Parkinsons Disease and Nonmotor Dysfunction (Current Clinical Neurology)

The first edition of Parkinson's Disease and Nonmotor Dysfunction was Current Clinical Neurology Depression in Parkinson's Disease: An Update. Benton.
Table of contents

Neuropathology and Neurochemistry of Nonmotor Symptoms in Parkinson's Disease

Olfactory bulb synucleinopathy has high specificity and sensitivity for Lewy body diseases, and it has been suggested that olfactory bulb biopsy might be considered to confirm diagnosis in PD [ 78 ], an indication not approved by others [ 79 ]. It may be hypothesized that as in other regions, olfactory alterations in PD are the result of more complicated settings resulting from several molecular deficits.

Although no direct information is as yet available in PD, recent studies have yielded substantial data about the molecular pathology of the olfactory bulb. Targets of oxidation in aged olfactory bulbs, as revealed by redox proteomics, are aldolase 1 and ferritin heavy chain [ 81 ]. The effects of aging on oxidative stress damage in the olfactory bulb have been further demonstrated in accelerated senescence-prone, short-lived SAMP mice when compared with accelerated senescence-resistant, longer lived SAMR strains [ 82 ].

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Therefore, aging in the olfactory bulb is associated with increased oxidative stress and oxidative damage. A different approach has brought about interesting results. A series of PD patients underwent [ 11 C]methylpiperidinyl propionate acetylcholinesterase brain PET emission tomography and olfactory testing with the University of Pennsylvania Smell Identification Test. Cholinergic denervation of the limbic archicortex was a more robust determinant of hyposmia than nigrostriatal dopaminergic denervation in subjects with moderately severe PD [ 83 ].

However, it is worth stressing that no apparent abnormalities in the cholinergic system appear to be present at stages 1 and 2 of Braak, and, therefore, cholinergic denervation of the limbic cortex is probably not the only factor accounting for olfactory disorder in early premotor stages of PD. Disorders of olfaction also occur in familial PD but they appear to be more benign in certain familial cases, linked with LRRK2 or parkin mutations, than in sporadic PD [ 84 , 85 ].

Early studies demonstrated the presence of LBs in the parasympathetic ganglia, sympathetic ganglia, and enteric nervous system in PD [ 86 , 87 ]. LBs are consistently found in the hypothalamus, sympathetic intermediodorsal nucleus of the thoracic cord and sympathetic ganglia and parasympathetic system dorsal vagal and sacral parasympathetic nuclei, and peripheral parasympathetic ganglia , and enteric plexus [ 88 — 90 ].

Regarding central medullary autonomic areas, the number of catecholaminergic and serotoninergic neurons is not significantly reduced in PD, although raphe neurons decline in number with disease progression [ 91 ]. Neuropathological studies in large cohorts of neurologically unimpaired aged individuals have shown that the autonomic nuclei of the spinal cord and the peripheral autonomic nervous system are affected early on by LB pathology [ 74 , 92 — 94 ]. The highest densities occurred in the spinal cord, paraspinal sympathetic ganglia, vagus nerve, gastrointestinal tract and endocrine organs.

Within the gastrointestinal tract, the lower esophagus and the submandibular gland had higher numbers of inclusions than the colon and rectum [ 96 ]. The cardiovascular autonomic system is also affected in PD, and alterations implicate both tyrosine hydroxylase-positive extrinsic and negative intrinsic nerves of the cardiac plexus [ 76 , 97 ]. Functional studies have also demonstrated cardiac involvement in PD. Importantly, decreased MIBG uptake precedes neuronal loss in the sympathetic ganglia [ — ]. Olfactory tests, polysomnographic studies and MIBG myocardial scintigraphy in combination may be used to discover early signatures of the disease [ ].

Interestingly, cardiac sympathetic denervation precedes nigrostriatal loss in individuals bearing the E46K mutation in SNCA [ ].

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These observations point to an association between synuclein deposits and impaired function in the autonomic nervous system. But this does not imply a causal relationship between these events. Several aspects are still elusive and require further study. Sleep disorders including sleep fragmentation, REM sleep behaviour disorders, and complex paroxysmal nocturnal motor behavioral disorders are common in PD [ — ], and they may precede by decades motor symptoms [ ].

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The neuropathological substrates are poorly understood although affected nuclei in the brain stem including the pedunculopontine nucleus probably play key roles [ ]. The ventral visual stream appears involved in visuoperceptive alterations associated with REM disorders [ ]. Finally, hypocretin orexin cell loss following an anterior to posterior gradient has been found in the hypothalamus of PD cases with disease progression [ , ].

This is not clearly accompanied by constant decrease in the expression levels of CSF orexin [ ]. Whether orexin correlates with sleep attacks and its action is mediated by dopamine receptors 3 needs validation [ ]. Changes in personality and moderate or mild cognitive debilitation are found in PD. Neuropsychiatric alterations and cognitive decline may occur at early stages of parkinsonism suggesting that they are an integral part of PD from the beginning of the disease in some patients. Characteristically, symptoms are often subtle at the beginning and difficult to detect without neuropsychological tests, although they become aggravated with progression of the disease.

Deficits mainly affect executive function including working memory and visuospatial capacity. These are often accompanied by anxiety and depression, and excessive daytime sleepiness probably related with sleep disturbances see [ , ], for review. Certain studies have shown an association between cortical LBs and cognitive impairment [ — ]. Yet other studies have not confirmed this assumption [ 57 , 58 , — ].

Moreover, associated AD pathology has been suggested as an important cofactor in the progression of cognitive impairment in PD [ 58 ]. Additional studies have not clarified a predictive role of LBs in the occurrence of cognitive deficits [ , ] although LB pathology correlates with visual hallucinations when present in the medial temporal lobe and visual areas [ , ].

Neuropathlogical studies in a large series have confirmed that staging of LB pathology is barely applicable to cognitive impairment and dementia. Only a percentage of cases showed a relationship between cortical LBs and cognitive impairment and dementia [ ]. Taken together, these observations strongly indicate that cortical Lewy bodies are not per se causative of dementia, but rather indicators of aggregates of pathological synuclein. Other factors are probably more responsible of altered cognitive function in PD. Therefore, abnormal aggregates at the synapses in greater numbers than large cytoplasmic and neuritic aggregates LBs and aberrant neurites, resp.

These are important independent observations showing that synaptic pathology occurs in the absence of LBs and that the most common alteration in the cerebral cortex in PD is pathology at the synapses rather than the presence of LBs. In other words, LBs per se have no direct impact on clinical symptoms but other more subtle abnormalities are causative of impaired cortical function. In addition to abnormal accumulation of altered proteins at the cortical synapses, a series of convergent approaches may help to increase understanding of the different factors leading to impaired cerebral function in PD.

Some of them relate to impaired dopaminergic, noradrenergic, cholinergic and serotoninergic innervation of the cerebral cortex; others, to intrinsic metabolic deficits. Cognitive and executive deficits have been related, in part, to reduced dopaminergic innervation in the nigrostriatal and mesocortical dopaminergic systems compromising directly and indirectly, via alteration of the basal ganglia, prefrontal cortical function [ — ].

However, altered cognitive performance is not clearly related with impaired dopaminergic innervations of the cerebral cortex at early stages of the disease. Along the same lines, attenuated dopamine release has been observed in the dorsal caudate but not in the medial prefrontal cortex in early PD patients [ ].

Yet nondopaminergic systems are known to be damaged in PD, including the monoaminergic cells of the locus ceruleus, serotoninergic neurons of the raphe and cholinergic neurons of the nucleus basalis of Meynert [ — ]. Langston JW, The parkinson's complex: Parkinsonism is just the tip of the iceberg, Ann Neurol, ; Mild cognitive impairment in Parkinson disease: Emre M, Dementia in Parkinson's disease: A community-based study, Arch Neurol, ; A case-control study, Neurology, ; Results from a pilot investigation, Parkinsonism Relat Disord, ; A randomized placebo-controlled study, Mov Disord, ; A follow-up study of untreated patients, Brain, ; Pt 6: Andersson KE, Treatment of overactive bladder: Simon and colleagues used single nucleotide polymorphisms in the SLC2A9 gene which explain a proportion of the genetically specified variability in serum urate to test whether these polymorphisms predicted rate of progression in early PD.

They demonstrated that SLC2A9 status was associated with elevated serum urate and was associated with slower disease progression. MR on the other hand operates more like a randomised controlled trial in which the exposure in this case a gene variant is randomly allocated at baseline conception along with known and unknown confounding factors.

Given the consistency of this relationship in the MR study with previous observational studies, therapeutic modulation of urate levels is a strong target for clinical trials. Increasing research activity in exploring the overlap between genes and the environment will further our understanding of the causal basis of disease. Recognition of the importance of non-motor features of PD has been building for several years. A number of studies have demonstrated the association of PD with earlier diagnoses such as depression, anxiety, constipation and erectile dysfunction.

The best characterised early non-motor features are idiopathic anosmia and RBD. Anosmia is relatively common in the ageing population and is non-specific, with only a proportion going on to develop neurodegenerative disease. PSG-confirmed RBD is rare in the general population, and the largest observational study amassed just over subjects despite international collaborative efforts. Preclinical PD—presence of neurodegenerative synucleinopathy without clinical symptoms this stage will be defined by disease biomarkers when available.

Clinical PD—diagnosis of PD has been made based on the presence of classical motor signs. The emergence of large longitudinal primary care datasets has allowed detailed exploration of the full range of early motor and non-motor symptoms that predate PD, while being free from the biases that many traditional observational studies have suffered from. Many of these devices demonstrate high sensitivity and specificity in differentiating patients with PD from controls, and are likely to see increasing use in clinical practice to guide decision-making.

Despite the indication that objective motor dysfunction occurs prior to diagnosis in PD, currently there are few examples of the application of remote or wearable devices in prediagnostic PD. A major foreseeable hurdle is ensuring that validation and regulatory approval for software and devices will keep abreast of rapid and continuous change in available technology. Radiotracer imaging with single photon emission computed tomography SPECT or positron emission tomography PET , and transcranial sonography TCS have repeatedly demonstrated the ability to differentiate patients with PD from healthy individuals with adequate sensitivity and specificity see table 1.

By contrast, TCS demonstrating hyperechogenicity of the substantia nigra SN appears to be a static rather than changing marker.

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High-field and novel sequences of MRI may also provide opportunities to address the challenge of imaging disease progression in the prediagnostic phase of PD. Correlations of MRI microstructural imaging abnormalities have been reported with postmortem findings and quantitative differences between patients with PD and healthy subjects in terms of iron deposition, loss of neuromelanin and alterations in nigrosome 1, in mainly single studies for examples see online supplementary material.

In addition to subtle structural abnormalities, application of functional MRI methods have shown differences in functional connectivity with the basal ganglia network, the default-mode network and the sensorimotor resting state network, between patients with PD and healthy controls, some of which are influenced by dopaminergic medication see online supplementary material for examples of studies. It is believed that cerebrospinal fluid CSF is most likely to show changes representative of disease occurring in the brain. Nonetheless, lumbar puncture is an invasive and costly procedure compared with blood draw, and is likely to remain most appropriate for use in clinical trials and in specific clinical practice settings, unless a high-performing biomarker can be identified.

The gut has been proposed as the site of initiation of PD pathology, but the burden of synucleinopathy correlates poorly with disease severity and the proximal more to distal less gradient in pathology appears at odds with this suggestion. Recently, interest has been stirred by demonstrable differences in the faecal microbiome of patients and controls.

Salivary glands may also be a peripheral source for demonstrating PD-related pathology but, like gut biopsies, the invasive nature and cost of deep tissue sampling or full colonoscopy currently make both undesirable.

Neurology - Topic 13 - Parkinson's disease female patient

A summary of tissue and fluid biomarkers is provided in table 2. Several studies table 3 have been initiated: As outlined above, some initiatives recruit individuals with a single strong risk factor such as carrier status for LRRK2 or GBA mutations, or idiopathic RBD or anosmia, in order that subjects may be followed prospectively, whereas other approaches employ large population-based cohorts or retrospective case—control methods to examine associations with PD and preceding diagnoses. From the former we learn more about the emergence of PD in specific risk cohorts, which, in turn, may prove to be appropriate for recruitment to clinical trials.

However, they are perhaps not representative of the spectrum of PD as a whole, and biomarkers developed in these groups must be replicated in sporadic PD cohorts before assuming that they are applicable to all. This, in turn, informs strategic combination of factors to try and delineate individuals at high risk while also capturing the full spectrum of PD. Although the magnitude of risk associated with individual risk factors and early non-motor features has been reported, the best combination of risk factors for predicting PD remains unknown. Baseline data from this cohort have been reported showing associations between selected prodromal markers and other early associated features of PD.

While not strictly looking at prediagnostic PD, the PPMI and PRoBaND studies will help define the role of clinical markers motor and non-motor in the early measurement of PD, and the identification of novel imaging and laboratory biomarkers, as well as giving insight into what might be apparent through back-extrapolation to the prediagnostic phase.

Clinical assessments, laboratory and imaging biomarker studies are being undertaken and early results are emerging.


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Risk scores were calculated based on a meta-analysis of the published literature. Using a priori odds of PD attributed to age, a Bayesian model of risk was constructed to yield combined risk estimates for each subject in the study. PREDICT-PD is the first study to try and combine large numbers of risk factors for PD and has the potential to screen a large, community-based population, and aims to facilitate recruitment into clinical trials in the future.

Unlike some of the other studies, it seeks to identify individuals spanning the full spectrum of PD, which makes this cohort highly applicable to occurrence of typical PD in clinical settings. These studies will help refine the determination of risk status and course of early disease progression see figure 3.

A schematic showing determinants of risk, the prediagnostic phase preclinical and prodromal phases and clinical phase of Parkinson's disease, along with the parallel application of risk and disease progression markers to measure disease activity across phases.

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There are additional hurdles that must be overcome before clinical trials recruiting subjects in this phase of disease can be planned: Prevention or delaying emergence of classical symptom onset is the ultimate aim, but PD is insidious, with its clinical manifestations emerging over months and years, making many clinical end points unsuitable and such studies difficult to fund for the duration required. A sensitive clinical marker of progression would be valuable in detecting subtle changes at this early phase, however, an imaging or laboratory marker that spanned the prediagnostic and early postdiagnostic phases may offer better sensitivity, specificity, reliability and precision overall see figure 3.

Clinical trials designed to show the disease-modifying effect of an agent may initially need to include homogenous samples or samples stratified for presentation and rate of progression in order to show an effect before trials in wider groups can be conducted; 3 other factors are continuity and applicability through the early stages of the disease. Longer-term observational studies that examine risk status could support registries through which subjects indicate their willingness to participate in future clinical trials and biomarker initiatives. Consenting eligible subjects could be offered inclusion into clinical trials with the benefit of extensive available pre-trial data, but issues of selection bias and generalisability of results must be considered; 4 Finally, there are ethical implications of treating at-risk populations.

For a repurposed drug, with previous data on safety and tolerance, the implications of undertaking clinical trials in those at-risk are perhaps less than for novel drugs with unknown safety profiles and potential toxicity. Justification for more invasive therapies could probably not be found without clear results in established PD. In addition, disclosure of risk status is likely to be a prerequisite for participation in clinical trials, but has the potential to bias recruitment and poses an ethical barrier in the absence of proven neuroprotective effects.

Ultimately, disclosure may be unavoidable in order to make an informed decision about trial participation. Significant progress has been made in the understanding and identification of subjects in the prediagnostic phase of PD and a number of initiatives are underway to further define these groups.

These studies may contain subjects that would be candidates for recruitment into clinical trials targeting neuroprotection within a few years. Parallel exploration of peripheral tissue, fluid and multimodal imaging is needed to identify differences between patients and controls across a range of markers. This will enable testing of drug therapies at a time when more neuronal tissue can potentially be preserved, and there is an absence of symptomatic effects of medication with the potential to confound.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author s and has not been edited for content. Contributors AJN conceived the topic and drafted the manuscript. AJL provided critical revision. AS conceived the topic and provided critical revision. Provenance and peer review Not commissioned; externally peer reviewed. You will be able to get a quick price and instant permission to reuse the content in many different ways.

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