Non-motor Features Of Parkinson's Disease Research Articles

Olfactory dysfunction in Parkinson disease

Olfactory dysfunction is among the earliest nonmotor features of Parkinson disease (PD). Such dysfunction is present in approximately 90% of early-stage PD cases and can precede the onset of motor symptoms by years. The mechanisms responsible for olfactory dysfunction are currently unknown. As equivalent deficits are observed in Alzheimer disease, Down syndrome, and the Parkinson-dementia complex of Guam, a common pathological substrate may be involved. Given that olfactory loss occurs to a lesser extent or is absent in disorders such as multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy, olfactory testing can be useful in differential diagnosis. The olfactory dysfunction in PD and a number of related diseases with smell loss correlates with decreased numbers of neurons in structures such as the locus coeruleus, the raphe nuclei, and the nucleus basalis of Meynart. These neuroanatomical findings, together with evidence for involvement of the autonomic nervous system in numerous PD-related symptoms, suggest that deficits in cholinergic, noradrenergic and serotonergic function may contribute to the olfactory loss. This Review discusses the current understanding of olfactory dysfunction in PD, including factors that may be related to its cause.

Functional Neuroimaging in Parkinson's Disease

The use of functional imaging in neurodegenerative diseases has increased in recent years, with applications in research into the underlying pathophysiology, aiding in diagnosis, or evaluating new treatments. In Parkinson's disease (PD), these imaging methods have expanded our understanding of the disease beyond dopaminergic deficits. Moreover, functional imaging methods have described alterations in functional networks relating not only to the motor symptoms, but also to many nonmotor features of PD, such as cognitive dysfunction. From a clinical viewpoint, functional imaging methods can assist in monitoring disease progression, such as in the context of clinical trials, and holds the potential to aid in early diagnosis of PD and differentiation from other parkinsonian disorders.

Diurnal Secretion Profiles of Growth Hormone, Thyrotrophin and Prolactin in Parkinson’s Disease

Recently, a massive loss of both hypocretin and melanin-concentrating hormone (MCH) neurones was found in the hypothalamus of Parkinson's disease (PD) patients. Because both hypocretin and MCH play a key role in the regulation of sleep, energy homeostasis and autonomic function, partly by modulation of the somatotrophic, thyrotrophic and lactotrophic axes, neuroendocrine dysregulation may contribute to some of the non-motor features of PD. In eight de novo, medication-free PD patients and eight age-, sex- and body mass index-matched controls, we measured serum levels of growth hormone (GH), thyroid-stimulating hormone (TSH) and prolactin every 10 min for 24 h. Auto-deconvolution, cosinor and approximate entropy analysis were applied to quantify GH, TSH and prolactin secretion rates, diurnal rhythmicity, as well as regularity of hormone release. Sleep was polygraphically-recorded throughout the night. Total 24-h secretion of GH (191 ± 31 versus 130 ± 39 mU/l/24 h), TSH (38 ± 9 versus 36 ± 2 mU/l/24 h) and prolactin (102 ± 14 versus 116 ± 17 μg/l/24 h), as well as their diurnal rhythmicity and regularity of release, were not significantly different between PD patients and controls (all P ≥ 0.12). Fasting levels of insulin-like growth factor-1 were also unaltered in PD patients. However, free thyroxine (T(4) ) levels were significantly higher in PD patients compared to controls (16.19 ± 0.80 versus 13.88 ± 0.40 pmol/l; P = 0.031). In PD patients, prolactin levels were related to disease duration (r = 0.76, P = 0.028), whereas both GH (r = -0.91, P = 0.002) and free T(4) (r = -0.71, P = 0.050) levels correlated inversely with body fat content. Apart from a mild increase in free T(4) levels, we found no indications for altered somatotrophic, thyrotrophic and lactotrophic axes activity in early-stage PD patients.

Synuclein deposition and non-motor symptoms in Parkinson disease

Parkinson disease (PD) is a multisystem neurodegenerative disorder clinically characterized by motor and non-motor (NM) symptoms. The causes of NM symptoms in PD, many of which antedating motor dysfunction, are multifocal and unlikely explained by single lesions. They include olfactory, autonomic, sensory, skin, sleep, visual, neuropsychiatric, and other manifestations. Most NM features in PD are related to α-synuclein pathology which, in addition to the dopaminergic striatonigral system, involves non-nigral brainstem nuclei, sympathetic, parasympathetic, enteric and pelvic plexuses, cardiac systems, submandibular gland, adrenal medulla, skin, retina, and other visceral organs. This suggests a topographical and chronological spread of lesions, particularly in the prodromal stages of the disease, which, however, awaits further confirmation. A few animal models are available that recapitulate NM symptoms in human PD, but their validity is under discussion. More studies are warranted to refine the exact correlations between presymptomatic and late-developing NM features of PD and α-synuclein pathology as a basis for more effective preventive and therapeutic options of this devastating disease.

Tai Chi Training And Non-motor Features Of Parkinson's Disease

A substantial number of individuals with Parkinson's disease (PD) experience accelerated cognitive decline and postural instability leading to reduced balance confidence and quality of life. To date few treatments have proven efficacious to ameliorate these deficits. Tai Chi interventions are known to improve postural control, balance confidence and executive function in older adult populations. PURPOSE: To evaluate the ability of Tai Chi to improve cognitive function, balance confidence and quality of life in persons with PD. METHODS: Twenty-four individuals with idiopathic PD were randomized to either a Tai Chi intervention group or a noncontact control in a 2:1 ratio. The Tai Chi group (n=16) participated in 48 1-hour long training sessions, whereas the control group (n=8) had two testing sessions 16 weeks apart without interposed training. Indices of cognitive function measured included: visual conceptual and visuomotor tracking (Trails A and B), directed attention (Stroop Color Word), and working memory (digits backwards). Balance confidence was measured via the Tinetti Scale and quality of life was measured by the PD-specific PDQ-39. RESULTS: Tai Chi training led to enhanced performance on all indices of cognitive performance: Trails A (4 sec); Trails B (20 sec); Stroop (5 words); digits backward (1 digit), whereas performance of the controls did not change or worsened. The control group experienced reduced quality of life as evidenced by increases in the PDQ-39 total score (9pts), as well as PDQ-39 dimensions: Activities of Daily Living (ADL, 4pts), Emotional Well Being (11pts), and Communication (11pts). Tai Chi significantly improved ADL related quality of life (5pts). Lastly, individuals who underwent Tai Chi training also exhibited important increases (6pts) in self-reported balance confidence whereas the control exhibited a 6 pt worsening. CONCLUSIONS: Tai Chi appears to be an appropriate and effective intervention for improving non-motor features of PD.

Clinical subtypes of Parkinson's disease

The clinical heterogeneity of Parkinson's disease (PD) may point at the existence of subtypes. Because subtypes likely reflect distinct underlying etiologies, their identification may facilitate future genetic and pharmacotherapeutic studies. Aim of this study was to identify subtypes by a data-driven approach applied to a broad spectrum of motor and nonmotor features of PD. Data of motor and nonmotor PD symptoms were collected in 802 patients in two different European prevalent cohorts. A model-based cluster analysis was conducted on baseline data of 344 patients of a Dutch cohort (PROPARK). Reproducibility of these results was tested in data of the second annual assessment of the same cohort and validated in an independent Spanish cohort (ELEP) of 357 patients. The subtypes were subsequently characterized on clinical and demographic variables. Four similar PD subtypes were identified in two different populations and are largely characterized by differences in the severity of nondopaminergic features and motor complications: Subtype 1 was mildly affected in all domains, Subtype 2 was predominantly characterized by severe motor complications, Subtype 3 was affected mainly on nondopaminergic domains without prominent motor complications, while Subtype 4 was severely affected on all domains. The subtypes had largely similar mean disease durations (nonsignificant differences between three clusters) but showed considerable differences with respect to their association with demographic and clinical variables. In prevalent disease, PD subtypes are largely characterized by the severity of nondopaminergic features and motor complications and likely reflect complex interactions between disease mechanisms, treatment, aging, and gender.

The impact of left prefrontal repetitive transcranial magnetic stimulation on depression in Parkinson's disease: A randomized, double‐blind, placebo‐controlled study

Based on several open-label and case studies, repetitive transcranial magnetic stimulation (rTMS) seems to have an antidepressive effect on patients with Parkinson's disease (PD). However, this hypothesis requires further confirmation. We conducted a randomized, double-blind placebo-controlled study to evaluate the effect of rTMS over the left dorsolateral prefrontal cortex (DLPFC) on depression and various motor and nonmotor features of PD. Twenty-two PD patients with mild or moderate depressive episodes were assigned into two groups, one receiving real-rTMS (90% of resting motor threshold, 5 Hz, 600 pulses-a-day for 10 days) over the left DLPFC, and another group receiving sham-rTMS. An investigator blinded to the treatment performed three video-taped examinations on each patient: before stimulation (baseline), 1 day (short term), and 30 days after treatment session ended (long-term effect). Mini-Mental State Examination, Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr, Epworth Sleepiness, Visual Analog and Montgomery-Asberg Depression Rating Scales (MADRS), Beck Depression Inventory (BDI), and Trail making and Stroop tests were applied. In the actively treated group, not only depression rating scales showed significant improvement 30 days after treatment ended (BDI by 44.4% and MADRS by 26.1%), but also the accuracy of Stroop test (by 16%). We could also demonstrate an insignificant improvement in UPDRS-III by 7.5 points (31.9%, P = 0.06). In the sham-treated group none of the examined tests and scales improved significantly after sham stimulation. Our study demonstrated the beneficial effect of the left DLPFC rTMS on depression in PD lasting at least 30 days after treatment. However, this result should be confirmed in patients with severe depression by further clinical trials.

New small molecules for the treatment of Parkinson's disease

Importance of the field: Parkinson's disease (PD) is characterized by a slowly ongoing neuronal death, which affects neurotransmitter metabolism and causes a wide variety of motor and non-motor features. Until now, therapy approaches have predominantly focused on motor behavior associated with dopamine substitution.Areas covered in this review: This review aims to discuss putative reasons for recent failures of investigated treatment approaches, and to introduce currently tested and future compounds.What the reader will gain: We will describe how development programs of novel molecules now additionally consider non-motor features of PD as promising targets in order to obtain regulatory approval. Regulatory authorities increasingly exert influence on trial designs, demanding therapeutic effects that are not always clinically feasible given the variety of manifestations of the disease entity known as PD.Take home message: In the past, research pitfalls have resulted in the failure of promising new compounds. Among the many reasons for this are massive placebo responses; the participation of too many investigators, with consequent wide variations of efficacy assessments; and a misconception of preclinical drug development, with models of PD that do not mimic its clinical nature. A few compounds are now being tested that have modes of action indirectly modulating the dopamine system; however, critical analysis of the preclinical and clinical research concept and drug approval is warranted to prevent further frustration in this field.

The Relationship Between Self-Perception of Ability and Actual Ability in Parkinsonian Patients Performing Motor Tasks

In Brief Despite an increasing awareness of the nonmotor features of Parkinson disease (PD), it remains common for disability to be measured primarily in terms of motor impairment in these patients. The effect of dopamine on mood and emotion in PD is well known, but the extent to which the patient's perception of his or her ability to carry out motor tasks is a true reflection of their actual ability has not been studied. To investigate this important aspect of PD, we assessed the ability to carry out timed motor tasks during a levodopa challenge test in 36 PD patients and used visual analogue scales (VASs) to measure self-perception of "on-off" state and of physical ability. We also recorded aspects of mood on the VAS to see whether these were relevant in relation to the patients' perception. The levodopa challenge test involves assessing patients in both an "off medication" and "on medication" state and so allowed us to observe the patients throughout the range of states of PD that they may experience during the day. Most patients' perception of their motor ability fairly accurately reflected their actual ability on the timed motor tasks throughout the levodopa dose cycle during the levodopa challenge test; however, 5 patients were disproportionately pessimistic about their ability when in the "off" medication state. These patients recorded worse scores on the VAS for aspects of mood and were also taking their PD medication doses more frequently than were the other patients. A better understanding of the patients' perspective of their disability could lead to improved care for PD patients in general and also has implications for our management of patients following surgical procedures, such as deep brain stimulation, that predominantly improve motor symptoms. The nonmotor features of Parkinson disease (PD) are increasingly being identified as a contributor to the level of disability experienced by individuals with PD. The authors examine patients' disproportional perception of the disability in comparison to their observed motor function.

O.014 Neuropathology of non-motor features of Parkinson disease

O.014 Neuropathology of non-motor features of Parkinson disease

Neuropathology of non-motor features of Parkinson disease

Non-motor manifestations of Parkinson disease (PD) are common and some may actually antedate motor dysfunction. Extrapyramidal signs in PD are tightly linked to striatonigral dopaminergic denervation associated with neuronal loss and Lewy bodies in the residual neurons of the substantia nigra. Lewy bodies composed of abnormal alpha-synuclein are the histologic hallmark of PD, and their presence beyond midbrain dopaminergic neurons is considered to be the pathologic substrate of many, if not all, of the non-motor manifestations of PD. We review the pathologic correlates of autonomic dysfunction (cardiac and gastrointestinal), hyposmia, depression, rapid eye movement behavior disorder and dementia in PD For each non-motor clinical feature there is strong evidence to suggest a role for alpha-synuclein pathology, lending further support for the notion that PD is a multisystem alpha-synucleinopathy.

Non-motor features of Parkinson's disease: depression and dementia

Parkinson's disease (PD) is the second most common neurodegenerative disease and primarily considered as a movement disorder defined by the presence of motor symptoms, such as bradykinesia, tremor and rigidity. However, it is nowadays widely recognized that in addition there is impairment of cognitive function, mood and the autonomic nervous system in a high percentage of PD patients, which is sometimes even more harming quality of life. These symptoms not only occur during the course of the disease but may even precede the onset of motor symptoms. Typical examples of non-motor features of PD are depression, constipation, REM sleep behaviour disorder, and hyposmia.

A longitudinal program for biomarker development in Parkinson's disease: A feasibility study

Long-term follow up is necessary to understand the natural history of treated Parkinson's disease (PD). The Longitudinal and Biomarker Study in PD (LABS-PD) is an observational study designed to prospectively measure the evolution of motor and non-motor features of PD and sample promising biomarkers from early to late stage illness. LABS-PD is organized on the premise that cohorts from completed clinical trials can be re-recruited for long-term follow up. LABS-PD will eventually contain multiple cohorts, but to test the feasibility of the strategy, we examined enrollment and biomarker sampling in the initial cohorts. The first PD cohort (PostCEPT) comes from the de novo clinical trial of a mixed lineage kinase inhibitor (PRECEPT). We assessed the recruitment from PRECEPT to PostCEPT, the ability to link data from the two studies, and sample collection for a variety of biomarkers. A total of 537 of 709 eligible PRECEPT subjects (76%) enrolled in PostCEPT; 509 (95%) had repeat dopamine transporter imaging. PRECEPT clinical and imaging data were successfully linked to PostCEPT, to provide 3 to 4 year follow-up. A biomarker sub-study enrolled over 100 PD cases from PostCEPT and 100 controls to measure olfaction and blood markers of gene expression, alpha-synuclein, and proteomic profiles. We were also successful in linking clinical and biomarker data to DNA samples that have been collected in the publicly accessible Coriell repository. The PostCEPT cohort and associated studies strongly support the feasibility of the LABS-PD approach of retaining and repurposing clinical trial cohorts to collect longitudinal clinical and biomarker data.

Comparative responsiveness of Parkinson's disease scales to change over time

The objective of the study is to examine the comparative responsiveness of outcome measures to assess progression over time in Parkinson's disease (PD). One hundred twenty-eight patients participating in a clinic-based naturalistic study of PD were assessed with the Hoehn and Yahr, UPDRS, MMSE, PDQ-39, PDQL, EQ-5D, and BDI scales at baseline and at 1 year. In addition, 82 patients in a community-based study of patients with PD who had completed self-rated Schwab and England, PDQ-39, EQ-5D, and BDI scales at baseline, were sent the same questionnaires at 1 and 4 years. Responsiveness was assessed using t-tests, standardised effect size, and standardised response mean. In both samples, the Hr-QoL measures were less responsive to change over time than the impairment and disability scales (Hoehn and Yahr, UPDRS, Schwab and England scales). In addition, in the clinic-based sample, Hoehn and Yahr and UPDRS ADL scale ("on") were more responsive to progression over time than UPDRS motor part and ADL part ("off"). Hr-QoL measures are less responsive to change over time than measures of impairment and disability. Although this suggests that these measures are less accurate in detecting subtle changes, it may also indicate that the multifactorial subjective assessment of Hr-QoL adapts to changes over time. Global assessment of overall impairment and disability (which incorporates motor and nonmotor features of PD), however, appeared relatively responsive to change over time in patients in a naturalistic setting.

Pain as a Nonmotor Symptom of Parkinson Disease

To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls. Case-control study. Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects. The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy. These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.

Characterizing clinical phenotypes

Cognitive/behavioral neurologists increasingly recognize that demented patients with features of parkinsonism often have dementia with Lewy bodies (DLB), whereas movement disorder specialists identify cognitive impairment and dementia as a common nonmotor feature of Parkinson disease (PD). The article by Ballard et al.1 in this issue of Neurology examines the neurochemical and pathologic changes in these two Lewy body–related disorders, with an eye toward better understanding of their biology as well as the relationship between these two clinical entities. Patients with both PD dementia (PDD) and DLB have Lewy body pathology in the nucleus basalis of Meynert, leading to cortical cholinergic deficits, which are greater than those seen in patients with Alzheimer disease (AD).2,3 These data suggest that patients with Lewy body–related dementias have the potential to benefit more from therapy with cholinesterase inhibitors than patients with AD. The study by Ballard et al. adds to what we know about cholinergic losses in PDD and DLB by examining a range of patients with earlier, later, and late development …

Testosterone Therapy in Men With Parkinson Disease

Testosterone deficiency has been reported in patients with Parkinson disease (PD), Alzheimer disease, and Huntington disease. It is not known whether testosterone therapy (TT) in men with borderline hypogonadism and neurodegenerative diseases will be of substantial benefit. Previously, we reported that testosterone deficiency is more common in patients with PD compared with age-matched control subjects, and we also reported in 2 small open-label studies that some nonmotor symptoms responded favorably to TT. To define the effects of TT on nonmotor and motor symptoms in men with PD and probable testosterone deficiency. Double-masked, placebo-controlled, parallel-group, single-center trial. Two experimental groups: patients with PD who were receiving either TT or placebo. Participants received either the study drug by intramuscular injection (200 mg/mL of testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium chloride solution injections). In patients in each group, the testosterone serum concentration was obtained at each study visit. During 2 study visits, testosterone levels were blindly evaluated and the intramuscular testosterone dose was increased by 200 mg/mL if the free testosterone value failed to double from the baseline value. The primary outcome variable was the St Louis Testosterone Deficiency Questionnaire, and secondary outcome measures included measures of mood, cognition, fatigue, motor function, and frequency of adverse events. At the end of the double-blind phase, all patients were offered open-label TT and were followed up after 3 and 6 months. Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7 years), receiving an average total levodopa equivalent dose of 734 mg/d, who had a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally well tolerated. More subjects in the TT group experienced lower extremity edema (40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels were elevated from baseline. The improvement in the TT group compared with the placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not statistically significant. In addition, there were no significant differences in motor and nonmotor features of PD between the 2 groups, although a few subscales showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but sustained improvement in subjects in the TT group who continued to receive treatment (n = 6) compared with subjects in the placebo group who elected not to receive TT (n = 3). Testosterone therapy was generally well tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the TT and placebo groups at the end of 8 weeks compared with baseline, this may be due to several study limitations, including small sample size, a strong placebo effect with intramuscular therapy, and short follow-up that did not allow measurement of delayed effects of TT in some subjects. Until more definitive studies are reported, practitioners should be particularly cautious in treatment of low testosterone concentrations in men with PD and borderline testosterone deficiency, and careful consideration should be given to the risks vs the benefits of TT.

Estudio longitudinal de pacientes con enfermedad de Parkinson (ELEP): objetivos y metodología

Parkinson's disease (PD) is a chronic and progressive disorder. It produces a significant burden not only for patients, but also for their family and caregivers, with a major socio-economic impact on society. Current knowledge on PD is characterized by scarce information about the evolutionary course of: 1) the non-motor PD features; 2) impact of non-motor PD features on disability and health related quality of life (HRQL) impairment; 3) factors related to disability and HRQL determinants; 4) factors that speed or slow the progression of PD; 5) differential long-term effect of available PD therapeutic schedules and their relationships with disability, complications, and HRQL; and 6) impact of the disease on patients' caregivers. In addition, heterogeneity in the metric quality of the applied measures and selection bias are frequently found. Due to the aforementioned limitations and from a multidimensional perspective, a new longitudinal study in PD is deemed necessary. The longitudinal study of PD patients (ELEP) includes a long-term follow-up of never before systematically assessed aspects, will allow to increase the global knowledge about PD.

Neuropsychiatric Aspects of Parkinson’s Disease

Parkinson's disease (PD), a disorder characterized by movement abnormalities, is frequently complicated by psychiatric syndromes. Psychiatric assessment of the PD patient requires familiarity with the motor and cognitive aspects of PD, the various effects of antiparkinsonian medications, and how these relate to mental status changes and psychiatric phenomena. This review describes the various motor and nonmotor features of PD and focuses on the differential diagnosis of affective disorders in PD and their treatment.