Introduction

Alzheimer’s disease (AD) is the most common cause of dementia and typically presents with the gradual onset of short-term memory impairment. AD then progresses to involve other domains of cognition including language, visuospatial abilities, and executive function. Advancing age is the greatest risk factor for AD. However, AD is also a common cause of dementia among patients younger than 65 years (early-onset AD). Frontotemporal dementia (FTD) is one of the most common forms of dementia in patients younger than 65 years and may present with behavioral symptoms or language impairment.

Both conditions are neurodegenerative diseases, characterized by unique pathologies on brain autopsy and by progressive neuronal cell death in specific cortical regions. Although often clinically very distinct, an expert clinical diagnosis of dementia due to AD or FTD may be only 70–80% sensitive to match with autopsy findings [1, 2]. In particular, dementia with predominant aphasia, apraxia, dysexecutive function, or personality change may be caused by either AD or FTD pathology.

In this review, we will discuss the background, evidence, and clinical scenarios for the use of the main categories of clinically available biomarkers for the diagnosis of AD and FTD. These include structural imaging (MRI), functional imaging (FDG-PET, SPECT), and markers of AD pathology, namely, amyloid PET and cerebrospinal fluid (CSF) biomarkers including amyloid beta 1–42 (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau). Specifically, the measurement of biomarkers is helpful in the clinical diagnosis and treatment of dementia to detect (1) the presence and spatial pattern of neurodegeneration in an early clinical stage, and (2) a specific pathology, such as the cardinal pathologies of AD, amyloid-beta, and phospho-tau.

We will also briefly mention those biomarkers that have shown promise in recent research and are likely to enter the clinical arena in the not-distant future. Moreover, challenges to the use of biomarkers in clinical practice will be discussed, including the high prevalence of AD biomarkers in cognitively intact elderly, the lack of identified biomarkers for the specific FTD pathologies of TDP-43 and tau, the lack of coverage for biomarker testing by insurance or national health plans, and the importance of seeking patient consent for biomarker testing and disclosure.

Illustrative cases

Case 1

A 70-year-old right-handed man presented with 1 year of gradually progressive personality change with irritability, apathy, lack of hygiene, and susceptibility to financial scams. His wife reported he was less interested in and caring toward his family and he had isolated himself to play Solitaire on his computer and read political conspiracy websites. On neuropsychological testing, he had moderate impairment in executive function, low-normal verbal memory, and otherwise intact cognition. His neurologic examination was intact. An MRI brain showed mild diffuse cortical atrophy without a specific pattern. Initial diagnosis was behavioral variant FTD. His CSF testing showed a reduced level of Aβ1–42 and elevated T-tau/Aβ1–42 and P-tau/Aβ1–42 ratios. His diagnosis was revised to “frontal variant” Alzheimer’s disease and he was started on donepezil. He was also enrolled in an AD clinical trial testing an anti-amyloid antibody.

Case 2

A 64-year-old right-handed man presented with a 2-year history of word-finding difficulty. Clinical and neuropsychological assessments confirmed a profound anomia and relatively preserved function in other cognitive domains. His brain MRI showed evidence of medial and anterior temporal lobe atrophy with greater left-sided emphasis. With a clinical diagnosis of Alzheimer’s disease, he was commenced on memantine that did not lead to a tangible benefit. He underwent CSF analysis for amyloid and tau measurement as he was being considered for enrollment in an AD clinical trial, but the CSF profile was not compatible with AD. A second opinion was sought. Clinical assessment confirmed the presence of profound anomia, but it was also noted that there was a striking preservation of non-verbal episodic memory and visuospatial function. An FDG-PET demonstrated strikingly asymmetrical temporal hypometabolism (mainly left sided). On longitudinal follow-up, the patient developed behavioral features including mental rigidity, apathy, and lack of empathy. He also developed a sweet tooth which led to significant weight gain. He underwent amyloid PET scan that was reported as normal. His diagnosis was revised to semantic variant of frontotemporal dementia with behavioral features.

Alzheimer’s disease

Alzheimer’s disease most often presents with the gradual onset of short-term memory impairment, and patients may present to clinicians while in an amnestic mild cognitive impairment (MCI) stage, wherein memory impairment is evident on testing, but activities of daily living remain generally independent. Over time, patients will develop impairment in other domains of cognition including language, visuospatial function, executive function, and attention, and patients will develop impairments in their activities of daily living. Behavioral symptoms are common in Alzheimer’s disease, particularly depression, anxiety, and irritability in early stages, and paranoid delusions and agitation in moderate-to-severe stages. However, personality and social behavior often remain relatively preserved.

Although an amnestic presentation is most typical in Alzheimer’s disease, variant presentations are possible, including primary progressive aphasia due to underlying AD pathology, posterior cortical atrophy presentation, or a frontal variant of AD, characterized by personality change and a dysexecutive syndrome.

The cardinal pathologies of Alzheimer’s disease are amyloid plaques and neurofibrillary tangles, and longitudinal studies indicate that these pathologies may accumulate years prior to any cognitive decline [3•, 4]. In the clinical setting, biomarker testing may be pursued for prognosis, future planning, and to guide treatment. The National Institute on Aging–Alzheimer’s Association guidelines for the diagnosis of Alzheimer’s disease dementia recommend biomarkers for research purposes and as “optional clinical tools for use where available and when deemed appropriate by the clinician.” Biomarker testing allows a diagnosis of AD to be made to a greater level of certainty “with evidence of AD pathophysiological process” (Table 1) [5]. The majority of clinical trials for AD now require biomarker confirmation as inclusion criteria.

Table 1 Most recent consensus guidelines for the diagnosis of AD, bvFTD, nfvPPA, and svPPA all endorse the concept of greater diagnostic certainty with the use of imaging or CSF biomarkers [5]
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Frontotemporal dementias

Frontotemporal dementia is the umbrella term used to denote degenerative brain diseases that, as the name implies, predominantly affect frontal and temporal lobes of the brain [6]. The frontotemporal lobar degeneration (FTLD) spectrum also includes corticobasal degeneration and progressive supranuclear palsy, in addition to FTD; however, this review will focus on imaging and CSF biomarkers for FTD.

FTD syndromes are the second most common type of dementia in the younger-than-65 age group [7] (AD is the most common) and the third most common type overall [8]. Clinically, FTD syndromes are broadly categorized to behavioral variant FTD (bvFTD) [9] and primary progressive aphasias (PPAs) [10], and with the caveat that evolution from one clinical syndrome to another is a common occurrence [11]. bvFTD is characterized by a variable combination of behavioral features. According to the latest consensus recommendations [9] (Table 1), presence of at least three out of six clinical features is required for the diagnosis of possible bvFTD. Significant functional decline and consistent neuroimaging is required for moving to the next level of certainty (probable bvFTD). The presence of one of the FTD-causing mutations [chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or progranulin (GRN)] or histopathological evidence of FTLD is necessary for diagnosis of bvFTD with definite FTLD pathology. Language variants of FTD are divided to semantic variant PPA (svPPA) and non-fluent/agrammatic variant (nfvPPA). According to the latest consensus criteria [12], svPPA is characterized by impairment in confrontation naming and single-word comprehension whereas nfvPPA patients suffer from a variable combination of grammatical violations and effortful halting speech. Neuroimaging is helpful in identifying different patterns of atrophy and hypometabolism and presence of atrophy and/or hypometabolism in the relevant areas (Table 1) will improve the degree of confidence in clinical diagnosis [12, 13]. Similar to bvFTD, presence of either histopathological evidence of degenerative pathology or presence of known pathogenic mutation is required for the diagnosis of PPA with definite pathology.

Abnormal phosphorylation of MAPT without concomitant amyloid pathology (primary tau pathology) and cytoplasmic aggregation of trans-activation response DNA binding protein of 43 kDa (TDP-43) are the two main pathological hallmarks of FTD with almost equal contribution to FTD pathology [14]. Also, a minority of patients (~ 10%) harbor fused-in-sarcoma pathology [15].

Imaging biomarkers

Imaging biomarkers are mainly divided into two main categories: structural imaging such as MRI or high-resolution CT and functional imaging which includes PET and advanced MR-based techniques such as functional MRI or diffusion tensor imaging. For the purpose of this review, we focus mainly on imaging techniques available in clinical setting. The recommendations from all current guidelines on imaging biomarkers including European Federation of Neurological Societies, Fourth Canadian Consensus Conference on Diagnosis and Treatment of Dementia, and UK National Institute of Health and Care Excellence have been summarized in Table 2.

Table 2 Current consensus guidelines for using imaging biomarkers in diagnosis of dementia in clinical setting
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Structural imaging

There is a consensus between all current guidelines [16,17,18] that cases with clinical dementia syndrome should be investigated by structural imaging at least once during their work-up. Structural imaging is not only used to identify the pattern of atrophy specific for different dementia syndromes but also to exclude the presence of non-degenerative pathologies manifesting with cognitive impairment. Examples of such conditions include tumors, vascular disease, inflammatory or infective processes (e.g., encephalitis), subdural collections, or normal-pressure hydrocephalus.

MRI is considered the modality of choice because of its superiority in depicting vascular and inflammatory changes. High-resolution CT, however, can be used as an alternative when MRI is not available or contraindicated. The minimum MRI sequences required to investigate dementia are high-resolution 3D or volumetric T1-weighted images in coronal and one additional plane mainly to identify the pattern and degree of atrophy, and T2-weighted and fluid attenuation inversion recovery (FLAIR) images to determine the degree of vascular changes. T2* or gradient echo or susceptibility-weighted imaging is used to assess the presence of cerebral microbleeds or vascular amyloid deposition in Alzheimer’s disease. Diffusion-weighted imaging, on the other hand, shows foci of restricted diffusion in cases with acute cerebrovascular event and is very helpful to exclude Creutzfeldt-Jacob disease presenting with restricted diffusion in posterior thalamus or cortical ribboning.

Although specific patterns of atrophy have been described for each dementia syndrome, these patterns are commonly observed in group level compared with healthy controls. Given the considerable anatomical overlap between different degenerative diseases, making accurate diagnosis could be challenging for an individual case.

In typical amnestic AD, atrophy mainly involves the medial temporal lobes and hippocampi and extends to parietal lobes (Fig. 1). In atypical AD presentations such as posterior cortical atrophy (PCA), the volume loss is more prominent in posterior–superior parietal lobes involving posterior cingulate cortex (PCC), while atrophy in logopenic variant of PPA (lvPPA) mainly involves the posterolateral and inferior temporal and parietal lobes which can also extend to PCC [19].

Fig. 1
figure 1

Patient with AD (top row) shows atrophy in medial temporal lobe and hippocampi in MRI (a), hypometabolism in temporal lobes in FDG-PET (b), and widespread cortical amyloid deposition in frontal, parietal, and temporal lobes in amyloid PET (c). Patient with nfvPPA (bottom row) demonstrates atrophy in lateral and anterior temporal lobes and frontal operculum on the left side in MRI (d), hypometabolism in left peri-insular region in FDG PET (e) with no evidence of amyloid deposition (f).

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The pattern of atrophy in different FTD syndromes are as follows: in bvFTD, the atrophy is mainly in the prefrontal cortex, anterior temporal lobes, and insula with involvement of striatum and thalamus [20]. There is a group of patients who meet the diagnostic criteria for bvFTD but have very slow disease course. They have normal MRI and PET and are classified as FTD phenocopy [8]. In semantic variant of PPA (svPPA), atrophy is asymmetric, usually more severe on the left, and involves the anterior and inferior temporal lobes. The MRI changes in svPPA precede the clinical symptoms. Patients can have remarkable atrophy in the temporal poles while they are still independent in daily activities [21]. In non-fluent variant of PPA (nfvPPA), atrophy is also left predominant and mostly seen in the inferior frontal lobe (mainly pars opercularis), dorsolateral prefrontal region, superior temporal gyrus, and insula. Also, atrophy can extend to caudate head bilaterally and putamen on the left [22] (Fig. 1).

To help the clinicians and radiologists in reporting cases with dementia, different visual scales have been developed to assess the pattern of atrophy and determine the degree of small vessel disease.

  1. 1-

    MTA (Scheltens) visual scale scores the degree of atrophy from 0 to 4 based on the maximum height of choroid fissure (CSF space above the hippocampus), width of the temporal horn (CSF space lateral to the hippocampus), and maximum height of hippocampal formation in T1W coronal image [23]. 0 means no change in the above measures while 4 means severe loss of height in hippocampal formation and widening of both choroid fissure and temporal horn.

  2. 2-

    Global cortical atrophy (GCA) (Pasquier) scale assesses general brain atrophy in 13 regions based on degree of sulcal dilatation with a score range from 0 (no atrophy) to 3 (knife-blade atrophy) [24]. Although GCA has more extensive coverage, it has less reliability because it includes regions susceptible to partial volume effect [25•].

  3. 3-

    White matter changes (Fazekas) scale is based on size, shape, and extension of small vessel changes (hyperintensity in T2/FLAIR or hypodensity in CT) in the white matter of both cerebral hemispheres. The scores are 0, no change; 1, punctuate focal lesion; 2, beginning of confluence of lesions; and 3, diffuse involvement of the entire region with or without U fiber involvement [26].

To optimize the utility of structural imaging in clinical setting, it is crucial to have a specific protocol for acquisition and a standard, structured reporting system. Having a standardized method becomes more important when the images are required to be assessed longitudinally or across different centers. In a recent paper by Imaging Cognitive Impairment Network, they suggested that standard radiological report on cases with dementia should include MTA, GCA, and white matter scores to improve the accuracy of diagnosis [27].

Functional imaging

18F-FDG PET and perfusion hexamethylpropyleneamine oxime (HMPAO) SPECT

18F-FDG PET provides information on the first stages of glucose metabolism and is a proxy of synaptic activity and neurodegeneration in dementia. HMPAO SPECT or perfusion SPECT measures cerebral blood flow, which represents an indirect estimate of metabolism.

In all current guidelines (Table 2) [16,17,18], both 18 F-FDG PET and perfusion SPECT are considered as the second tier of imaging biomarkers when the combination of clinical evaluation and structural imaging fails to secure the diagnosis. Most guidelines recommended perfusion SPECT as an alternative to FDG when PET is not available. It has been shown that HMPAO SPECT has less sensitivity and specificity [28]. In the USA, Medicare and Medicaid services have approved the utility of 18F-FDG PET in differentiating AD from other dementia (particularly FTD).

The main roles of 18F-FDG PET are to

  1. 1.

    Confirm the presence of neurodegeneration and differentiate dementia from normal aging or psychiatric illnesses mimicking degenerative brain disease. Overall sensitivity of FDG for diagnosis of AD from control is around 76% with the median specificity of 82% [29•].

  2. 2.

    Differentiate AD from other types of dementias. The pattern of hypometabolism can help to distinguish AD from FTD with 86% sensitivity and 97% specificity [30] and AD from dementia with Lewy bodies (DLB) with > 90% sensitivity and 70% specificity [31, 32]. These early studies have very small subject numbers and differ between specific regional measures used and are best used with close attention to clinical context of PET acquisition.

Hypometabolism in 18F-FDG PET, as a marker of neurodegeneration, precedes atrophy in structural imaging and cognitive decline in clinical examination [33, 34], although it has strong spatial correlation with MRI changes and its pattern is highly associated with clinical symptoms [34].

Nevertheless, neurodegeneration is a relatively late finding in the course of AD and 18F-FDG PET might still be within normal limits in preclinical or early MCI cases. Therefore, while absence of hypometabolism makes neurodegeneration less likely, it cannot exclude the early stages of dementia. Presence of hypometabolism, on the other hand, has predictive value in identifying individuals progressing from MCI to AD [35].

In typical AD, hypometabolism is seen in medial temporal lobe, parieto-temporal regions, precuneus, and posterior cingulate gyrus [36, 37] (Fig. 1). In atypical AD presentations, PCA is associated with hypometabolism in parieto-occipital lobes. lvPPA, on the other hand, is characterized by left temporoparietal junction metabolic deficit [38].

In bvFTD, maximum abnormality is seen in orbitofrontal, dorsolateral, and medial prefrontal cortex and anterior temporal poles [39, 40]. In svPPA, there is evidence of asymmetrical hypometabolism in temporal poles, more severe on the left, with extension to the medial, inferior, and lateral temporal lobes [7]. The prominent hypometabolic regions in nfvPPA are left inferior frontal and superior temporal regions [41] (Fig. 1).

Like structural imaging, the abovementioned syndrome-specific patterns of hypometabolism are derived from group differences. Therefore, the caveat in using them to make a diagnosis for an individual case is that there are overlaps between areas of abnormality across dementia syndromes and many cases might have mixed pathologies.

The presence or absence of hypometabolism in 18F-FDG PET images can be visually assessed by a highly skilled rater although studies from experienced centers have concluded that qualitative evaluation of FDG images can be ambiguous and difficult [42, 43]. To overcome this challenge and improve the diagnostic accuracy of FDG, PET images can be assessed quantitatively using standard uptake value ratio (SUVr) [44]. SUVr is a ratio of activity in each region of brain relative to a reference area where metabolism is unaffected or mildly affected. Examples of such areas include cerebellar cortex, vermis, whole cerebellum, and pons [45].

Amyloid PET

Deposition of extracellular amyloid β (Aβ) plaques as one of the main pathological hallmarks of AD appears well before any other changes in the course of disease [34]. In vivo imaging of amyloid in the last decade has revolutionized AD research. There are different PET ligands binding selectively with high affinity to fibrillar Aβ aggregates in vivo. 11C-Pittsburgh Compound B (11C-PiB) is the best characterized PET tracer, but its short half-life (20 min) has restricted its use to centers with an on-site cyclotron. Recently, several 18F-labeled amyloid derivatives have emerged to overcome the limitation of 11C-PiB. They include 18F-flutemetamol [46] (GE-067; Vizamyl™, GE Healthcare), the stilbene derivative 18F-florbetapir [47] (AV-45; AMYViD™, Eli Lilly), and the strylpyridine derivative 18F-florbetaben [48] (BAY-94-9172; Neuraceq™, Piramal).

These tracers have been approved by the US FDA “for PET imaging of the brain to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment being evaluated for AD and other causes of cognitive decline.”

The results of 18F-labeled tracers are comparable with 11C-PiB, although PiB is slightly superior in differentiating AD from control [49, 50]. They all show increased cortical binding in regions known to be affected by Aβ deposition such as frontal, parieto-temporal, and posterior cingulate cortices [51,52,53,54] (Fig. 1), and they have strong correlation with autopsy and postmortem findings [55,56,57,58]. Although non-specific retention in white matter is higher in 18F-labeled tracers, there is no evidence that it might affect the interpretation of the images significantly [49, 50, 59].

In comparison to FDG PET, amyloid imaging has higher accuracy in differentiating AD from healthy controls [42]. The sensitivity and specificity of amyloid PET—with either 11C- or 18F-labeled tracers—are above 85% [60, 61•]. Different studies have also claimed that the inter-rater reliability of visual reading is higher in amyloid imaging compared to FDG and it has higher agreement with quantitative classification. PiB PET can differentiate AD from FTD with more than 90% sensitivity [62].

Based on current imaging guidelines, amyloid PET is not part of routine imaging work-up in dementia. The European Federation of the Neurological Societies [18], the Amyloid Imaging Task Force [63, 64], and the recent Canadian Consensus Conference on the Use of Amyloid Imaging [65] all have similar recommendations on utility of amyloid imaging in clinical setting. Similar to FDG, amyloid PET should only be used in cases presenting with cognitive decline in whom the diagnosis is still uncertain despite comprehensive clinical assessment by a dementia expert and structural imaging. The clinical applications of amyloid PET according to different guidelines have been summarized in Table 2. Amyloid imaging is particularly useful in the following scenarios:

  1. 1-

    In AD cases with atypical or early onset presentation (age < 65) or when there is evidence of psychiatric illnesses or heterogeneous syndromes.

  2. 2-

    To differentiate AD pathology from FTD.

  3. 3-

    In MCI cases with progressive unexplained cognitive decline when confirming diagnosis can alter the management [18, 64, 65].

It should be noted that amyloid PET cannot distinguish clinical variants of AD pathology from each other or AD from DLB. It is also not useful in staging the severity of the disease [65]. As 10–30% of cognitively normal individuals can have positive amyloid PET [66], according to current recommendations, it is not appropriate to use amyloid PET on cognitively normal individuals based on family history or genetic predisposition such as APOE4 [64].

Early data from IDEAS (Imaging Dementia-Evidence for Amyloid Scanning) study of amyloid PET in US Medicare beneficiaries showed that amyloid PET can have a substantial impact on patient management in day-to-day practice [67]. There is also a growing body of evidence showing that the early diagnosis and intervention at preclinical stage of AD is paramount in tackling the disease. Therefore, the clinical utility of amyloid PET, as one of the earliest diagnostic biomarkers in AD, may change in the near future.

Amyloid burden can be assessed both visually and quantitatively using SUVr. Cerebellar gray matter or pons with low Aβ plaque density demonstrates the minimum binding in amyloid imaging, hence being used as reference regions for SUVr calculation [52]. Longitudinal studies on Alzheimer Disease Neuroimaging Initiative data have shown using subcortical white matter as reference might improve the accuracy of detecting cortical changes over time [68].

One of the main issues in performing amyloid PET on a wider population and at an early stage of the disease is interpretation of amyloid images. It is important to remember that positive amyloid PET alone does not confirm the diagnosis of AD or MCI. As mentioned above, 10–30% of normal individuals can have positive amyloid PET. The long-term prognosis of this group is still not completely clear. A meta-analysis on prevalence of amyloid PET positivity in dementia syndromes showed amyloid PET can be positive in 51% of cases with dementia with Lewy bodies, 38% in corticobasal syndrome, 30% in vascular dementia, and 12% in cases with FTD. As the authors have concluded, presence of Aβ in non-AD dementia syndromes could be either because of clinical misdiagnosis or secondary to concordance/mixed pathologies in many cases where the clinical manifestation is not driven by Aβ [69]. Moreover, although negative PET excludes the diagnosis of AD, it cannot exclude the diagnosis of non-amyloid-related dementia. Therefore, interpretation of images should only be done by a dementia expert and based on clinical evaluation, risk factors, and cognitive status.

Another sensitive issue with amyloid PET is disclosure of the result. It can be stressful for patients and might have a legal or social impact. The Canadian consensus on the use of amyloid imaging [65] has recommended using the disclosure methods developed by Harkins et al. [70]. Recommendations for communicating amyloid PET results to patients with MCI were recently formulated [71]. Before amyloid PET becomes available for wider clinical use, more studies are required on disclosure issues.

Tau PET

The presence of neurofibrillary tangles, phosphorylated tau protein aggregates, is another pathological hallmark of AD. Tau deposition occurs in a particular spatiotemporal pattern starting from transentorhinal/entorhinal cortex to hippocampus and then extending to the rest of temporal lobe and neocortical regions [72]. Tau deposition has a close association with cognitive decline [73], severity of dementia symptoms [74], and brain atrophy [75]. Recently, different tau selective PET tracers have been developed and used for human studies: 18F-THK523, 18F-THK5117, 18F-THK5105, 18F-THK5351, 18F-AV1451(T807), and 11C-PBB3 [76]. Despite promising results in initial studies, Tau PET is still some way from being qualified to be used in a clinical setting.

CSF

Cerebrospinal fluid (CSF) testing can be important in the diagnosis of dementia, first and foremost to rule out an infectious or inflammatory cause. CSF markers of the cardinal Alzheimer’s disease pathologies can also be measured and are helpful in determining if Alzheimer’s disease pathology is present. The core CSF biomarkers for AD are amyloid-b1–42 (Aβ1–42), total-tau (t-tau), and phospho-tau181 (p-tau) and are felt to correspond, respectively, to Aβ deposition in senile plaques, neuronal death, and hyperphosphorylation of tau in neurofibrillary tangles. Lower levels of Aβ1–42 and higher levels of t-tau and p-tau, and especially a high ratio of t-tau/Aβ1–42 or p-tau/Aβ1–42, are found in patients with AD compared to patients with FTD or normal controls, with a sensitivity and specificity reaching 85–90% [77•]. The AD CSF biomarkers are also helpful in identifying if AD is the underlying pathology in PPA. The Alzheimer’s Biomarkers Standardization Initiative (2014) reached a consensus that “lumbar puncture for AD CSF biomarker analysis be considered as a routine clinical test in patients with early-onset dementia, at the prodromal (MCI) stage or with atypical AD” [78]. However, specifically in MCI patients, the Cochrane Collaboration described “a state of uncertainty” and cautioned about the risk of misdiagnosis and overdiagnosis of AD when measuring CSF t-tau, p-tau, or p-tau/Aβ1–42 ratio in patients with MCI [79•].

An elevated level of CSF t-tau is seen in several conditions associated with rapid neuronal cell death including Creutzfeldt-Jakob disease and brain trauma. Thus, in the diagnosis of AD, it is important to use both the tau and Aβ1–42 markers, and not simply rely on elevated t-tau levels. An important practical note is that standard CSF collection tubes are polyethylene, but collection of CSF for measurement of Aβ1–42 must utilize polypropylene tubes because of the possibility of Aβ1–42 adhering to the walls of a polyethylene tube leading to underestimation of CSF Aβ1–42 [80].

While it is often appropriate to measure the AD CSF biomarkers in patients with clinical FTD, there are currently no FTD-specific CSF biomarkers. Overall, patients with FTD do not show the gross elevations in CSF t-tau or p-tau as seen in patients with AD. Several previous studies did not find a difference in CSF p-tau between patients with FTD with or without underlying tau pathology. However, a recent study comparing CSF p-tau levels to postmortem tau pathology on autopsy found that there was a positive association [81]. Specifically, patients with pathologic FTD with underlying tau pathology had higher CSF p-tau levels than patients with underlying TDP-43 pathology. In both groups, p-tau levels were significantly lower than in AD patients. Further studies will be needed to test this finding in other cohorts and to develop potential diagnostic cut points.

One CSF marker that appears promising for the diagnosis of FTD is neurofilament light chain (NfL), a major component of the axonal cytoskeleton and a putative marker of axonal injury. CSF levels of NfL are greatly elevated (2.5–11-fold) in all forms of FTLD, including bvFTD and PPA subtypes, when compared to normal controls, and correlate with disease severity [82]. NfL are also elevated, to a lesser extent, in AD and other neurodegenerative diseases. There is also a strong correlation between NfL levels in CSF and serum [83].

There are currently no blood or serum biomarkers available in clinical practice for the diagnosis of AD or FTD, but this is an area of great research activity. Potential candidates include more sensitive measures of amyloid-beta and tau, as well as novel biomarkers such as lipids, microRNAs, and immunologic markers [84].

Conclusion

Structural MRI is the most commonly used biomarker to aid in the diagnosis of AD and FTD. MRI often demonstrates atrophy in areas of the cortex evidently impaired based on history and cognitive testing, and in the prototypical areas of the brain affected by these diseases (usually symmetric medial temporal lobes proceeding to biparietal lobes in AD versus often asymmetric frontal or temporal lobes in FTD). However, there are certain circumstances in clinical practice wherein the pursuit of further biomarkers of spatial patterns of neurodegeneration (as in FDG PET or SPECT) or biomarkers of amyloid beta and tau (amyloid PET or CSF) will be helpful. These circumstances include (1) early-onset dementia, (2) atypical dementia not meeting classic clinical criteria, (3) cases with strong confounders by history (vascular dementia, depression, alcohol abuse) but with a suspicion for underlying contributing AD or FTD pathology, and (4) cases of MCI wherein patients are well informed and desiring to know if AD pathology is present. Published recommendations for appropriate use of biomarker testing, particularly amyloid PET and CSF testing for AD biomarkers, do not always agree. Furthermore, in many cases, insurers or national health plans may not cover biomarker testing, and out-of-pocket costs may be prohibitive. Being mindful of those limitations, it is appropriate to pursue biomarker testing if the patient understands the implications and ramifications, and if the clinician deems that performance of the biomarker test will affect diagnostic decisions or change management, whether by way of patient counseling, pursuit (or non-pursuit) of further diagnostic work-up, or guiding treatment (lifestyle modification, pharmacologic treatment, or referral to clinical trials).