2005) performed cerebral glucose metabolism measurements applying [¹⁸F]-FDG-PET in 53 AD patients. Neuropsychiatric symptoms were assessed using the NPI (Cummings et al. 1994), of which depression and apathy were the most frequently encountered of all symptoms. The patient group with apathy (n = 17) revealed significant decreases in glucose metabolism in left orbitofrontal regions (Brodmann area (BA) 10 and BA 11) compared to non-apathic AD patients (n = 17) (P < 0.008) (Fig. 11.7). In addition, depression in AD patients (n = 10) was significantly associated with hypometabolism in left and right dorsolateral prefrontal regions (BA 6 and 45) in comparison with nondepressed AD patients (n = 10) (P < 0.02) (Fig. 11.8) (Holthoff et al. 2005).

Fig. 11.7

Overlay images of the significant decreases in regional cerebral glucose metabolism in AD patients with clinically significant apathy (n = 17) compared to AD patients free of apathy (n = 17). Measured with [¹⁸F]-FDG-PET in left orbitofrontal regions (BA 10 and 11) on an MRI template (SPM analysis; P < 0.05, corrected). The left image displays the right hemisphere, in the middle the left hemisphere is displayed, and finally the right image visualizes the caudal view of the brain. Abbreviations: AD Alzheimer’s disease, BA Brodmann area, [ ¹⁸ F]-FDG-PET [¹⁸F]-fluorodeoxyglucose-positron emission tomography, MRI magnetic resonance imaging (Reprinted from Holthoff et al. (2005), with permission. Copyright@2005 Elsevier)

Fig. 11.8

Overlay images of the significant decreases in regional cerebral glucose metabolism in depressed AD patients (n = 10) compared to nondepressed AD patients (n = 10). Measured with [¹⁸F]-FDG-PET in left and right dorsolateral prefrontal regions (BA 6 and 45) on an MRI template (SPM analysis; P < 0.05, corrected). The left image displays the right hemisphere, in the middle the left hemisphere is displayed, and finally the right image visualizes the caudal view of the brain. Abbreviations: AD Alzheimer’s disease, BA Brodmann area, [ ¹⁸ F]-FDG-PET ¹⁸F-fluorodeoxyglucose-positron emission tomography, MRI magnetic resonance imaging (Reprinted from Holthoff et al. (2005), with permission. Copyright@2005 Elsevier)

5.1.2 Psychosis

As described above, psychosis is a distinct AD syndrome and includes the presence of at least one (or more) hallucination(s) and/or delusion(s) among others (Jeste and Finkel 2000). Hirono et al. (1998) studied the neuroanatomical basis of delusions in AD using [¹⁸F]-FDG-PET to measure cerebral glucose metabolism in 65 mild to moderate probable AD patients. The Behave-AD or NPI were used to assess for delusions, categorizing 26 patients as being delusional while 39 were not delusional. Surprisingly, a significant increase in glucose metabolism in the left inferior temporal gyrus and a significant decrease in the left medial occipital region in delusional AD patients were observed when compared to their non-delusional counterparts.

Sultzer et al. (2003) similarly used FDG-PET and identified three specific regions in the right frontal cortex of 25 AD patients which were strongly associated with the Neurobehavioral Rating Scale delusion scores, i.e., the right superior dorsolateral frontal region (BA 8) (hypometabolism), the right inferior frontal pole (BA 10) (hypometabolism), and the right lateral orbitofrontal region (BA 47) (hypometabolism), confirming a link between delusional ideation and right hemispheric pathology.

More recently, Reeves et al. (2009) tested if delusions were associated with striatal dopamine (DA) D2/D3 receptor function in AD. The investigators used in vivo [¹¹C]-raclopride-PET imaging ([¹¹C]-RAC-PET) in 23 patients with mild to moderate probable AD who underwent behavioral assessment by means of the NPI. Reeves et al. (2009) found that the mean [¹¹C]-RAC-PET binding potential levels for striatal DA D2/D3 receptors were higher in AD patients with (n = 7 of which 5 men) than without (n = 16 of which 6 men) delusions. When women were excluded from the analysis, striatal [¹¹C]-RAC-PET binding potential levels were still higher in delusional male AD patients compared to male AD subjects without delusions (P = 0.05). Furthermore, these results were comparable with the dopaminergic D2/D3 receptor availabilities of drug-naïve schizophrenia patients as was mentioned by Reeves et al. (2009).

5.1.3 Other Behavioral Syndromes

It becomes clear from the collective PET neuroimaging evidence that psychiatric and behavioral symptoms in dementia are not random consequences of diffuse brain illness but are fundamental expressions of regional cerebral pathological events (Sultzer 1996). Tanaka et al. (2003) revealed that a dysfunction of the striatal dopaminergic D2 receptor metabolism, characterized by significantly lowered [¹¹C]-RAC-PET binding potential levels, is manifested in AD patients with more severe Behave-AD Frequency Weighted Severity Scale scores (Monteiro et al. 2001) compared to AD patients without BPSD. This study however comprised no more than 10 AD patients and only reported Behave-AD total scores.

Unfortunately, besides depression, apathy, and psychosis in AD, no in vivo PET imaging studies have been performed yet with regard to aggression, agitation, diurnal rhythm disturbances, or anxiety.

5.2 Other Dementia Subtypes

Rackza et al. (2010) examined the behavioral deficits in 17 FTLD patients (diagnoses consisted of FTD (n = 10) and SD (n = 7)) using [¹⁸F]-FDG-PET imaging. Behavioral deficits were assessed using the NPI. Total NPI scores were significantly correlated with hypometabolism in various frontomedial regions, the left anterior middle frontal gyrus, the left anterior and superior insula, and the left inferior temporal gyrus. Imaging results were based mainly on apathy, disinhibition, and appetite changes because these behavioral disorders occurred most frequently in this cohort.

Moreover, Peters et al. (2006) indicated that the known cerebral metabolic impairment in FTLD patients specifically affects areas specialized in emotional evaluation. This Belgian study obtained PET imaging and NPI behavioral data from 41 FTLD patients from specialized European PET centers around the world. The investigators primarily found decreased posterior orbitofrontal cortical activity to be related with both apathy and disinhibition.

A very recent PET imaging study investigating the neuroanatomy and pathophysiology of BPSD in FTD patients came from Schroeter et al. (2011). In total, 13 FTLD patients underwent [¹⁸F]-FDG-PET imaging after being behaviorally rated by the NPI scale. The researchers performed a conjunction analysis across the common neural correlates of the three most relevant behavioral disorders as identified in the single regressor analysis. All three behavioral disorders, i.e., apathy, disinhibition, and eating disorders, were related to mainly frontomedian hypometabolism. Afterwards, a disjunction analysis aimed to specifically identify the neural correlates of these three relevant behavioral disorders individually. Disinhibition was correlated with hypometabolism in both anterior temporal lobes, anterior hippocampi, left amygdala, left anterior and superior posterior insula, caudate head, and bilaterally in the lateral and posterior orbital gyri. Smaller clusters were detected additionally for disinhibition in the right superior middle insula, postcentral gyrus, left superior frontal gyrus, and posterior thalamus (P < 0.001); apathy was related to hypometabolism in, most remarkably, the ventral tegmental area and left inferior and middle temporal gyrus, whereas eating disorders were finally associated with the right inferior, middle, and superior frontal gyri with the same statistical threshold (Schroeter et al. 2011).

Lastly, PET imaging studies in DLB patients with BPSD, although sparse, have been performed as well. The first study investigated visual hallucinations in 14 DLB patients compared to 7 DLB patients without such visual hallucinations by means of [¹⁸F]-FDG-PET imaging (Perneczky et al. 2008). The imaging results revealed hypometabolic regions at the right occipitotemporal junction and in the right middle frontal gyrus only in the DLB group with visual hallucinations, suggesting that hypometabolism in visual association areas rather than in the primary visual cortex might be involved in psychosis in DLB (Perneczky et al. 2008). Secondly, [¹⁸F]-FDG-PET data in 10 DLB patients with delusions revealed a hypometabolism of the right middle frontal gyrus (BA 9) and pars triangularis of the right inferior frontal gyrus (BA 45) in comparison with non-delusional DLB patients (n = 11) (Perneczky et al. 2009). The delusion frequency and severity subscores of the NPI within the past 4 weeks prior to the examination were used to distinguish between delusional and non-delusional DLB patients.

A hypometabolism of the right middle frontal gyrus (BA 9) thus seems to be associated not only with visual hallucinations but also with delusions in DLB patients.

6 SPECT in the Differential Diagnosis of Dementia

The other commonly used nuclear gamma ray-emitting imaging modality besides PET which provides functional information about the pathophysiological processes of neurodegenerative diseases is single-photon emission computed tomography (SPECT). It is well recognized that PET has a higher resolution, sensitivity, and better quantitative capacity than SPECT; however, SPECT imaging is more practical as a routine clinical diagnostic procedure, and SPECT scanners are widely installed in most hospitals (Kung et al. 2004).

6.1 ^99mTc-HMPAO-SPECT

For the differential diagnosis in dementia, the most common tracer applied in SPECT is ^99mTc-HMPAO (hexamethylpropyleneamine oxime). The technetium isotope Tc-99m has a half-life of 6 approximate hours and is bound to HMPAO which allows Tc-99m to be taken up by the brain tissue rapidly in a manner proportional to the brain’s blood flow. Many research during the last decade has indicated that ^99mTc-HMPAO-SPECT is very valuable not only in establishing an (early) AD diagnosis (Bonte et al. 2006; Nagao et al. 2006) but also in distinguishing between different types of dementia (Charpentier et al. 2000; Pickut et al. 1997; Rollin-Sillaire et al. 2012) or between very early AD/MCI and normal aging (Nagao et al. 2006).

Pickut et al. (1997) studied the discriminative use of ^99mTc-HMPAO-SPECT in 21 FTLD- versus 19 age- and severity-matched AD patients. The researchers found significantly more bilateral hypoperfusion of parietal lobes in the AD patients as compared to more pronounced bifrontal hypoperfusion in FTLD patients. This bifrontal hypoperfusion was afterwards identified by stepwise logistic regression as the most significant contributing parameter to correctly classify FTLD versus AD patients on SPECT. Comparable with Pickut et al. (1997), Charpentier et al. (2000) examined 20 probable AD and FTD patients by means of ^99mTc-HMPAO-SPECT imaging and detected five specific variables after the bivariate and multivariate analyses with the highest predictive value rate for the differential diagnosis between both neurodegenerative disorders, i.e., right median frontal, left lateral frontal, left parietotemporal, and left temporoparietal-occipital areas as well as the MMSE scores. More recently, Rollin-Sillaire et al. (2012) evaluated the contribution of ^99mTc-HMPAO-SPECT imaging to the differential diagnosis of dementia in 48 neuropathologically confirmed patients with a degenerative (AD or FTLD) or vascular dementia. SPECT-based diagnoses were then compared with clinical and neuropathological diagnoses. Compared with clinical diagnoses alone, SPECT imaging improved the specificity of the etiological diagnosis in degenerative dementia, although its sensitivity was not as good as that of the clinical diagnosis. Furthermore, for AD and FTLD patients, the agreement between the clinical and SPECT-based diagnoses was always confirmed by neuropathological assessment, again indicating that ^99mTc-HMPAO-SPECT is very helpful in the differential diagnosis of dementia.

One last ^99mTc-HMPAO-SPECT study quantified the heterogeneity of cerebral perfusion on SPECT images in elderly controls (n = 31) and very mild AD patients (n = 75) by using a three-dimensional fractal analysis (Nagao et al. 2006). Especially the posterior limbic fractal dimension significantly differed between very early AD and control persons so that authors concluded that ^99mTc-HMPAO-SPECT imaging of the posterior limbic region (consisting of the hippocampal-amygdaloid complex, thalamus, a part of the anterior/posterior cingulate cortex, and precuneus) combined with 3D fractal analysis may be useful in objectively distinguishing patients with very early AD and MCI from healthy elderly.

6.2 [¹²³I]-IMP-SPECT

Another frequently administered SPECT imaging radionuclide to differentially diagnose dementia patients is the intravenous injection of N-isopropyl-p-[¹²³I]-iodoamphetamine ([¹²³I]-IMP). Combined with magnetic resonance imaging (MRI), Goto et al. (2010) were able to distinguish patients with mild DLB (n = 19) from those with AD (n = 19) with a high level of accuracy. More particularly, Goto et al. (2010) found a significantly lower striatal volume on MRI plus a lower occipital SPECT-ratio in the DLB group as opposed to the AD patients. These results therefore point to a strong and added value of MRI combined with ¹²³I-IMP-SPECT imaging when distinguishing AD from DLB patients.

Hanyu et al. (2010) used the similar ¹²³I-IMP-SPECT imaging technique in 24 rapidly progressing- and 24 slowly progressing AD patients based on annual MMSE-score changes and assessed the possible relationship between the rate of cognitive decline and the initial and follow-up regional cerebral blood flow (rCBF) patterns. At the initial evaluation, the rapidly progressing AD group had greater rCBF-deficits mainly in the parietotemporal, frontal and left posterior cingulate regions compared to the slowly progressing AD group. Moreover, follow-up SPECT data of the rapidly progressing AD group showed a significant rCBF-reduction in widespread regions, including parietotemporal and frontal lobes while in the slowly progressing AD group, rCBF patterns were reduced in rather small and more scattered regions of the parietal, temporal, and limbic lobes among others. Based on these results, Hanyu et al. (2010) consequently suggested that rCBF-deficits in specifically the parietotemporal, posterior cingulate, and frontal brain regions are associated with subsequent rapid cognitive decline and rCBF-deterioration in AD.

6.3 SPECT Imaging with Cholinergic and Monoaminergic Radioligands

Altered neurochemical processes in AD have been described extensively throughout the years. One well-known example is the cholinergic denervation in cerebral AD pathology (Mash et al. 1985) which already occurs in very mild- or even presymptomatic stages of the disease. Using a sensitive in vivo cholinergic neuron marker in combination with regular SPECT imaging might therefore be useful in establishing a very early AD diagnosis (Boundy et al. 1997) or in studying the involvement and alteration of cholinergic activity in an AD brain (Boundy et al. 2005; Mazère et al. 2008).

Mazère et al. (2008) used a specific marker of the vesicular acetylcholine transporter, namely, [¹²³I]-iodobenzovesamicol ([¹²³I]-IBVM), combined with SPECT imaging to image cholinergic activity in very early AD patients (n = 8 with MMSE scores of 23.8 ± 1.6). In comparison with 8 age-matched control subjects (28.3 ± 1.3), the researchers found a significant decrease in [¹²³I]-IBVM-binding (47–62 %) in the cingulate cortex and parahippocampal-amygdaloid complex of AD patients. These patterns however appeared to be independent of atrophied areas. These results suggest that a cholinergic degeneration already occurs in the very early stages of AD and that it could be associated with cognitive impairment. As a result, the imaging of cholinergic neurons by using [¹²³I]-IBVM-SPECT might also be an effective approach to identify potential cholinergic treatment responders.

Another cholinergic radioligand combined with SPECT to visualize cholinergic brain activity, is [¹²³I]-iododexetimide ([¹²³I]-IDEX), which has shown to effectively bind muscarinic acetylcholine receptors (mACh) (Muller-Gartner et al. 1992). Possible alterations in mACh-levels were evaluated by Boundy et al. (2005) in early clinical AD patients (n = 11) compared to 10 age- and gender-matched control subjects. In this study, [¹²³I]-IDEX was combined with the previously described ^99mTc-HMPAO-SPECT-technique. Boundy et al. (2005) examined a deficit of [¹²³I]-IDEX-binding in the posterior cingulate cortex of the mild AD group using a voxel based approach with SPM99-software. In parallel with previous results of Mazère et al. (2008), this study provides further evidence for the involvement of altered cholinergic activity in the posterior cingulate region in early AD. Moreover, SPM99 found no deficits on ^99mTc-HMPAO-SPECT-scans, suggesting that neither atrophy nor hypoperfusion were involved in the reduced [¹²³I]-IDEX-binding. Based on this evidence, Mazère et al. (2008) suggested that cholinergic changes in AD might proceed alterations in rCBF-patterns.

Already in 1997, a complementary but earlier study of Boundy et al. indicated that the use of [¹²³I]-IDEX combined with ^99mTc-HMPAO-SPECT might be discriminative enough to be used in the early diagnosis of AD.

The discriminative use of radio-iodinated monoaminergic SPECT-ligands might be another efficient approach to distinguish between AD patients and cognitively healthy volunteers. Versijpt et al. (2003b) assessed this possibility by studying the binding potential of [¹²³I]-5-I-R91150, a ¹²³I-labeled 5HT_2A-receptor antagonist. [¹²³I]-5-I-R91150-SPECT images of 9 AD patients revealed a generally decreased neocortical binding potential with a significant reduction in orbitofrontal, prefrontal, lateral frontal, cingulate, sensorimotor, parietal inferior, and occipital regions in comparison with SPECT images of 26 healthy control subjects. Furthermore, Versijpt and colleagues found an age-related decline in 5HT_2A-receptor binding potentials by which they stressed the necessity for matched advanced age study samples.

Finally, several other monoaminergic SPECT-ligands have been developed to distinguish AD- from DLB patients based on the fact that severe nigrostriatal neurodegeneration occurs in DLB but to no extent in AD as well as that due to the overlap in clinical symptoms, particularly in early stages of the disease, the differential diagnosis between both conditions might be challenging (Tatsch 2008). Multiple examples of monoaminergic SPECT-ligands targeting the dopaminergic neurotransmitter system are given by Tatsch (2008), of which [¹²³I]-β-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) and [¹²³I]-FP(fluoropropyl)-CIT have shown to be most promising in correctly categorizing AD and DLB. Both [¹²³I]-β-CIT and [¹²³I]-FP-CIT-SPECT imaging modalities measure presynaptic striatal dopamine transporter levels which were always found to be significantly lower in DLB patients compared to AD patients (Tatsch 2008). In contrast, corresponding monoaminergic SPECT-ligands which targeted postsynaptic dopamine receptors showed to be much less efficient in differentiating DLB from AD patients.

Regarding the clinical diagnostic issues between AD and DLB patients, another radioligand binding the dopamine transporter located in the presynaptic membrane of dopamine nerve terminals that is frequently used to identify in vivo loss of dopamine transporters in the striatum of DLB patients, is [¹²³I]-ioflupane (Antonini 2007). [¹²³I]-ioflupane combined with SPECT is more familiar under the trade name of “DaTSCAN.” The main advantage of [¹²³I]-ioflupane is that a steady state allowing SPECT imaging is reached at 3 h after a single bolus injection of the radioligand compared with the 18–24 h of [¹²³I]-β-CIT. Evidence shows that [¹²³I]-ioflupane uptake in the basal ganglia is markedly reduced in DLB compared to AD patients (Walker et al. 2002). Nowadays [¹²³I]-ioflupane-SPECT is commonly used in clinical routine for the differential diagnosis between PD and essential tremor although it might also be valuable to differentiate between DLB and AD patients. In general, DaTSCAN favors the diagnostic work-up of DLB (Antonini 2007).

6.4 SPECT Imaging of Neuroinflammation

As mentioned before, inflammation in AD primarily contributes to neurodegeneration and is acknowledged to be a primary source of pathology. Consequently, SPECT imaging of neuroinflammation in an AD brain might also be useful to differentially discriminate between AD patients and control subjects. One example comes from Versijpt et al. (2003a), who studied AD inflammation by using the radioligand [¹²³I]-PK11195 with SPECT imaging. PK11195 is an isoquinoline carboxamide that selectively binds to peripheral benzodiazepine receptors which are expressed on microglia in the brain. Additionally, PK11195 becomes upregulated under inflammatory circumstances. Versijpt et al. (2003a) compared the SPECT images of 10 AD and 9 control subjects and revealed that the mean [¹²³I]-PK11195-uptake was increased in nearly all neocortical regions of AD patients, however, statistical significance was only achieved in the frontal and right mesiotemporal regions.

As a result, PK11195 may be considered a valuable cellular disease activity marker for the in vivo evaluation of microglial inflammation in AD.

6.5 SPECT-Tracers Imaging Aβ-Plaques

The development of PET- as well as SPECT-tracers for amyloid-beta (Aβ) imaging represents an active area of radiopharmaceutical design (Valotassiou et al. 2010). These tracers are either monoclonal antibodies against Aβ, radiolabeled Aβ-peptides or derivatives of histopathological stains such as Congo red, chrysamine-G, and thioflavin-T. Finding a suitable radioligand is however very challenging as Aβ-plaques are not homogenous and contain multiple binding sites for structurally different compounds (Valotassiou et al. 2010). One good example comes from Kung et al. (2004), who developed 6-iodo-2-(4′-dimethylamino-)phenyl-imidazo[1,2]pyridine (IMPY) and 4-N-methylamino-4′-hydroxystilbene (SB-13) as ligands for specifically targeting amyloid plaques. The researchers evaluated binding properties of these two potential Aβ-imaging agents in temporal, parietal and cerebellar cortex of AD patients (n = 4) and control persons (n = 4). When labeled with I-125 or H-3, [¹²⁵I]-IMPY- and [³H]-SB-13-SPECT respectively showed an abundant binding capacity with high binding affinities for Aβ-plaques in all affected brain regions of AD patients compared to very low specific binding in cortical tissue of control brain homogenates. These properties suggest that both ligands are valuable in quantifying and localizing amyloid plaque burden in living AD patients.

Please visit http://www.clinicaltrials.gov/ to see ongoing clinical trials concerning the development of novel SPECT probes related to amyloid imaging or other neurodegenerative-specific disease markers in the differential diagnosis of dementia.

7 SPECT Imaging in Neuropsychiatric Disturbances of Dementia

During the last two decades, many studies have conducted SPECT-related research regarding neuropsychiatric disturbances in dementia. Generally speaking, literature comprises more SPECT- than PET-related BPSD studies probably because SPECT, as an imaging technique, is more accessible. Of all BPSD items, depression, apathy, and psychosis in AD have been studied the most. Besides these three main behavioral disturbances, also activity disturbances, aggression, and sleep disorders were the subject of SPECT imaging in AD. Last but not least, SPECT imaging of psychosis and apathy in DLB and FTD patients has only been performed very recently over the last 7 years.

The most important SPECT imaging studies related to all these behavioral phenomena are summarized below.

7.1 Alzheimer’s Disease

7.1.1 Depression

One of the first studies that dealt with mood disorders in AD was published by Galynker et al. (2000) who examined the relationship between rCBF patterns and negative symptoms in AD patients (n = 25). The AD group was subdivided in a high- (more negative symptoms) (n = 12) and low (less negative symptoms)-severity group (n = 13). Each patient underwent ^99mTc-HMPAO-SPECT. Categorization of negative symptoms was performed by means of the Scale for the Assessment of Negative Symptoms, the Hamilton Rating Scale, and the Positive and Negative Symptom Scale. Authors observed a significantly lower rCBF pattern in the dorsolateral prefrontal cortex bilaterally (right: P = 0.002 and left: P = 0.02), the main right frontal cortex (P = 0.02), and cingulate gyrus (P = 0.022) of the high-severity AD group compared to the low-severity group. Results pointed to a high association between negative symptoms and hypofrontality in AD. Somewhat later in 2003, Liao et al. (2003) tested the hypothesis that depression in AD is the result of a specific cerebral pathogenesis rather than a diffuse event, as was previously shown by Galynker et al. (2000). In total, 43 AD patients received a behavioral assessment with the Hamilton Depression Rating Scale and underwent ^99mTc-HMPAO-SPECT imaging. An inverse correlation was found between depression scores and cerebral perfusion in the bilateral anterior and posterior cingulate gyri and precuneus, which was in agreement with Galynker et al. (2000). Surprisingly, no hypoperfusion in (pre)frontal cortices of depressed AD patients was identified.

Akiyama et al. (2008) scrutinized previous results and used the so-called easy Z-score imaging system (eZIS) combined with ^99mTc-ethyl-cysteinate dimer (ECD)-SPECT imaging, another frequently used radioligand (ECD) which binds the technetium isotope Tc-99m, to investigate if hypoperfusion in prefrontal cortex or cingulate gyrus is associated with depression in AD. Depression scores were based on NPI depression items, so that in total 44 AD patients were subdivided into 26 depressed and 19 nondepressed AD subjects. Data from eZIS-^99mTc-ECD-SPECT scans revealed that mean Z-scores of the left prefrontal cortex in the depressed AD group were significantly higher (P < 0.0125) than those in the nondepressed group. Moreover, there were no significant differences in Z-scores of the right prefrontal cortex or in the bilateral anterior cingulate gyrus between the two groups, which is in contrast but also in agreement with previous studies who either found hypoperfusion in cingulate gyrus alone (Liao et al. 2003) or in the prefrontal cortex as well as in the cingulate gyrus (Galynker et al. 2000). Also in 2008, Levy-Cooperman et al. (2008) used the CSDD with a cutoff score of 8 or more as being indicative for depression to dichotomize depressed (n = 27) from nondepressed (n = 29) AD patients with the same ^99mTc-ECD-SPECT technique combined with MRI. Similarly, this study aimed to determine neural correlates of depressive symptoms in 56 AD patients who met the criteria for probable AD. Results showed a hypoperfusion in the right superior and bilateral middle frontal (P < 0.005), left superior frontal (P < 0.05), and anterior cingulate gyri (P < 0.005) of depressed AD patients compared to nondepressed patients. SPM analyses also revealed a significantly lower perfusion in bilateral dorsolateral and superior prefrontal cortex of depressed AD patients (right: P < 0.005 and left: P < 0.05), which is consistent with previous reports that suggested that the prefrontal cortex and cingulate gyrus are involved in affect and emotional regulation in AD.

Finally, in 2010, Kataoka et al. again used ^99mTc-ECD-SPECT but afterwards analyzed all SPECT images with 3D stereotactic region of interest template (3DSRT) software to compare rCBF ratios of each brain segment between depressed- (n = 17) and nondepressed AD patients (n = 18). Depression scores were based on the Japanese version of the NPI depression subscale, and AD patients had mild to moderate AD according to DSM-IV criteria. The authors found that perfusion ratios (rCBF patterns) on 3DSRT images of the left callosomarginal segment, i.e., left prefrontal cortex, were significantly lower (P < 0.05) in the depressed AD group than those of the nondepressed group. In comparison with their own previous study where they used eZIS-^99mTc-ECD-SPECT instead of 3DSRT-^99mTc-ECD-SPECT (Akiyama et al. 2008), current results remained consistent thus suggesting that frontal dysfunction is associated with the expression of depressive symptoms in AD patients.

7.1.2 Apathy

Apathy is closely related to depression as it is one of the main components of the CSDD (lack of reactivity to pleasant events, loss of interest (Alexopoulos et al. 1988)) to decide whether or not an AD patient might be depressed. Therefore, it is very likely that the same affected brain regions of interest in depressed AD patients (prefrontal cortex, cingulate gyrus) might be comparable with those of apathic AD patients on SPECT.

The first study that agrees with this hypothesis comes from Benoit et al. (1999) who studied regional cerebral perfusion with ^99mTc-ECD-SPECT in 20 apathic AD patients rated by the apathy subscale of the NPI. Authors indeed revealed that the apathy NPI scores were correlated with a right cingulate deficit whereas MMSE scores positively correlated with the left temporoparietal area. A comparable study in 2002 from Benoit et al. used ^99mTc-ECD-SPECT imaging again but this time in combination with SPM99 analysis. Brain perfusion patterns were compared between apathic (n = 15) and non-apathic AD patients (n = 15) as well as healthy control subjects (n = 11). SPECT data showed that compared with healthy subjects, the apathy-free AD subgroup had significantly lower cerebral perfusion of the inferior temporal and occipital regions. In contrast, the apathy subgroup had significantly decreased perfusion of the left anterior cingulate, right inferior medial and left orbitofrontal gyrus, and right gyrus lingualis. When both AD groups were compared, a significantly lower perfusion in BA 8, 9, and 10 (bilateral medial frontal gyri) was observed in the apathic AD group but not in the group free of apathy. On the other hand, apathic AD patients tended towards a decreased perfusion in the anterior cingulate gyrus even though this finding did not reach statistical significance.

Benoit et al. (2004) further assessed apathy in AD by making a distinction between the separate behavioral, cognitive, and emotional aspects of apathy using the Apathy Inventory. Thirty AD patients were included and brain perfusion was once more performed with ^99mTc-ECD-SPECT and SPM99 analysis. The lack of initiative score was negatively associated with perfusion in the right anterior cingulate cortex, whereas the lack of interest score was negatively associated with perfusion in the right middle orbitofrontal gyrus. Lastly, emotional blunting scores inversely correlated with perfusion in the left superior prefrontal dorsolateral cortex.

Similarly as with Benoit et al. (2004), Robert et al. (2006) also studied the two major dimensions of apathy, i.e., lack of initiative and lack of interest, by using the Apathy Inventory combined with ^99mTc-ECD-SPECT and SPM99 analysis in 19 AD subjects presenting this type of behavioral phenomenology compared to 12 AD subjects who did not. On the whole, AD patients with lack of initiative and interest again showed a significantly lower perfusion in the right anterior cingulate gyrus than AD patients without such specific behavior (P = 0.00012). These parallel results however are not surprising as they both resulted from the same research group and were derived from a rather small subgroup of patients. Nonetheless, this is yet another confirmation of the cingulate gyrus to be involved in the pathophysiological processes of apathy in the AD brain.

One last and recent study that related to apathy as well as depression in AD comes from Kang et al. (2011). A rather large number of patients, namely, 81, were enrolled in this prospective study. ^99mTc-HMPAO-SPECT was performed to evaluate rCBF patterns, and according to the NPI subscores for apathy as well as depression, unfortunately, only 9 were classified as clinically significant depressed and 9 as clinically significant apathic. In addition, 18 more nondepressed and non-apathic AD patients were classified as an age- and MMSE-score-matched disease control group. Results showed that depressed AD patients had a significantly lower perfusion in the right orbitofrontal and inferior frontal gyri than nondepressed AD patients while apathic AD patients displayed a hypoperfusion in the right amygdala and temporal, posterior cingulate, right superior frontal, postcentral, and left superior temporal gyri compared to non-apathic AD patients. Secondly, when the rCBF patterns were correlated with NPI subscores in the total group of 81 AD patients, depression subscores negatively associated with perfusion in the left inferior frontal and right middle frontal gyri, whereas apathy subscores inversely correlated with perfusion in the right temporal and right medial frontal gyri.

In conclusion, much evidence resulting from not only SPECT but also PET imaging uniformly suggests that mainly (pre)frontal areas as well as the anterior/posterior cingulate gyrus are involved in the cerebral pathophysiology of depression and apathy in AD.

7.1.3 Psychosis

Already in 1994, Starkstein et al. investigated whether delusions in AD were associated with dysfunction in specific brain areas. In total, 45 probable AD patients received ^99mTc-HMPAO-SPECT and delusions were assessed by the Present State Examination so that patients were subdivided in delusional (n = 16) or non-delusional (n = 29). The most common delusion was “paranoia,” which was present in 75 % of AD patients besides hypochondriac-, grandiose-, and infidelity-type delusions. Four patients also suffered from Capgras (impostors) and two from Cotard syndrome (delusions of deformity of body parts). Imaging results only revealed that delusional AD patients had a bilateral hypoperfusion in inferior and temporal lobes compared to non-delusional subjects. However, the mixture of different types of delusions might have accounted for the lack of laterality and loss of frontal significance (Ismail et al. 2012).

Somewhat later, Ponton et al. (1995) included 15 initially non-delusional AD patients who underwent SPECT scanning and psychometric testing with the Alzheimer’s Disease Assessment Scale. Procedures were repeated 1 year later when 6 out of the original 15 AD patients had developed several types of delusions. When comparing the original baseline SPECT data between delusional (n = 6) and non-delusional (n = 9) subjects, the investigators found that delusional patients already had a significantly higher perfusion in the right hemisphere, particularly in the inferior and superior temporal gyrus, the temporoparietal area, Broca’s area, the prefrontal region, and primary visual cortex. Afterwards, when comparing the SPECT data which were yielded at year 1 between both subgroups, a lower perfusion in the right temporal region was observed in the delusional group compared with those who did not develop any type of delusion. Ponton et al. (1995) subsequently were the first to suggest that specifically right temporal lobe dysfunction might predict the onset of delusions in AD. Staff et al. (1999) were also able to identify a relationship between right hemispheric hypoperfusion, namely, in right frontal and limbic regions, and delusions in 18 probable AD patients compared to 15 AD patients who were free of delusions using ^99mTc-HMPAO-SPECT with SPM. The same goes for Fukuhara et al. (2001) who investigated a very specific type of delusion, i.e., delusion of theft, in only 9 age- and cognitive-matched AD patients by means of ^99mTc-HMPAO-SPECTimaging and SPM. AD patients with delusions of theft showed a significant hypoperfusion in right medial posterior parietal region compared to patients without such delusions, indicating that right parietal dysfunction may play a role in producing this type of delusions in AD.

Nakano et al. (2006b) obtained similar results, also using ^99mTc-HMPAO-SPECT, when examining the relationship between delusions and rCBF in AD. This time, however, SPECT data of 64 probable AD patients were compared to a group of 76 age-matched controls. Delusions were assessed by the NPI delusion subscale so that AD patients were also categorized into delusional (n = 25) and non-delusional (n = 39), without any significant difference between age and MMSE scores. Neuroimaging results showed that when compared to normal healthy volunteers, AD patients had significantly decreased perfusion in the posterior cingulate gyri, precuneus, and parietal association cortices. In comparison with non-delusional AD subjects, the delusional one’s displayed a significantly decreased perfusion in prefrontal cortex, anterior cingulate gyri, inferior to middle temporal cortices, and parietal cortex of the right hemisphere (P < 0.01).

More recently, in 2010, Matsuoka et al. studied the relationship between brain perfusion and associated delusion severity in individuals with AD, using SPECT and NPI. In total, 35 patients entered this study of which 14 suffered from delusions whereas 21 did not. The delusion subscale scores of the NPI were negatively correlated with rCBF patterns in the right anterior insula (P < 0.01) when the total AD group was taken into account (n = 35). However, rCBF patterns in the right anterior insula were not significantly decreased in delusional AD patients when compared to non-delusional patients. The authors suggest that although it may not be responsible for the onset of delusions, the right anterior insular dysfunction may be responsible for the exacerbation of these symptoms.

SPECT imaging has also been used to investigate gender differences in regional perfusion in the brains of psychotic AD patients (Moran et al. 2008). Moran et al. (2008) assessed cerebral perfusion of 51 probable AD patients with psychosis (16 males, 35 females) compared to 52 nonpsychotic probable AD patients (19 males, 33 females). The researchers used the Behave-AD scale to rate the presence or absence of psychosis within 1–2 weeks of ^99mTc-HMPAO-SPECT imaging. The results revealed that perfusion was lower in female patients with psychotic symptoms in the right inferolateral prefrontal cortex and in the inferior temporal regions compared to female patients without such symptoms. In contrast, perfusion was higher in male patients with psychotic symptoms in the right striatum compared to nonpsychotic male subjects. Comparison groups did not differ in age or dementia severity, which was estimated by the MMSE. These results support the role of the right hemispheric prefrontal and lateral temporal cortex in psychosis of AD in women, but not in men, and raise the possibility that there might be a gender-related regional specificity in the pathophysiology of psychosis in AD.

As distinct from delusions, SPECT studies examining the neuropathophysiology of hallucinations are very limited. One example from Mori et al. (2006) investigated rCBF changes in a case of AD with music hallucinations compared to a control AD group (n = 747). The patient was a 73-year-old right-handed woman who developed AD at the age of 69. ^99mTc-HMPAO-SPECT imaging data revealed that rCBF of the case was significantly increased in the left superior temporal and left angular gyrus compared to control persons. This specific profile thus could be relevant to the neuroanatomical basis of music hallucinations.

In summary, delusions in AD seem to be primarily associated with the right hemispheric pathology as was shown not only by SPECT but also PET imaging data. More neuroimaging research however is essential with regard to hallucinations in AD.

7.1.4 Activity Disturbances

Wandering is a common activity disturbance in AD and one of the most exhausting for the caregiver (Rolland et al. 2003). For the moment, only one SPECT study tried to study the brain’s possible underlying physiological processes of wandering behavior in AD patients (Rolland et al. 2005). For this purpose, Rolland et al. (2005) used ^99mTc-ECD-SPECT imaging and the NPI to define wandering in AD subjects. SPECT scans were then compared between AD subjects with (n = 13) and without (n = 13) wandering behavior. Despite similar clinical dementia severity based on MMSE scores, wanderers exhibited a more severely reduced rCBF in the left parietotemporal lobe than AD patients without wandering behavior. SPM analysis further revealed a reduced rCBF in the left middle temporal gyrus (BA 21) and left parahippocampal gyrus (BA 37). Unfortunately, these results did not confirm the authors’ hypothesis of the involvement of the supervisory role of the frontal lobes and neither seemed to be associated with a dysfunction of the spatial navigation located in the right parietal cortex nor with a disorder of perception or reality which should have involved the right temporal lobe. On the contrary, wandering in AD, as a physical activity and aberrant motor behavior, might enhance an extensive cortico-subcortical network interaction.

7.1.5 Aggression

Another very common behavioral disturbance in AD is aggression. So far, only two studies have investigated regional brain perfusion in dementia patients with this specific behavioral phenomenology.

The first one of Hirono et al. (2000) used a group of 10 mixed dementia (MXD) patients, i.e., AD + CVD, with and without aggression based on the NPI subscale for aggression. As imaging technique, ^99mTc-HMPAO-SPECT was performed and MXD patients with aggression revealed a significant hypoperfusion in the left anterior temporal cortex (P < 0.001) and additionally in the bilateral dorsofrontal and right parietal cortex.

The second study of Lanctôt et al. (2004) was slightly different as they used 30 aggressive and 19 nonaggressive AD patients whom were rated by the Behave-AD and underwent ^99mTc-ECD-SPECT instead of ^99mTc-HMPAO-SPECT. This time, diagnoses were made according to the NINCDS-ADRDA criteria for probable AD thereby excluding vascular pathology. Unfortunately, SPECT scanning had to be performed only within 3 months of their behavioral assessments, which is a rather large interval. Compared with nonaggressive patients, the aggressive subjects displayed hypoperfusion in the right and left middle temporal regions of interest (P = 0.02 for both). Supplementary SPM analysis further revealed a right middle medial temporal hypoperfusion in the aggressive AD group (P = 0.008). This region includes the hippocampus, parahippocampus, and posterior amygdala and corresponds to BA 28, 35, and 36. Lanctôt et al. (2004) therefore suggested that the right middle medial temporal region is an important neural correlate of aggression in AD, which is somewhat comparable with Hirono et al. (2000) who also identified the temporal cortex as an important key factor in the onset of aggression, although in this case the hypoperfusion was located in the left hemispheric temporal region.

7.1.6 Sleep Disorders

Sleeplessness in AD is one last behavioral variant besides depression, apathy, psychosis, activity disturbances, and aggression which has been explored in the neuroimaging field of AD. Noteworthy, literature only mentions one related SPECT study so far (Ismail et al. 2009).

In this specific study of Ismail et al. (2009), authors aimed to investigate the possible association of regional cerebral perfusion and sleep loss in AD. A group of 55 AD patients in total were characterized as having or not having nocturnal sleep loss based on standard AD scales assessing sleep over the previous 4 weeks. Regular ^99mTc-ECD-SPECT imaging scans were performed when patients were in a relaxed, wakeful state. Afterwards, SPM5 analysis was performed to compare brain perfusion across both groups. In addition, the two AD groups were also compared with a healthy control group of the same age and gender. Results showed increased perfusion in the right middle frontal gyrus (BA 9) (P = 0.016) in AD patients suffering from nocturnal sleep loss as opposed to AD patients who were free of sleep loss. However, hyperperfusion in the right middle frontal gyrus among AD patients with sleep loss was not supreme, given the fact that the level of hyperperfusion of this region which was found in the healthy control group could not be exceeded. Authors thus concluded that in mild to moderate AD, relative hyperperfusion (rather than absolute hyperperfusion) of the right middle frontal gyrus might be associated with reports of sleeplessness in AD. Furthermore, this region might play an important role in the regulation of sleep.

7.2 Other Dementia Subtypes

Personality changes such as antisocial behavior are a prominent part of the behavioral symptomatology in FTD patients. This matter was studied by Nakano et al. (2006a) who assessed 22 FTD patients with the NPI and categorized 5 types of antisocial behavior (stealing, traffic accident (e.g., hit and run), physical assault, sexual comments or advances, public urination). These antisocial behaviors were rated independently by three different geriatric psychiatrists who had not been given the information of the SPECT images. A control group of 76 normal, healthy volunteers was included also, and both groups underwent ^99mTc-ECD-SPECT and SPM99 analysis. Compared to normal controls, FTD patients showed a significant reduction of rCBF in the widespread frontal cortical areas (such as the superior, middle, and inferior frontal gyri) as well as in subcortical structures (particularly thalamus and caudate nuclei). A subsequent correlation analysis further revealed that antisocial behavioral symptoms were associated with reduction of the rCBF in the orbitofrontal cortex, BA 47, BA 32, the right caudate nucleus, and left insula of FTD patients, suggesting that mainly a functional decline of the orbitofrontal cortex in FTD patients is related to antisocial behavior (Fig. 11.9). This conclusion is not surprising at all, given the fact that orbitofrontal cortex dysfunction is mostly associated with disinhibiton, facetiousness, sexual and personal hedonism, and lack of concern for others (Nakano et al. (2006a)).

Fig. 11.9

Results of SPM analyses showing rCBF patterns that correlated with antisocial behavioral scores in FTD patients (n = 22) displayed on a 3D surface anatomical template (P < 0.005, not corrected for multiple comparisons). Views are medial right (a), medial left (b), posterior (c), anterior (d), right lateral (e), left lateral (f), inferior (g), and superior (h). Abbreviations: FTD frontotemporal dementia, rCBF regional cerebral blood flow, SPM statistical parametric mapping (Reprinted from Nakano et al. (2006a), with permission. Copyright@2006 Elsevier)

The study of Roselli et al. in 2009 targeted BPSD symptoms in 18 well-characterized DLB patients and measured striatal dopamine transporter levels by [¹²³I]-FP-CIT-SPECT imaging after NPI assessment. Imaging data showed a significant correlation between decreased dopamine transporter levels and visual hallucinations. Although no other correlations were observed, delusions, apathy, and depression were also inversely correlated to decreased caudate dopamine transporter levels when putamen and caudate nucleus were considered separately. Hence these results provide important evidence on the involvement of mesocortical dopaminergic pathways in neuropsychiatric symptoms in DLB such as delusions, apathy, and depression.

Furthermore, ^99mTc-HMPAO-SPECT imaging in 14 DLB patients with hallucinations showed a significant inverse correlation between brain perfusion in the midline posterior cingulate gyrus and hallucination severity as was illustrated by O’Brien et al. (2005).

Finally, Nagahama et al. (2010) more recently found after using ^99mTc-HMPAO-SPECT imaging that visual hallucinations in DLB patients (n = 100) were related to hypoperfusion in the left ventral occipital gyrus and bilateral parietal areas, whereas delusions were rather associated with hypoperfusion in the right rostral medial frontal cortex, left medial superior frontal gyrus, and bilateral dorsolateral frontal cortices. Based on these results, the authors concluded that visual hallucinations may therefore be related to a dysfunction of parietal and occipital association areas, while delusions may rather be associated with dysfunctions of the frontal cortex.

8 Concluding Remarks

PET and SPECT neuroimaging techniques have played an important role in the differential diagnosis of dementia over the past two decades. They have both provided invaluable information regarding the characteristic changes that match the pathophysiology of AD among others. Presently, both imaging modalities have proven to be crucial to most efficiently facilitate dementia diagnosis, indicate disease staging, visualize plaque burden as well as monitor the effects of disease-modifying therapies. PET and SPECT also work very complementary if both imaging techniques are combined. However, the challenge for the future will be to develop novel radioligands which target different and unique aspects of the etiology of dementia so that subjects might be even more adequately recognized even in a presymptomatic or prodromal state.

With regard to BPSD, PET and SPECT have repeatedly shown that depending on the behavioral phenomenon and dementia subtype, BPSD such as depression, apathy, or psychosis are the result of a very specific, cerebral pathophysiology rather than a diffuse brain event. This discriminative capacity even points to the diagnostic utilities of PET and SPECT in BPSD. More PET but also SPECT neuroimaging research however is mandatory with regard to especially activity disturbances, anxieties, hallucinations, diurnal rhythm disturbances, and aggression/agitation to fully characterize the pathophysiology of each of these neuropsychiatric disturbances not only in AD but also other dementia subtypes.