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Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications., Methods: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT., Results: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [ p < 0.001], of MDS-UPDRS Part IV 6.0 points [ p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [ p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS., Discussion: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection., Classification of Evidence: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting., (© 2023 American Academy of Neurology.)

Objective: To evaluate the effects of levodopa and the dopamine D2 agonist cabergoline on striatal dopamine turnover estimated as the inverse of the effective dopamine distribution volume ratio (EDVR) measured by (18)F-dopa PET in de novo Parkinson disease (PD)., Methods: Single-center, parallel-group, randomized, observer-blinded study of cabergoline (3 mg/day) and levodopa (300 mg/day) over 12 weeks in patients with de novo PD. Primary efficacy measure was the change of the side-to-side averaged putaminal EDVR comparing baseline and end-of-maintenance period., Results: Thirty-five out of 39 randomized patients were assigned to the primary efficacy analysis (cabergoline, n = 17; levodopa, n = 18). At the end of treatment period, mean EDVRs were significantly lower compared to baseline solely in the levodopa group (relative change -1.0 ± 13.0% in cabergoline [p = 0.525 when compared to baseline], -8.3 ± 11.8% in levodopa group [p = 0.006]) with a nonsignificant trend between groups (mean relative difference: 7.3% (95% confidence interval -1.2% to 15.8%; p = 0.091). There was significant clinical improvement in both groups at 12 weeks compared to baseline, but no significant differences between groups in clinical and PET secondary outcome measures. Both pharmacologic treatments and PET scanning were well-tolerated and safe., Conclusion: Putaminal dopamine turnover is increased by levodopa treatment in de novo PD. The nonsignificant trend toward a larger influence by levodopa compared to cabergoline is supported by ancillary statistical analyses. This augmentation of early compensatory events by levodopa might contribute not only to its symptomatic effects, but also to its induction of motor complications.

Purpose: The aim of the study was to estimate normal ranges and test-retest measures for various parameters characterising dopamine metabolism from a prolonged (18)F-dopa positron emission tomography (PET) measurement using a reference tissue model and compare their value for the detection of early Parkinson's disease (PD)., Methods: Healthy volunteers (n = 9) and patients (n = 36) in an early stage of PD underwent an (18)F-dopa PET measurement lasting 4 h. The influx rate constant k(occ) and the effective distribution volume ratio (EDVR, its inverse is an indicator for dopamine turnover) were estimated by a graphical approach using dynamic data in the striatum and, as a reference region, the occipital cortex. Furthermore, ratios of activity concentrations between striatum and occipital brain taken for three time intervals completed the data analysis. All parameters were determined both in eight small volumes of interest placed in the striatum as well as averaged for caudate nucleus and putamen. For the control group, reproducibility was checked in a second study 3 months later and ranges for normal values were derived from mean ± 2 standard deviations. Receiver-operating characteristic (ROC) analyses were performed to assess the value of the parameters for diagnostic purposes., Results: Patients with early-stage PD and healthy volunteers could be separated by the values of the putamen, not the caudate nucleus. The normal ranges of the putamen were 0.0151-0.0216/min for the influx rate constant k(occ) and 2.02-3.00 for EDVR. For the various time intervals used the striato-occipital ratios yielded 2.24-3.06, 2.43-3.42 and 2.35-3.21, respectively. Patients were characterised by significantly lower values (p < 0.001) and significant differences between ipsi- and contralateral sides (p < 0.001) with regard to their clinical symptoms and a rostrocaudal gradient. EDVR as well as k(occ) for the putamen were able to effectively differentiate between groups (sensitivity >97%, specificity 100%). In contrast, striato-occipital ratios showed a sensitivity of about only 85%., Conclusion: For clinical applications, our data do not demonstrate any superiority of the EDVR determination compared to influx rate constant, while requiring long and tedious acquisition protocols. The normal range estimates do not represent absolute quantitative measures for dopamine metabolism but are specific for the chosen acquisition and processing procedures.

Although extrapyramidal diseases are commonly thought to solely affect the (extrapyramidal) motor system, non-motor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also frequently observed. Autonomic dysfunction is an important clinical component of extrapyramidal disease, but it is often not formally assessed, and thus frequently misdiagnosed. Symptoms of autonomic dysfunction can impact more on quality of life than motor symptoms. Appropriate symptom-oriented diagnosis and symptomatic treatment as part of an interdisciplinary approach can greatly benefit the patient. This review elaborates a limited overview on the treatment of cardiovascular, gastrointestinal, urogenital and sudomotor autonomic dysfunction in various extrapyramidal syndromes.

The cold hand sign (CHS) is a distinct feature of multiple system atrophy (MSA), but its pathophysiology is poorly understood. We, therefore, conducted a study to examine the skin temperature and the skin blood flow at rest and after local heating in 6 age-matched MSA patients with CHS (MSA + CHS), 18 MSA patients without CHS (MSA - CHS) and 13 patients with idiopathic Parkinson's disease (PD). Basal skin temperature and blood flow were significantly lower in MSA + CHS patients than in MSA - CHS or PD patients. Local heating induced a greater response in terms of amplitude in MSA + CHS compared to MSA - CHS and PD. Considering kinetics, skin blood flow increment per 1 degrees C was higher in MSA + CHS than MSA - CHS but was similar when compared to PD patients. Skin blood flow rate (change per second) did not differ among the groups. Our findings suggest that despite impaired basal skin perfusion, the skin vasomotor response to local heating is intact in MSA + CHS but disturbed in MSA - CHS. By measuring skin temperature and blood flow, the presence of CHS can be diagnosed in MSA patients. Further studies are necessary to understand regulation of skin perfusion in patients with extrapyramidal disease.

Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes. The cross-sectional study included 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (IPD) and 27 age-matched healthy controls. Autonomic symptoms were evaluated by a standardized questionnaire. The performance of patients and controls was compared on five autonomic function tests: deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring (ABPM). Disease severity was significantly lower in IPD than PSP and MSA. Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination. The same was observed on the questionnaire. Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal blood pressure change. The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP. Our study supports the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP. Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA. Pupillography, ABPM and the questionnaire may assist in delineating the three syndromes when applied in combination.

Previous data on the prevalence of olfactory dysfunction in Parkinson's disease (PD) range from 45% to 90%. The present multicenter study aimed to provide data on the prevalence of smell loss in a large sample of PD patients from three independent populations. Olfactory sensitivity was tested in 400 patients from Australia, Germany, and The Netherlands by means of a psychophysical olfactory test, the "Sniffin' Sticks", which is comprised of 3 subtests of olfactory function. Out of the total number of patients 45.0% presented as functionally anosmic, 51.7% were hyposmic, whereas only 3.3% were normosmic. This indicates that 96.7% of PD patients present with significant olfactory loss when compared to young normosmic subjects. This figure falls to 74.5%, however, when adjusted to age-related norms. Thus, olfactory dysfunction should be considered as a reliable marker of the disease.

Purpose of this cross-sectional study was to estimate the occurrence of depressive symptoms, as related to other clinical data, in a sample of Parkinson's disease (PD) patients (n=226). Furthermore, we examined the medical care of depressive symptoms in this sample. H&Y stages, cognitive status, sleeping disorders, and dysphagia resulted as significant predictors for depression. Prevalence of depressive symptoms was 35.4%. Only 25.0% of patients suffering from moderate to severe depressive symptoms were prescribed antidepressants. This study supports the view that depression may be underrecognized and undertreated in PD patients. A significant proportion of patients continues to experience depressive symptoms despite antidepressive medication. Recognition and treatment of depression remains a challenge for management of PD. Possible coexisting depressive symptoms should be revealed and assessed by standardized interviews in everyday clinical routine. Large scale randomized controlled trials examining efficacy and safety of antidepressants in PD patients are urgently required.

Olfactory function is diminished in patients with idiopathic Parkinson disease (IPD). Because previous work almost exclusively relied upon cross-sectional studies, the present investigation aimed to address the correlation between olfactory loss and duration of disease within the context of a longitudinal study, accompanying well-diagnosed patients over an average period of 4.4 years. A group of 27 IPD patients was examined (5 women, 22 men; age range 27-64 years; duration of disease: 0 to 19 years). Psychophysical olfactory testing was performed after 3-6 years (mean 4.4 years) using the "Sniffin' Sticks" test battery which consists of subtests for odor thresholds, odor discrimination, and odor identification. The study yielded the following major results: (1) olfactory function in IPD patients changes in an unpredictable manner, (2) especially when considering results from the second session relatively few IPD patients were completely anosmic; none of the patients, however, were normosmic. One possible explanation for these findings may lie in the hypothesis based on results by Huisman et al. (2004) who reported an increase of dopaminergic neurons in the olfactory bulb in IPD patients. In this scenario, olfactory loss seen early in the disease may be based on an incomplete inhibition of olfactory input at the level of the olfactory bulb.

Olfactory dysfunction is a prominent symptom in Parkinson's disease (PD) and found in about 70-100% of patients. In earlier studies significant loss of olfactory function seemed to be unrelated to disease duration, did not correlate with motor function, and was uninfluenced by antiparkinsonian medication. We suggest that the increase of dopaminergic cells in the olfactory bulb is responsible for the hyposmia in PD patients. Interestingly, this olfactory dysfunction is not found in progressive supranuclear palsy or corticobasal degeneration. In multiple system atrophy, the deficit is mild and indistinguishable from cerebellar syndromes of other aetiologies. Intact olfaction has also been reported recently in Parkin disease (PARK 2) and vascular parkinsonism. Olfactory tests may significantly enhance the diagnostic armamentarium in the differential diagnosis of parkinsonian syndromes and indeterminate tremors. Furthermore, olfactory testing may also prove to be a useful aid in the early or "preclinical" detection of PD, once effective disease-modifying therapies are found. Braak and coworkers have confirmed the widespread, extranigral pathology in PD and suggested that pathology in the anterior olfactory region may be one of the earliest appearances of neurodegeneration in PD.

Background: Major hallmarks in the pathophysiology of Parkinson disease are cellular energy depletion and oxidative stress leading to cellular dysfunction and death. Coenzyme Q(10) (CoQ(10)) is an electron acceptor bridging mitochondrial complexes I and II/III and a potent antioxidant that consistently partially recovers the function of dopaminergic neurons., Objective: To determine whether nanoparticular CoQ(10) is safe and displays symptomatic effects in patients with midstage Parkinson disease without motor fluctuations., Design: Multicenter, randomized, double-blind, placebo-controlled, stratified, parallel-group, single-dose trial., Setting: Academic and nonacademic movement disorder clinics., Patients: One hundred thirty-one patients with Parkinson disease without motor fluctuations and a stable antiparkinsonian treatment. Intervention Random assignment to placebo or nanoparticular CoQ(10) (100 mg 3 times a day) for a treatment period of 3 months. Stratification criterion was levodopa treatment., Main Outcome Measure: The subjects underwent evaluation with the Unified Parkinson's Disease Rating Scale (UPDRS) at each visit on a monthly basis. The primary outcome variable was the change of the sum score of the UPDRS parts II and III between the baseline and 3-month visits., Results: One hundred thirty-one subjects were randomized according to the protocol. The mean changes of the sum UPDRS parts II/III score were -3.69 for the placebo group and -3.33 for the CoQ(10) group (P = .82). Statistical analysis according to the stratification did not result in significant changes of the primary outcome variable. No secondary outcome measure showed a significant change between the placebo group and the CoQ(10) group. The frequency and quality of adverse events were similar in both treatment groups., Conclusions: Nanoparticular CoQ(10) at a dosage of 300 mg/d is safe and well tolerated and leads to plasma levels similar to 1200 mg/d of standard formulations. Add-on CoQ(10) does not display symptomatic effects in midstage Parkinson disease.

Idiopathic Parkinson's disease (IPD) is a neurodegenerative disorder of unknown aetiology. Histopathological similarities between IPD and Creutzfeldt-Jakob prion disease (CJD) have been suggested. Homozygosity at polymorphic prion protein gene codon 129 (PRNP129) is a risk factor for developing CJD. Therefore we investigated a putative genetic link between CJD and IPD by studying PRNP129 genotype segregation in 81 patients with IPD. We did not ascertain a different PRNP129 genotype distribution in IPD patients compared to healthy Germans. We found a significant difference in PRNP129 genotype in dependence of the clinical predominance type of IPD. Patients with tremor-dominant IPD presented less frequent a methionine homozygosis at PRNP129 than hypokinetic-rigid IPD patients (30% versus 62.5%; p<0.033). In conclusion, genotype distribution at codon 129 is obviously not essential in determining IPD. But our results may provide first evidence of an association between certain PRNP129 polymorphisms and the clinical presentation of IPD.

Olfactory loss is among early signs of idiopathic Parkinson's disease (IPD). The present pilot study aimed to investigate whether this loss would be reflected in a decreased volume of the olfactory bulb (OB) established through magnetic resonance imaging. Eleven consecutive IPD patients were compared to 9 healthy, age-matched controls. Results indicated that there is little or no difference between IPD patients and healthy controls in terms of OB volume. Based upon the relation between loss of olfactory input to the olfactory bulb and consecutive decrease in volume, these data support the idea that olfactory loss in IPD is not a primary consequence of damage to the olfactory epithelium but rather results from central-nervous changes.

Approximately 25% of patients with idiopathic Parkinson's disease (IPD) later develop dementia, with the typical characteristics as detailed in ICD-10 and DSM-IV. Differential diagnosis has to exclude dementia due to Lewy bodies, subcortical vascular encephalopathy and subcortical dementia due to progressive supranuclear paralysis or corticobasal degeneration. Several studies showed promising results for cholinesterase inhibitors such as donepezile, rivastigmine and galantamine. The demented Parkinsonian patients then present with improvement in cognitive function while motor skills do not deteriorate.

Depression occurs in approximately 45% of all patients with Parkinson's disease (PD), reduces quality of life independent of motor symptoms and seems to be underrated and undertreated. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms, diagnosis is based on subjectively experienced anhedonia and feeling of emptiness. Available rating scales for major depression may not be adequate to correctly measure severity of depression in PD. Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergic, noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD. Tricyclic and newer, selective antidepressants including serotonin and noradrenaline reuptake inhibitors (SSRI, SNRI) appear to be effective in treating depression in PD. Selective reuptake inhibitors seem to have a favorable side effect profile. Recent controlled studies show antidepressant effects of pramipexole in bipolar II depression. New dopamine agonists pramipexole and ropinirole appear to ameliorate depressive symptoms in PD in addition to effects on motor symptoms. There is a lack of appropriate rating scales and controlled studies regarding depression in PD.

Switching from one dopamine agonist to another is common practice in the treatment of patients with Parkinson's disease. This paper describes some ideas on the most practical way to perform switching. In addition, it describes the possibilities of combining various dopamine agonists and discusses pros and cons for doing so.

Idiopathic Parkinson's disease (IPD) is a neurodegenerative disorder of unknown aetiology. Several antigens have been associated with IPD using serological methods. We systematically analysed HLA class I and II alleles in 45 German Caucasian IPD patients using sequence-specific oligonucleotides and sequence-specific primer technology. Applying Bonferroni adjusted p values, we demonstrate a statistically significant increase of the DQB1*06 allele (p = 0.002) in IPD which may indicate an association between IPD and the immune system. Alternatively, HLA alleles might be in linkage disequilibrium with genes located next to the HLA locus., (Copyright 2003 S. Karger AG, Basel)

The treatment of idiopathic Parkinson's disease becomes rather difficult if levodopa-induced late complications such as motor fluctuations or dyskinesias occur. This prospective and open study shows that an add-on therapy with entacapone can significantly lower wearing-off and end-of-dose akinesia. This treatment is well tolerated and easy to perform.