Journal of Parkinson’s Disease

BackgroundMinor hallucinations (MH) affect 30-60% of patients with Parkinsons disease (PD), and are considered precursors to structured visual hallucinations and cognitive decline. While the link between structured visual hallucinations and dementia is well established, the neuropsychological correlates of MH in PD remain unclear; most studies finding no significant cognitive differences between patients with MH and those without any hallucinations. ObjectivesPresence hallucinations (PH) being among the most prevalent MH in PD, we used a robotic procedure delivering somatomotor conflicts inducing PH experimentally to investigate whether sensitivity to such robot-induced PH aids in detecting cognitive differences between patients with MH and without hallucinations. Methods31 PD patients with MH (PD-MH) and 37 without hallucinations (PD-nH) underwent neuropsychological assessment and the robotic procedure inducing PH. The sensitivity to report robot-induced PH was analyzed in relation to cognitive performance in neuropsychological tests. ResultsPD-MH patients reported more robot-induced PH than PD-nH patients, supporting previous findings. While both groups showed comparable performance in neuropsychological testing, we found a significant association between increased sensitivity to the PH-induction and poorer performance in frontal subcortical functions (executive functions), in PD-MH patients, but not in PD-nH patients. ConclusionsThese findings demonstrate that sensitivity to robot-induced PH reveals a previously undetected link between MH and frontal subcortical cognitive deficits in PD, pointing to shared underlying mechanisms between executive dysfunction and somatomotor processes involved in MH. This approach offers a novel and clinically valuable means of identifying early cognitive vulnerability that assessments relying only on standard testing may overlook. Plain language summaryO_ST_ABSInduced minor hallucinations are linked to executive function alteration in Parkinsons diseaseC_ST_ABSThis study investigated two groups of Parkinsons disease (PD) patients: one group with minor hallucinations (MH) and another without any hallucinations. Using cognitive tests and a robotic task designed to temporarily induce a presence hallucination (hallucination of someone being there when no one is actually present), the study examined the relationship between cognitive impairment and sensitivity to robot-induced presence hallucinations (riPH). While both groups performed similarly on traditional cognitive tests, patients with MH were more sensitive to the riPH procedure. This increased riPH sensitivity was linked to difficulties with cognitive functions, especially executive functions, which are generally supported by the brains frontal and deeper regions (frontal subcortical network). These results from both tests (riPH, neuropsychology) suggest that elevated sensitivity to riPH is associated with mild signs of cognitive decline in PD patients that traditional tests might not detect. The use of the robotic induction of hallucinations as a tool for assessing cognitive deficits could offer a more sensitive method for identifying cognitive issues earlier in PD, potentially enabling earlier interventions.

BackgroundData-driven approaches identified Mild Motor Predominant (MMP), Intermediate (IM), and Diffuse Malignant (DM) as Parkinsons Disease (PD) subtypes with different motor and non-motor impairment at diagnosis. It remains unclear whether these subtypes remain stable over time or whether they represent distinct biological substrates. The alpha-synuclein seed amplification assay in CSF (CSF-Syn-SAA) might provide further insights. Objectiveto evaluate the association between baseline CSF-Syn-SAA parameters and 10-year clinical evolution of PD subtypes. Methods323 sporadic PD patients from PPMI dataset were classified as MMP, IM, or DM at baseline and 10-year follow-up based on motor, cognitive, sleep and dysautonomia features. CSF-Syn-SAA parameters were collected at baseline using a 150-hrs protocol. CSF A{beta}1-42, tTau and pTau181, CSF and serum NfL were also considered at baseline. ResultsReaction times (T50, TTT) and area under the curve (AUC) respectively were shorter and larger in DM compared to IM/MMP. The difference in baseline amplification parameters was more evident when comparing subtypes based on 10-year clinical features (T50, 2=0.036; TTT, 2=0.031; AUC, 2=0.033; all p values < 0.05) than when comparing subtypes based on baseline clinical features (T50, 2=0.012; TTT, 2=0.012; AUC, 2=0.013; all p<0.05). Shorter T50 and TTT at baseline were associated with greater risk of DM versus MMP at 10-year follow-up (T50, OR=3.3, 95%CI: 1.3-8.1, p=0.010; TTT, OR=4.6, 95%CI: 1.8-11.6, p=0.001). A{beta}, Tau and NfL were similar between groups. ConclusionsBaseline CSF-Syn-SAA parameters predicted long-term PD progression. Faster reactions were associated with a more severe 10-year PD phenotype considering motor and non-motor features. Plain Language SummaryO_ST_ABSBackgroundC_ST_ABSThe diagnosis of Parkisons Disease is drastically changing by the development of Alpha-Synuclein Seed Amplification Assay. The assay enables, for the first time, the detection of pathological forms of alpha-synuclein in cerebrospinal fluid in living patients. Alpha-Synuclein Seed Amplification is very accurate in discerning individuals with Parkinsons Disease versus healthy subjects, but it remains unknown whether it can also inform about prognosis. ObjectiveWe assessed the ability of the assay to predict the 10-year clinical progression of Parkinsons Disease. MethodsPublic data from an international cohort were used. At time of diagnosis, we classified 323 individuals with Parkinsons Disease into three clinical subtypes: Mild Motor Predominant, Intermediate, and Diffuse Malignant. These subtypes were characterized by a progressively increasing burden of motor and non-motor symptoms. Subjects with available follow-up data were re-classified using the same subtypes after 10 years of disease. Time-dependent signal changes of Alpha-Synuclein Seed Amplification Assay in Cerebrospinal Fluid were measured at baseline and used to predict the 10-year phenotype. ResultsFirstly, we found that subtypes were not stable categories. Around a half of participants changed subtype over time, mostly shifting towards a more aggressive one. Notably, our results showed that faster reactions on Alpha-Synuclein Seed Amplification Assay at baseline were associated with a 10-year phenotype more aggressive in terms of motor symptoms, dysautonomia, sleep and cognitive impairment, i.e the Diffuse Malignant subtype. ConclusionCharacteristics of the assay underlying the final positivity or negativity outcomes performed at a milder and early stage of PD may identify a subgroup of subjects that are more likely to undergo a more rapid clinical deterioration. Further studies, however, are needed to confirm and expand this result.

BackgroundNovel supportive diagnostic and prognostic biomarkers for Parkinsons disease (PD) are needed to enable its early diagnosis and inform clinical trials. Proteomic studies have identified cerebrospinal fluid (CSF) DOPA decarboxylase (DDC) as a promising biomarker candidate, but its role has not been well characterized. The aim of this study was to gain further insight into the potential of DDC as biomarker for PD. MethodsWe developed and validated a single molecule counting immunoassay for DDC quantification in CSF based on commercially available monoclonal antibodies. DDC levels were quantified in the Parkinsons Progression Markers Initiative cohort including healthy controls (n=29), dopaminergic drug-naive patients with PD (n=27) and with scans without evidence for dopaminergic deficit (SWEDD) (n=18). Their relationship with ioflupane-[123I]-single-photon emission computed tomography-based dopamine transporter (DaT-SPECT) imaging was analyzed. The prognostic potential of CSF DDC was evaluated by assessing the relationship between baseline DDC levels and yearly changes of Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) scores. CSF DDC levels were also quantified three years after the diagnosis, and their relationship with the L-DOPA equivalent daily dose (LEDD) was investigated. Finally, absolute DDC levels determined by our assay were correlated with relative concentrations obtained from Olink technology. ResultsOur DDC assay detected elevated levels in CSF from dopaminergic drug-naive PD patients and discriminated them from untreated SWEDD and control with high sensitivity and specificity. There was an inverse correlation between baseline DDC levels and DaT-SPECT striatal binding ratios (SBR) from the putamen and caudate nucleus. Baseline CSF DDC levels demonstrated prognostic potential for MDS-UPDRS total change five to eight years after the diagnosis. DDC levels were further increased at the three-year follow-up visit in PD patients and were positively correlated with the LEDD. Finally, there was a strong correlation between relative CSF DDC levels determined with the Olink assay and absolute DDC levels determined with our assay. ConclusionsOur monoclonal antibody-based assay for DDC quantification provided further insight into the potential of DDC in CSF to serve as a diagnostic and prognostic biomarker for PD. The unchanged levels in SWEDD patients and the inverse correlation with DaT-SPECT SBR suggest that DDC levels in CSF are connected to dopaminergic deficit.

Background: People with Parkinsons disease (PD) experience substantial psychosocial burden, but the extent of their concern about the future is not well characterized. Objective: The objective of the present study is to characterize concerns about the future among people with PD (PwP), with an emphasis on the clinical and demographic correlates of future-oriented concerns. Methods: A survey in the online Fox Insight study platform asked PwP to rate their degree of concern about the future across seven domains: quality of life, disease progression, healthcare needs, social relationships, financial responsibilities, stigma, and specific symptoms. Relationships among uncertainty and demographic and clinical features, such as age of onset, gender, and disease severity, were examined. Latent class analysis was conducted to identify patterns of fear/uncertainty. Results: Among 3372 respondents, concerns about the future were common and spanned cognitive, functional, social, and symptom-related domains. Concerns about future cognitive impairment, independence, mobility, and disease progression were most prominent. Women and individuals with young-onset PD reported higher levels of concern than other groups. Latent class analysis revealed two clear patterns, including a high-concern subgroup with elevated worry across nearly all domains. Fewer than half of respondents had discussed these concerns with a healthcare professional. Conclusion: Future-related concerns are common among people with PD but is not routinely explored in clinical care. Greater attention to these concerns, especially for young-onset individuals and women, may help clinicians offer more timely and supportive guidance.

BackgroundDepression in Parkinsons disease (PD) is common, disabling and responds poorly to standard antidepressant medication. Motivational symptoms of depression, such as apathy and anhedonia, are particularly prevalent in depression in PD and predict poor response to antidepressant treatment. Loss of dopaminergic innervation of the striatum is associated with emergence of motivational symptoms in PD, and mood fluctuations correlate with dopamine availability. Accordingly, optimising dopaminergic treatment for PD can improve depressive symptoms, and dopamine agonists have shown promising effects in improving apathy. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known. AimsWe hypothesised that there would be dissociable effects of dopaminergic medications on different depression symptom dimensions. We predicted that dopaminergic medication would specifically improve motivational symptoms, but not other symptoms, of depression. We also hypothesised that antidepressant effects of dopaminergic medications with mechanisms of action reliant on pre-synaptic dopamine neuron integrity would attenuate as pre-synaptic dopaminergic neurodegeneration progresses. MethodsWe analysed data from a longitudinal study of 412 newly diagnosed PD patients followed over five years in the Parkinsons Progression Markers Initiative cohort. Medication state for individual classes of Parkinsons medications was recorded annually. Previously validated "motivation" and "depression" dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging. ResultsLinear mixed-effects modelling was performed across all simultaneously acquired data points. Dopamine agonist use was associated with relatively fewer motivation symptoms as time progressed (interaction: {beta}=-0.07, 95%CI [-0.13,-0.01], p=0.015) but had no effect on the depression symptom dimension (p=0.6). In contrast, monoamine oxidase-B (MAO-B) inhibitor use was associated with relatively fewer depression symptoms across all years ({beta}=-0.41, 95%CI [-0.81,-0.01], p=0.047). No associations were observed between either depression or motivation symptoms and levodopa or amantadine use. There was a significant interaction between striatal DAT binding and MAO-B inhibitor use on motivation symptoms: MAO-B inhibitor use was associated with lower motivation symptoms in patients with higher striatal DAT binding (interaction: {beta}=-0.24, 95%CI [-0.43,-0.05], p=0.012). No other medication effects were moderated by striatal DAT binding measures. ConclusionsWe identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists may be effective for treatment of motivational symptoms of depression. In contrast, MAO-B inhibitors may improve both depressive and motivation symptoms, albeit the latter effect appears to be attenuated in patients with more severe striatal dopaminergic neurodegeneration, which may be a consequence of dependence on pre-synaptic dopaminergic neuron integrity.

BackgroundParkinsons disease (PD) is a progressive neurodegenerative disorder with complex pathophysiology. The potential of integrating biomarkers of neuronal injury, neuroinflammation, and modulators of Wnt signaling for PD diagnosis remains largely unexplored. ObjectiveThis study aimed to evaluate the diagnostic and clinical predictive value of a ten-biomarker serum panel encompassing markers of neuronal injury (NSE, UCHL1), neuroinflammation (GFAP, HMGB1), synaptic plasticity (BDNF), proteinopathy (-Synuclein, {beta}-Amyloid-42), and Wnt signaling (R-spondin-1, DKK1, Sclerostin), with a particular focus on chronic fatigue in PD. MethodsIn this case-control study, 90 PD patients and 45 healthy controls were enrolled. Serum biomarkers were quantified using ELISA. Clinical severity was assessed using the Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and Fibro-Fatigue (FF) scales. Binary logistic regression and multiple linear regression analyses were used to evaluate the diagnostic and predictive value of biomarkers for PD diagnosis, psychiatric and motoric scores, and an FF score reflecting chronic fatigue syndrome (CFS) severity. ResultsA model incorporating NSE, DKK1, and {beta}-Amyloid-42 effectively discriminated PD patients from controls, yielding an area under the curve (AUC) of 0.932 and an overall accuracy of 83.0%. NSE and DKK1 emerged as the main predictors of overall disease severity, motor symptoms, and CFS severity. Regression analyses indicated that 41.3% of the variance in the FF score was explained by increased NSE, DKK1, {beta}-amyloid, and UCHL1, while 42.9% of the variance in psychiatric symptoms was explained by increased NSE, DKK1, and {beta}-amyloid. Increased GFAP levels were significantly associated with motor dysfunction. ConclusionThe combined presence of neuronal injury, Wnt signaling dysregulation, and amyloid pathology may represent a key pathophysiological component underlying PD, CFS-like fatigue, and psychiatric symptoms in PD. Targeting neuronal injury and Wnt signaling pathways may offer novel therapeutic strategies for managing fatigue and psychiatric manifestations in PD.

BackgroundThe role of blood uric acid and more recently bilirubin as biomarkers in symptomatic motor PD has been increasingly established in the literature. ObjectiveOur present study assessed the role of serum uric acid and total bilirubin as putative biomarkers in a prodromal PD cohort followed longitudinally. MethodsLongitudinal 5-year serum uric acid and total bilirubin measurement data of 65 Prodromal PD patients (including REM Sleep Behavior disorder (RBD), N=39 and Hyposmia, N=26) with an abnormal DATSCAN imaging were downloaded from the Parkinsons Progression Markers Initiative (PPMI) database. This cohort was compared with 423 de novo sporadic PD patients and 196 healthy controls enrolled in the same study. ResultsAfter adjusting for age, sex and Body Mass Index (BMI), baseline and 5-year longitudinal serum uric acid levels were higher in the Prodromal cohort and RBD subgroup as compared to the motor PD cohort. This was also true for longitudinal measurements in the Hyposmic subgroup. In contrast, baseline and longitudinal serum total bilirubin did not differ between each prodromal group and the PD cohort. ConclusionsOur results are indicative of a role of serum uric acid (but probably not of total bilirubin) as a marker of neuroprotection, in a certain subgroup of premotor patients exhibiting exclusively non motor features (hyposmia or RBD). It is possible that an inherent antioxidant resistance of a subset of RBD or hyposmia patients with high serum uric acid level delayed or precluded the emergence of a motor PD phenotype as opposed to the PD cohort.

IntroductionMotor complications are major determinants of disability in Parkinsons disease (PD), yet clinician-rated motor complication severity does not fully explain variability in health-related quality of life (HRQoL). Research questionTo examine the contribution of illness perceptions and cognitive-behavioural responses to HRQoL alongside motor complication severity in people with PD. MethodsThis multi-centre, cross-sectional study recruited 58 people with idiopathic PD (median age 68 years; 55.2% male; 48.3% from minoritised ethnic backgrounds; Hoehn & Yahr stage 2-3). All underwent assessment of motor complications (Movement Disorder Society-Unified Parkinsons Disease Rating Scale; MDS-UPDRS Part IV) and HRQoL (Parkinsons Disease Questionnaire-39 Summary Index; PDQ-39 SI). Illness perceptions were measured with Illness Perception Questionnaire-Revised (IPQ-R) Part 2, and cognitive-behavioural responses with Cognitive and Behavioural Responses Questionnaire (CBRQ). Regression models were adjusted for age, sex, disease duration, motor severity (MDS-UPDRS Part III), levodopa equivalent daily dose (LEDD), anxiety, depression, and cognitive function. A subset (n=47) completed 7-day Parkinsons KinetiGraph monitoring. ResultsDemographic and clinical covariates explained 77.3% of variance in HRQoL (R{superscript 2}=0.773). Adding motor complication severity explained a significant additional 3.7% ({Delta}R{superscript 2}=0.037, P=0.004). Subsequent inclusion of illness consequences (IPQ-R) and catastrophising (CBRQ) explained a further 4.1% ({Delta}R{superscript 2}=0.041, P=0.004), yielding a final adjusted R{superscript 2} of 0.815. In the fully adjusted model, catastrophising (B=0.797, P=0.027) and perceived consequences (B=0.767, P=0.013) remained independently associated with HRQoL. ConclusionHRQoL in PD appears to depend not only on motor complication severity, but also on patients interpretations and responses. Clinicians should assess both to guide holistic care and support adaptive coping.

Traditional binary classifications of Parkinsons disease (PD) cognitive dysfunction fail to capture its inherent heterogeneity. This study introduces the Partially Ordered Set (POSET) model, a Bayesian framework, to analyze cognitive trajectories using Parkinsons Progression Markers Initiative (PPMI) data. Five cognitive domains: Attention, Visuospatial Judgement, Executive Functioning, Working Memory, and Episodic Memory, were mapped onto nine neuropsychological measures to calculate Cognitive Performance Scores (CPS). Of 264 patients without baseline cognitive dysfunction, 21.7% developed dysfunction by Year 3. These individuals exhibited significantly lower median CPS across all domains during follow up visits in Years 1-3. Notably, baseline Attention and Visuospatial CPS were significant predictors of future impairment, with an area under the curve (AUC) of 0.782; a specificity of 91.3%, and a sensitivity or 35.7%. POSET modeling provides a sophisticated approach to characterizing PD cognitive decline, offering greater granularity than conventional schemes. Further large-cohort studies are needed to confirm these findings.

BackgroundMotivational symptoms such as apathy and anhedonia are common in Parkinsons disease, respond poorly to treatment, and have been hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in Parkinsons disease, but the association has never been examined longitudinally. We investigated whether the progression of dopaminergic neurodegeneration was associated with emergent apathy and anhedonia symptoms in Parkinsons disease. MethodsLongitudinal cohort study of 412 newly diagnosed Parkinsons disease patients followed over five years as part of the Parkinsons Progression Markers Initiative (PPMI) cohort. Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item geriatric depression scale (GDS-15) and part I of the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS). Dopaminergic neurodegeneration was measured using repeated ioflupane [123-I] single photon emission computed tomography imaging of striatal dopamine transporters (DAT). ResultsLinear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio(SBR) and apathy/anhedonia symptoms, which emerged as Parkinsons disease progressed (interaction: {beta}=-0.09, 95%CI[-0.15 -0.03], p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average two years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) ({beta}=-0.06, 95%CI[-0.13 0.01]) or motor symptoms indexed by the MDS-UPDRS part III ({beta}=0.20, 95%CI[-0.25 0.65]). ConclusionThe relationship between the progression of dopaminergic neurodegeneration and emergent apathy/anhedonia symptoms supports a central role for dopaminergic dysfunction in motivational symptoms in Parkinsons disease. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies.

Functionality is considered the third health indicator, complementing the traditional mortality and morbidity metrics. However, functionality is rarely assessed systematically in Parkinsons disease (PD) clinical practice and research, where symptom-based scales predominate. Identifying declines across various dimensions of functionality in PD is essential for patient education, disease management, and guiding new intervention strategies. The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a comprehensive assessment tool developed by the World Health Organization (WHO) based on the International Classification of Functioning, Disability and Health (ICF) to standardize the measurement of functionality and disability impacts across diverse health conditions and cultural contexts. This study aimed to characterize functionality across PD severity stages using the WHODAS 2.0, independent of age, sex, socioeconomic status (SEC), and education. A total of 352 patients were divided into four clinically severity PD stage groups according to the Hoehn & Yahr (H&Y) scale. The age, sex, SEC and education levels were controlled to guarantee paired groups. All participants were evaluated remotely using the Telephone - Montreal Cognitive Assessment (T-MoCA), Beck Depression Inventory (BDI), Movement Disorder Society - Unified Parkinsons Disease Rating Scale, Part I (MDS-UPDRS I) and Part II (MDS-UPDRS II) and WHODAS 2.0. The most affected functionality dimensions were Mobility, Activities of Daily Life related to the Household, and Participation. The nonparametric Kruskal-Wallis test revealed a significant effect of the group for all functionality dimensions. Notably, Mobility, Activities of Daily Life related to the Household, and Self-Care showed a gradual decline starting from stage 1 of H&Y. In contrast, Cognition, Getting Along and Participation exhibited progressive impairment only from stage 2 of H&Y. This study is the first to describe functionality in PD using WHODAS 2.0 across severity stages controlling for key demographic factors. Findings highlight that WHODAS captures functional limitations not identified by symptom-focused scales such as MDS-UPDRS. Incorporating WHODAS into routine assessment may improve patient-centered care by informing interventions targeting functional limitations from early disease stages. HighlightsWHODAS 2.0 captures functionality domains not assessed by MDS-UPDRS. Functional decline in mobility, self-care, and household tasks starts at early PD stages. Participation, cognition, and interpersonal relationships decline from stage 2 onwards. Functionality decline is independent of age, sex, education, and socioeconomic status. WHODAS provides a biopsychosocial assessment essential for person-centered PD care.

BackgroundThe prodromal phase of Parkinsons disease (PD), much like the disease itself, displays marked heterogeneity, with varied rates of progression and symptom severities. A detailed clinical characterization of prodromal subgroups may provide useful insights for both clinical and research settings. ObjectivesTo compare clinical assessments in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and those with isolated hyposmia. MethodsA cross-sectional study was conducted on 191 patients with iRBD, 213 patients with isolated hyposmia and 150 healthy controls recruited in the Parkinsons Progression Markers Initiative. The earliest available assessment for each participant was selected. Our analysis investigated and compared the Montreal Cognitive Assessment, Scales for Outcomes in Parkinsons Disease Autonomic Dysfunction (SCOPA-AUT) and Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Parts I, II and III scores across the three groups. To assess differences, after adjusting for age and sex, we employed permutations testing. We further investigated the specific question items that contributed most significantly to the observed variations between the groups. ResultsWe found significant differences between the healthy control group and a combined prodromal group across all assessment categories, with prodromal participants displaying poorer scores. For between prodromal groups comparison, significant differences emerged in SCOPA-AUT and MDS-UPDRS Part I scores, with the iRBD group presenting with more severe scores. ConclusionOur study highlights that even in the premotor stage of PD, clinical distinctions exist in terms of autonomic burden between individuals with iRBD and those with isolated hyposmia.

BACKGROUNDThere is a need for reliable, objective, and easily accessible biomarkers for Parkinsons disease. OBJECTIVESThe purpose of this study was to screen biomarkers from vital signs and routine blood tests. METHODSLongitudinal data of up to 7 years of vital signs and routine blood tests from 418 patients with Parkinsons disease (PD) untreated at baseline and 185 individuals without any neurological disease were analyzed using linear mixed models. We nominated the biomarkers whose main associations with the measurements were significant as differentiating biomarkers. Similarly, we nominated the interaction effects between biomarkers and time from baseline as progression biomarkers. We tested for 49 biomarkers, and multiple comparison was corrected with the false-discovery-rate of 0.05. We further evaluated the potential biomarkers with regard to their importance in diagnosis prediction and their association with sub-scores on the Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS). We also assessed the relationship of the associations using bioinformatics. RESULTSHeart rate, systolic blood pressure, white blood cell fractions, neutrophil counts, serum albumin, sodium and AST were different between PD and controls. The causality or genetic correlations of these biomarkers to PD were not observed. Chronological changes in height, albumin, hemoglobin, and bicarbonate were different in PD. These biomarkers were associated with MDS-UPDRS sub-scores. ConclusionsIn this study, the potential of some easily accessible biomarkers for diagnosis and disease progression was presented. Further investigation of the mechanisms underlying these associations is important for a deeper understanding of the disease and the better management of patients.

IntroductionPrevious research has shown that inflammatory immune biomarkers including peripheral white blood cell subpopulations differ between Parkinsons disease (PD) patients and healthy controls (HC), with idiopathic PD exhibiting higher neutrophil to lymphocyte ratio (NLR). The aim of our present report was to assess the peripheral immune profile in patients or asymptomatic carriers harboring the p.A53T alpha-synuclein (SNCA) mutation. MethodsData regarding 31 p.A53T SNCA PD patients, 9 asymptomatic mutation carriers and 194 HCs were obtained from the database of the Parkinsons Progression Markers Initiative (PPMI). Focus was placed on peripheral immune blood cells subpopulations and clinical/imaging parameters during the initial study assessment. ResultsNLR, Absolute Neutrophil cell count and Neutrophil to total Leukocytes ratio were increased in the p.A53T SNCA PD group as compared to HCs [2,77 vs 2,18 (p<0.001), 4,32x10^3 cells/L vs 3,67x 10^3 cells/L (p=0.001), 65,67% vs 59,55% (p<0.001) respectively]. Differences in NLR were mainly driven by the male patient subgroup. The absolute Lymphocyte cell count showed a trend towards being decreased in p.A53T PD, and Lymphocyte to total leukocytes ratio was lower in p.A53T SNCA cohort as compared to HC [26,16% vs 30,02% (p=0.001)]. Monocyte to total Leukocytes ratio was lower in p.A53T PD 5,49% vs 6,74% (p=0.002). Finally, we observed a positive correlation between the absolute Lymphocyte count and the mean putamen DATSCAN signal. Asymptomatic carriers did not differ statistically from p.A53T SNCA PD or HC regarding leucocyte subpopulations counts. DiscussionOur current study provides evidence of a specific pattern of peripheral immune response in the p.A53T SNCA PD group which aligns well with literature data in idiopathic and other genetic PD forms. Furthermore, given former evidence that alpha-synuclein represents an immune target in PD, we can speculate a putative underlying inflammatory pathway in this archetypal form of genetic synucleinopathy.

BackgroundHandwriting changes, such as micrographia, are recognised as an early manifestation of Parkinsons disease (PD). Whilst isolated rapid eye movement sleep behaviour disorder (iRBD) is strongly associated with future PD diagnosis, changes in handwriting remain under-explored. ObjectiveTo assess the handwriting of people with iRBD and develop a rating scale for detection of early disease clinical hallmarks. MethodsThis is a cross-sectional study involving 33 people with polysomnography (PSG)- confirmed iRBD and 29 healthy controls. Participants copied a standard sentence using a pen and paper. A graphologist analysed each handwriting script blindly and designed a scale based on observed abnormal patterns which included: micrographia, sentence slope, hidden tremor, retracing, resting marks, irregular shape, excessive pen pressure, and inconsistent word spacing. Each item was scored 0/1 based on their absence/presence. Separately, three blinded movement disorders experts assessed the scripts based on their global clinical impression as well as using the developed rating scale. ResultsPeople with iRBD were slower to complete the task than controls (76.70s (SD = 30.39) vs 61s (SD = 10.71); p=0.004). Hidden tremor was the most common feature amongst the iRBD group (72.0% vs 34.5%; p=0.005), followed by sentence slope (60% vs 24% p=0.005) and pen pressure (48% vs 14%; p=0.006). Micrographia was equally observed in both groups (iRBD 45.4%, controls 41.4% p=0.801). Classification accuracy of the scale for iRBD was higher than expert global assessment (AUC 0.76 vs AUC 0.62, p = 0.029). ConclusionsWriting speed, tremor, pen pressure and sentence slope are handwriting features that warrant further investigation to define early patterns in people with iRBD.

Background: Visual dysfunction is a common but underrecognized contributor to disability in Parkinsons disease (PD), particularly deficits in binocular vision and vergence that impair reading, near work, and quality of life. The relationship between objective oculomotor abnormalities and patient-reported visual disability remains incompletely understood. Methods: We studied 25 individuals with PD and 11 age-matched controls who completed the National Eye Institute Visual Function Questionnaire 25 (VFQ25) and the Convergence Insufficiency Symptom Survey (CISS). Participants underwent comprehensive clinical ophthalmologic assessment and high resolution binocular eye tracking to quantify vergence latency, gain, fixation dynamics, and drift variability. Associations between objective measures and patient reported outcomes were examined, and predictive models were developed using clinic-only and combined clinical plus eye tracking approaches. Results: Compared with controls, PD participants demonstrated significantly worse VFQ25 composite scores and higher CISS scores, driven primarily by impairments in near activities and mental health. Clinically, PD was characterized by convergence insufficiency rather than generalized visual loss. Objective eye tracking revealed delayed vergence initiation, reduced gain, and increased instability. In PD, both clinical convergence measures (notably nearpoint convergence) and dynamic eye tracking metrics strongly correlated with VFQ25 and CISS scores, whereas such relationships were absent in controls. Predictive models showed limited performance using clinic measures alone, but improved with inclusion of eye racking variables. Conclusions: Visual disability in PD is tightly linked to convergence insufficiency and dynamic oculomotor instability. Simple clinical measures such as nearpoint convergence, augmented by eye tracking when available, provide meaningful insight into patient reported visual quality of life.

Background: Gait variability is a hallmark of Parkinson's disease (PD) and has been linked to cognitive deficits and fall risk. Rapid eye movement sleep behavior disorder (RBD) is a strong predictor of synucleinopathies, yet evidence for gait changes in RBD is inconsistent. Performing a dual task increases gait variability, an effect that can be quantified using a cost function. Objective: Determine the degree to which dual task cost differs between control, RBD, and PD participants at baseline, and between RBD converters versus non-converters at follow-up. Methods: 46 RBD, 23 control, and 14 PD participants completed standardized gait analysis at baseline. Parameters chosen for analysis included enhanced gait variability index (eGVI), functional ambulation performance (FAP), velocity, step length, cadence, base of support, and double support time. Medical records were surveilled for 3 years following participant enrollment, determining that 6 RBD participants converted to PD or dementia. Baseline gait indices and dual task costs were compared between control, RBD, and PD groups at enrollment, and between RBD stable and RBD converters at follow-up. Results: The PD group had greater eGVI, as well as greater dual task cost for FAP, cadence, width, and double support time. No differences in gait variability were identified between RBD and control groups at baseline. Compared to the stable group, RBD converters had greater dual task cost for FAP, velocity, cadence, and double support time. Conclusions: Increased gait variability during dual task may identify RBD patients at imminent risk of phenoconversion.

Studies reporting alpha-synuclein seed amplification assay (aSyn-SAA) results are often cross-sectional. Here we investigated the intra-individual consistency of aSyn-SAA results over time from participants in the Parkinson's Progression Marker Initiative (PPMI). A total of 1238 participants had >1 CSF aSyn-SAA result for analysis (Parkinson's disease [PD]=633, prodromal =563, healthy control [HC]=42) which were collected over a median (min, max) of 2.0 (0.4, 11.4) years. Emphasis was placed on evaluating consistency in less common results such as aSyn-SAA- PD participants, aSyn-SAA+ HC and conversion rates from aSyn-SAA negative to positive results prodromal participants. Of aSyn-SAA+ PD participants, 96% (474/493, 95%CI 94-98%) remained positive in subsequent samples, and 92% (116/126, 95%CI 86-96%) of aSyn-SAA- PD participants remained negative. 99% (303/307, 95%CI 97-99%) of aSyn-SAA+ prodromal participants remained positive, and 95% (234/247, 95%CI 91-97%) of aSyn-SAA- prodromal participants remained negative. 89% (16/18, 95%CI 67-97%) of aSyn-SAA+ HC participants remained positive, and 87% (20/23, 95%CI 68-95%) of aSyn-SAA- HC participants remained negative. These results confirm a high consistency of aSyn-SAA results over time, even in less expected results.

ObjectivesTo determine the impact of dopamine deficiency and isolated REM sleep behavior disorder (iRBD) on cognitive performance in early neuronal alpha-synuclein disease (NSD) with hyposmia. MethodsUsing Parkinsons Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) developed by applying regression-based internal norms derived from a robust healthy control (HC) group. Performance was examined for participants with hyposmia classified as NSD-Integrated Staging System (NSD-ISS) Stage 2, either Stage 2A (CSF alpha-synuclein seed amplification assay [SAA]+, SPECT dopamine transporter scan [DaTscan]-) or 2B (SAA+, DaTscan+). ResultsParticipants were Stage 2A (N=101), Stage 2B (N=227) and HCs (N=158). Although Stage 2 overall had intact Montreal Cognitive Assessment scores (mean (SD) =27.0 (2.3)), Stage 2A had a numerically worse CSS (z-score mean difference =0.05, p-value NS; effect size=0.09) and Stage 2B had a statistically worse CSS (z-score mean difference =0.23, p-value <0.05; effect size=0.40) compared with HCs. In Stage 2A participants with hyposmia alone had normal cognition, but presence of comorbid iRBD was associated with significantly worse cognition (z-score mean difference =0.33, p-value <0.05, effect size =0.50). In Stage 2B participants with hyposmia had abnormal cognition (z-score mean difference =0.18, p-value =.0078, effect size =0.29), and superimposed iRBD had a non-statistically significant additive effect. InterpretationUsing a CSS, early NSD with hyposmia is associated with measurable cognitive deficits compared with robust HCs, particularly in presence of dopamine system impairment or comorbid iRBD, highlighting the importance of focusing on cognition in early-stage synuclein disease.

BackgroundIt is increasingly recognized that Alzheimers disease (AD) co-pathology contributes to dementia in PD, but its role in earlier stages of cognitive impairment remains uncertain. This study examined whether plasma phosphorylated Tau at threonine 217 (p-tau217), a biomarker of early AD-related pathology, is associated with cognitive impairment in PD. MethodsUsing cross-sectional data from 167 PD patients without dementia and 63 controls of the Quebec Parkinson Network registry we examined the association between plasma p-tau217 and three measures of cognitive impairment: performance on standard neuropsychological testing, and cognitive impairment as defined by a Montreal Cognitive Assessment (MoCA) score <26 and by self-report. Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Light chain (NfL) were also measured as non-specific markers of inflammation and neurodegeneration. ResultsNo significant difference in p-tau217 level was observed between groups; GFAP and NfL were higher in PD patients, but these differences did not survive multiple comparison correction (pFDR > 0.08). Among PD patients, higher p-tau217 was associated with worse visuospatial function (p=0.04) and greater self-reported cognitive impairment (p=0.03), but these associations did not survive multiple comparison correction (pFDR > 0.08). There was no association with cognitive impairment as defined by a MoCA <26. ConclusionPlasma p-tau217 was not clearly associated with early cognitive impairment suggesting that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. Replication of these findings and longitudinal research is needed to determine whether p-tau217 can predict progression to dementia in PD.