Introduction

Parkinson's disease (PD) is the second most common worldwide neurodegenerative disease after Alzheimer's disease and is hallmarked by damage to the dopaminergic neurons of the substantia nigra and by alpha-synuclein containing inclusion bodies (Lewy pathology) in the surviving neurons [1]. It has a prevalence of 0.3% in the general population and 1–3% in the population over the age of 65 [1]. Nearly 66% of the patients are disabled within 5 years, and 80% are disabled after 10 years [2]. The numbers of PD are projected to double in the next two decades with the increase in the aging population [3], increasing also the socioeconomic burdens. There is at present no cure for this disorder [1], also because the etiology and pathogenesis are only partly understood. No currently available treatment slows the progression of the disease [4].

PD manifests and is usually diagnosed with cardinal motor symptoms (resting tremor, muscle rigidity, bradykinesia, postural and gait instability). However, in front of a possible diagnosis of PD, one of the most pressing questions general practitioners, clinicians and geriatricians face is the broad spectrum of non-motor symptoms (NMSs) [5], that present years before the motor onset of the disease [6], may be interrelated, and affect patients’ health and quality of life.

As represented in Fig. 1, among NMSs we recognize psychiatric symptoms, urinary and sexual disfunction, gastrointestinal problems, sensory impairment, circadian rhythm disorder, hyposmia, unintentional weight loss and osteosarcopenia, which is the alteration of bone mineral density and quality (osteoporosis) and the synchronic decrease in muscle mass and strength or function (sarcopenia) [5, 7]. Although NMSs in the prodromal phase of PD (pre-PD) were already highlighted by James Parkinson in 1817 [8], only in the late 1990s they began to gain interest because of their clinical relevance, as well as for their potential role in broadening the understanding of the pathophysiological mechanisms involved [6]. Up to now, research has focused primarily on psychiatric symptoms and gastrointestinal problems, which are the most common NMSs in pre-PD [9]; hyposmia, weight loss and osteosarcopenia are still frequently neglected.

Fig. 1
figure 1

Motor and non-motor symptoms in Parkinson’s disease

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Hyposmia, the a reduced olfactory function, occurs in approximately 90% of early-stage cases of PD [10], usually is bilateral and may precede the onset of the dopamine deficiency-related motor symptoms [5].

Unintentional weight loss is another common NMS in PD patients [11], and it appears to be a continuous process that starts several years before the diagnosis [12]. The prevalence of malnutrition in PD patients varies in the literature due to the use of different assessment tools. However, a systemic review showed that the prevalence of malnutrition ranged from 0 to 24% in PD patients, while 3–60% of PD patients were at risk of malnutrition [13].

Finally, PD patients seem to have a 160% higher risk of osteoporosis than healthy controls [14, 15], as well as a high prevalence of sarcopenia whose prevalence has been estimated around 15% in this group of patients [16, 17].

Unfortunately, patients with these symptoms usually are not initially seen by a neurologist, and by the time they are consulted, until ~ 80% of the dopaminergic neurons in the substantia nigra have died [10]. The early diagnosis of PD before motor symptoms is also difficult because of the lack of distinguishable laboratory markers to identify pre-PD [18].

Herein we decided to investigate in pre-PD the lesser known NMSs, i.e., hyposmia, weight loss and osteosarcopenia.

Methods

In this opinion paper we review the existing data obtained in this field, with the desire to focus on general practitioners, clinicians and geriatricians in their daily practice on the importance of hyposmia, weight loss and osteosarcopenia as NMSs in PD.

Relevant studies were searched through the electronic data bases MEDLINE, PubMed, Scopus and Google Scholar from inception to July 2019. The search strategy used for the search included the following keywords: “Parkinson’s disease”, “Parkinson disease”, “non-motor symptoms”, “olfactory function”, “hyposmia”, “gustatory function”, “weight loss”, “malnutrition” and “osteoporosis”, “sarcopenia”, “osteosarcopenia”, “bone mineral density”, skeletal-muscle integrity”, “older adults”. Epidemiological studies, registry studies, database studies, retrospective, prospective, and observational studies were included. No geographic and language restrictions were applied. Publications indexed as editorials, letters, case reports, commentaries, legal cases, newspaper articles, or patient education hand-outs were excluded.

Parkinson’s disease and olfactory dysfunction

Olfactory function: pathogenesis

In 1975 Ansari and Johnson [19] first reported olfactory dysfunction (OD) in PD patients, finding a significant correlation between rate of progression of the disease and olfactory acuity; nevertheless the mechanisms responsible for OD in PD are currently unknown [20, 21]. The above cited Braak’s hypothesis [22] found aggregated and phosphorilated alpha-synuclein not only in the enteric nervous system, but also in the olfactory bulbs, leading to the fact that OD in PD seemingly owes to changes in central olfactory processing [23]. Through the olfactory bulb, the first cranial nerve provides a direct pathway from the periphery to cholinergic and adrenergic systems implicated in the pathophysiology of PD [24]. Although several NMSs of PD have been correlated with decreased dopamine transporter uptake, OD and reduced dopamine transporter uptake have not been widely investigated [25]. There is a different pattern of olfactory processing in patients with PD compared to OD of other origin [20, 26]. The OD in PD correlates with decreased numbers of neurons in structures such as the locus coeruleus, the raphe nuclei and the nucleus basalis of Meynart [20]. More dopaminergic impairment of the bilateral caudate nuclei was found in OD in PD [25]. These neuroanatomical findings, together with evidence for involvement of the autonomic nervous system, suggest that deficits in cholinergic, noradrenergic and serotonergic function may contribute to the OD in PD [20]. The initial causative event may start in the rhinencephalon (olfactory brain) prior to damage in the basal ganglia [27]. Autopsy studies show early synuclein pathology in the olfactory tract and anterior olfactory nucleus in the early stages of PD [28]. A recent study supports the idea that the reduction of olfactory perception in PD differs markedly from the dysfunctions that we see in other hyposmic conditions: these findings confirm the previous studies pointing towards a more central deficit rather than a damage of the peripheral olfactory system [29]. Indeed biopsy samples of the olfactory epithelium in PD are normal [23].

Hyposmia/anosmia: a PD biomarker

The fact that the olfactory tract is involved early in PD indicates the frequent occurrence of hyposmia/anosmia years or decades before motor symptoms [28]. Hyposmia/anosmia is now known to be one of the most frequently occurring NMSs of PD [20, 30], making it a potentially useful biomarker for the disease [28], also because it is not stationary by the time the motor phase is entered, but continues to progress over time [5]. Therefore, it has been accepted as a supportive diagnostic [20] and a subtler prodromal "soft" sign [31], and may be considered not only a potential but a reliable marker of the disease [32]. In a recent meta-analysis [33] it has been found that hyposmia was associated with a 3.84-fold risk of developing PD (pooled relative risk: 3.84, 95% CI 2.12–6.95). Olfactory function might thus serve as a useful indicator to improve the diagnostic processes underlying the early detection of PD [33].

Olfactory testing: pros and cons in PD

The decline of cognitive function in early PD in older adults is more rapid in patients with hyposmia at diagnosis, compared to normosmic ones [34]. Given the poor self-assessment of OD in PD, and not knowing when olfactory loss starts or whether it is progressive during the prodromal phase, olfactory testing is mandatory in suspected cases to establish the diagnosis of hyposmia/anosmia [35]. To assess olfactory function, psychophysical tests [20, 26] have been carried out. The psychophysical tests are widely used in clinical settings and are simple and fast to perform also when olfaction is only mildly impaired or normal as in multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and essential tremor [36, 37]. The most widely used commercially available tests to objectively examine olfaction include the University of Pennsylvania smell identification test (UPSIT) and the Sniffin’ test [24]. There is evidence from numerous studies, using a psychophysical test, that OD is a characteristic and early feature of PD [32]. Thus, a simple smell test may contribute to identify patients at risk of accelerated decline in global cognition, verbal memory and processing speed within the first 7 years from PD diagnosis [34].

Unfortunately there are limits regarding the acceptance of OD as a reliable marker.

Individuals often overestimate their ability to smell, as demonstrated in a recent study comparing self-reported ability to smell in 124 non-demented PD patients and 154 older controls [38]. Hyposmia often remains undetected also because the decrease in OD is usually gradual [35]. Moreover, psychophysical tests remain a non-objective observation and the results rely on the active collaboration of the patient, which can be inconvenient in cases affected by cognitive impairment, common in older adults [29]. Furthermore, olfactory testing is not suitable as a single screening test to detect the pre-PD, because OD can occur in many other conditions and disorders [39].

In fact, an abundant number of causes may result in OD including allergic disorders of nasal and paranasal sinuses, head traumatic injury, medications, radiotherapy, surgical procedures, psychiatric diseases, intracranial tumours, metabolic disorders, endocrine disorders, infections and intracranial vascular disorders [20]. Also age-related olfactory changes, due to reduced mucus secretion, hormonal changes, changes in epithelial thickness, reduced neuroregeneration in olfactory receptor cells, can result in reduced capacity of odour identification and discrimination [40, 41].

Nevertheless, olfactory testing could be useful at least in differential diagnosis as OD occurs to a lesser extent or is absent in disorders such as multiple system atrophy, corticobasal degeneration and progressive supranuclear palsy [20].

Therefore, the OD as a reliable prodromal biomarker in PD is still an open-ended question limiting its specificity for diagnosis of prodromal neurodegeneration in PD [24].

Gustatory function: PD biomarker, yes or no?

Ageusia is the loss of sense of taste, hypogeusia is the decrease in taste sensitivity, while dysgeusia is the distortion of the sense of taste. It is now evident that taste can be affected in PD although much less frequently than smell [42]. Thus ageusia, although present, is an underappreciated but likely important NMS of PD [28]. Ageusia is rare, while dysgeusia is common [35]. The available data are not consistent so that the incidence and the pathophysiology of taste function in PD remain so far unclear [42]. Gustatory disorders increase with advancing age [40, 41]. However, a gustatory deficit should be listed among the possible NMSs of PD, even if the presence of a specific pattern of loss in both olfaction and gustation in PD has not yet been confirmed [28].

Parkinson’s disease and weight loss

Weight loss is one of the common NMSs of PD [12] and is associated with poorer clinical outcomes and rapid disease progression. In fact, it has been associated with malnutrition [41, 43], risk of falls and fractures [44,45,46], infections [47] and worsening quality of life [48]. In addition, weight loss and malnutrition complicate the course of PD inducing cognitive decline [49], orthostatic hypotension [50] and dyskinesia.

Approximately half of PD patients experience unintentional weight loss during the course of their disease [12, 51], but this process seems to begin several years before PD diagnosis and may be more pronounced in patients with greater disease severity [12].

As a matter of fact, weight loss is a consequence of an imbalance between energy intake and energy expenditure. Although the causes of weight loss in PD have not been so far identified, potential contributors may include metabolic disregulation, reduction in food intake or increase in energy expenditure.

In early PD stages, basal metabolism seems to be modified as a direct consequence of brain damage [51]. A recent study has demonstrated longitudinal associations of weight loss with nigrostriatal dopaminergic degeneration in PD [52], and post-mortem investigations of PD have described a neuronal loss in the hypothalamus which is most closely involved with metabolism (balance between energy intake and expenditure) [53]. In addition, studies report in both PS and weight loss lower levels of leptin and GH-relin, which play an important role in metabolism and appetite regulation [54, 55].

Energy intake could be decreased also by gastrointestinal symptoms, as constipation, dysphagia and delayed gastric emptying [56]. All these symptoms may precede the onset of motor symptoms in PD by many years. Constipation may result in bloating, abdominal discomfort, hard stool and straining [57]. Dysphagia can limit both solid and liquid intake [58], and delayed gastric emptying may give rise to nausea, vomiting, early satiety, excessive fullness, bloating and abdominal discomfort [56].

Also hyposmia can play a role in reduced food intake, as demonstrated by Roods et al. who found a positive linear correlation between olfactory function and BMI in a recent pilot study [59]. Another factor that could affect food intake by reducing appetite in patients with PD is depression, which is the most common mood disorder in patients with PD, both in the earlier and in the later stages [60].

Finally, energy intake but also energy expenditure in PD may also be compromised by the onset of motor symptoms as resting tremor, muscle rigidity and levodopa-related dyskinesias.

Parkinson’s disease and osteosarcopenia

Osteoporosis in PD has not been widely studied, as shown by the small number of reports in the literature [46]. The Global Longitudinal Study of Osteoporosis in Women found that PD is the strongest single contributor to fracture risk compared with other studied factors [61]. As a confirmation of that, PD patients have been reported to have a lower BMD than age-matched controls [62, 63]. Osteoporosis in PD patients may be related with aging, polipharmacy, vitamin D deficiency, low body weight and low level of physical activity [62, 64,65,66].

Osteoporosis is an important issue to consider in facing patients with PD since that they have also an increased risk of falls compared with age-matched healthy subjects [65], due to various factors, including gait impairment and postural instability [67].

As well as osteoporosis, also sarcopenia has received scant attention in PD. Sarcopenia and PD are both common age-related syndromes so that the probability of the co-occurrence of these syndromes within one individual is high. Sarcopenia is common in PD, being diagnosed in 1 every 5 patients [68]. The link between early PD and sarcopenia could be the reduced nutritional intake (especially reduced protein intake) and malnutrition [69] due to the above mentioned factors, but also inflammation seems to play an important role especially in the earlier stages of the disease. Elevated levels of circulating inflammatory cytokines, which have been associated with the loss of muscle mass and poor physical performance, are detectable in patients in the early stages of both PD and sarcopenia [70, 71]. This fact reflects in reduced numbers of motor neurons in PD patients compared to healthy controls [72, 73].

General comments and recommendations

In the light of the topics discussed above, we can make the general following comments that can be limited by the fact that this paper is a brief revision of the literature and not a systematic review.

Until relatively recently, PD has primarily been considered only a motor disorder, with its dominant clinical motor symptoms the result of dopaminergic neuron pathways. The recognition that NMSs related to non-dopaminergic pathways may develop before motor symptoms, is currently leading to their assessment as possible “wake-up calls” of the disease, also because, unfortunately to date, no confirmed biomarkers can be applied clinically for the diagnosis in pre-PD. Obviously, these potential biomarkers need imaging and biochemical parameters, but if they are taken in consideration by general practitioners, clinicians and geriatricians, the onset of motor symptoms may be delayed and the quality of life may improve. Thus although there are many non-ended questions in understanding the pathophysiology of PD, identifying the NMSs may be very helpful, and among them hyposmia, weight loss and osteosarcopenia may play an important role in solving the limitations in the diagnosis of PD. As reported in Fig. 2, a multidisciplinary and multidimensional assessment could be useful to accelerate the diagnosis and treatment of PD, thus reflecting in an improvement in patient quality of life and delaying disability and mortality.

Fig. 2
figure 2

Possible pathway for early detection of Parkinson’s disease focusing not only on motor symptoms but also on non motor symptoms. PD Parkinson’s disease, BMI body mass index, MNA mini-nutritional assessment, DXA dual energy X-rays absorptiometry, BIA bioelectrical impedance analysis, NMSs non-motor symptoms

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Weight loss and malnutrition are conditions accompanied with more susceptibility to unfavourable outcomes in PD. Nevertheless there is scarce data related to weight loss and malnutrition in pre-PD patients. The Mini-Nutritional Assessment (MNA), a test developed to determine the risk of malnutrition in older people [74], is recommended in pre-PD. Any macro-micronutrient deficiencies should be taken into account and nutritional assessments should be performed routinely. Dietary patterns with a high intake of fruit, vegetables, legumes, whole grains, nuts, fish and poultry and a low intake of saturated fat and a moderate intake of alcohol such as the Mediterranean Diet, may protect against weight loss and malnutrition in pre-PD. Appropriate screening and assessment of weight loss and malnutrition in pre-PD may be especially important for early interventions and improved outcomes.

Patients with PD are prone to a higher risk of osteoporosis and sarcopenia but no sufficient data have been obtained on the relation between pre-PD and osteosarcopenia also because the new term, that is the coexistence of osteoporosis and sarcopenia in the same individual, has recently be found [7]. Sedentariety, metabolism dysfunction, weight loss and malnutrition are common factors that contribute to the onset of osteoporosis and sarcopenia in patients at risk of PD. Diagnosis of osteoporosis may be performed considering the history of previous low-trauma fractures (hip, spine, proximal humerus, pelvis) or using dual-energy X-ray absorptiometry (DXA) [75]. Another very useful instrument to predict fracture risk is FRAX, a World Health Organization-sponsored tool that combines BMD at the femoral neck with a group of well-validated and weighted clinical risk factors for major osteoporotic fractures [76].

The evaluation of sarcopenia, as defined by the European Working Group on Sarcopenia in Older People (EWGSOP) [77], requires objective measurements of muscle mass, muscle strength and physical performance. In patients with pre-PD, skeletal muscle mass can be measured using DXA or estimated using bioelectrical impedance analysis (BIA)-derived equations [78], muscle strength can be assessed by handgrip strength and physical performance by means of gait speed [77].

If osteoporosis is diagnosed, therapeutic interventions such as bisphosphonates, vitamin D and calcium should be initiated. With regard to Vitamin D, serum concentrations of 25 (OH) D near 100 nmol/L appear to be associated with a greater benefit for musculoskeletal integrity in older adults [79]. Moreover, administering protein supplementation in diet to improve muscle functions and prevent/delay sarcopenia and practicing resistance exercises, should be recommended in pre-PD.

Conclusions

At this point we can conclude that PD may be considered a complex systemic disease characterized by the occurrence of a variety of NMSs in pre-PD, not only the well-known GI symptoms, but also hyposmia, weight loss and osteosarcopenia that can precede the onset of the typical motor symptoms.

To date, no guidelines exist for screening, assessment and management of NMSs in pre-PD. Indeed it is so far unknown when the disease starts and where the neuropathological process develops. Nevertheless, targeting hyposmia, weight loss and osteosarcopenia may warn clinicians about a potential risk of PD, allowing an early diagnosis. Waiting until the motor symptoms develop and the patient is finally visited by the neurologist may be too late, considering the catastrophic prognosis of the disease. Moreover, a better understanding of NMSs, likely in the context of others, could make it possible to approach and optimise PD treatment, thereby enhancing patient’s welfare.

Future longitudinal studies in pre-PD are necessary to understand the pathogenesis of the NMSs; in particular they may clarify the influence of PD on body weight and osteosarcopenia which increase the risk of malnutrition with disease progression.