Parkinson disease (PD) is a progressive neurodegenerative disorder affecting 2% of the population over 70 with onset typically between 65 and 70 years. A group of proteins (principally alpha-synuclein in insoluble plaques) deposited in the central nervous system throughout the lifespan of patients are responsible for PD and related diseases. The clinical presentation of PD varies among individuals with differences in symptoms, severity, progression, and prognosis. In addition, PD bears a social stigma that presents a number of difficulities in disease management. Recent changes in PD management have created further challenges for general internal medicine providers. The goal of this review is to update general practitioners on current state-of-the-art diagnostic tools and practice strategies for PD.

AIM OF THE STUDY:CSF1R-related disorder (CSF1R-RD) is a rare, autosomal dominant microgliopathy characterized by leukoencephalopathy. While extrapyramidal symptoms are common, the underlying integrity of the presynaptic dopaminergic system in these patients remains poorly understood. The aim of our study was to analyze dopamine transporter availability using single-photon emission computed tomography (SPECT) 123I-ioflupane in patients with CSF1R mutations to differentiate the pathophysiology of their parkinsonism. MATERIAL AND METHODS:We conducted a retrospective review of 112 electronic medical charts from a large tertiary referral medical center. Four patients (3.6%) with CSF1R variants underwent SPECT 123I-ioflupane imaging. Clinical data, MRI findings, and genetic pathogenicity were assessed. RESULTS:SPECT 123I-ioflupane results were normal i n 3 patients, despite t he presence of parkinsonian symptoms, i ncluding tremor, rigidity, and bradykinesia. The only patient with an abnormal SPECT 123I-ioflupane result was a 70-year-old with a pathogenic CSF1R c.1924C > T, p.Gln642* variant and a clinical phenotype of classic Parkinson disease. CONCLUSIONS AND CLINICAL IMPLICATIONS:Parkinsonism in CSF1R-RD may present with a normal SPECT 123I-ioflupane results, suggesting that motor deficits arise from white matter degradation and disrupted connectivity rather than primary nigrostriatal loss.

Identifying plasma-based biomarkers that can accurately differentiate Lewy body disease (LBD) from Alzheimer's disease (AD) remains a major challenge. Extracellular vesicles (EVs), which carry molecular cargo from their parent cells and can cross the blood-brain barrier, offer a new path forward. We developed the multiplexed Track-Etch magnetic NanoPOre (mTENPO) platform, a highly parallelized microfluidic technology for cell-specific EV isolation, and demonstrated independent enrichment of GluR2+ (neuron-derived) and GLAST+ (astrocyte-derived) EVs from the antemortem plasma of 137 autopsy-confirmed LBD, AD, mixed pathology, and control subjects. By integrating miRNA sequencing of GluR2+ and GLAST + EV cargo with plasma measurements of Aβ40, Aβ42, tau, p-Tau181, and p-Tau231, we identified a multimodal 15-feature panel that more comprehensively reflects brain pathology than conventional biomarkers. Using tenfold cross-validation to mitigate overfitting, the panel achieved an accuracy of 0.95 and an area under the curve of 0.96 for distinguishing LBD versus AD.

Juvenile Parkinson's disease (JPD) is a rare condition characterized by the onset of parkinsonian motor symptoms before the age of 21. Sixteen patients with JPD who presented to the Mayo Clinic between 1990-2020 were included. The median age of symptoms onset was 18.5 years, and six cases had pathogenic PRKN mutations. Resting tremor was the most frequent initial symptom (81.3%), and non-motor symptoms were notably common, including mild cognitive impairment (56.3%), anxiety (62.5%), and depression (56.3%). Levodopa responsiveness was suboptimal in 9 patients and 14 exhibited motor fluctuations. JPD demonstrates distinct clinical characteristics compared with early-onset and late-onset PD.

In response to a case report on a patient with spinocerebellar ataxia type 8, presenting with early-onset parkinsonism and treated with deep brain stimulation, we report an analogous case, who responded optimally to continuous subcutaneous foscarbidopa/foslevodopa infusion.

Background:Lewy body disease (LBD) is a progressive neurodegenerative a-synucleinopathy, whereas isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of LBD. Although growing evidence implicates the gut-brain axis in neurodegeneration, the taxonomic and functional roles of the gut microbiome across the prodromal-to-symptomatic LBD continuum remain poorly defined. Methods:Here, we performed shotgun metagenomic sequencing on stool samples from 25 patients with LBD (10 mild cognitive impairment due to LBD [MCI-LB] and 15 dementia with Lewy bodies [DLB]), 10 individuals with iRBD, and their household matched cohabitant controls to characterize disease-associated microbial alterations while minimizing environmental confounding. Results:Despite no significant differences in global microbial diversity, we identified convergent shifts in microbial taxa, metabolic pathways, and gene families across disease stages. Both LBD and iRBD showed increased abundance of microbial taxa potentially associated with gut barrier disruption, as well as higher abundance of functional pathways related to lipopolysaccharide biosynthesis. LBD showed lower abundance of pathways related to complex carbohydrate fermentation, and both groups showed lower abundance of pathways associated with neurotransmitter-related metabolism. In particular, pathways and gene families associated with starch degradation were reduced in LBD, and those associated with histidine-to-glutamate/ GABA metabolism were reduced in both groups. Discussion:These exploratory findings represent the first high-resolution, shotgun metagenomic characterization of gut microbiome alterations across the LBD continuum, highlighting functional patterns that may serve as candidate markers of disease progression in future longitudinal and mechanistic studies.

Parkinson disease (PD) is a progressive neurodegenerative disorder affecting 2% of the population over 70 with onset typically between 65 and 70 years. A group of proteins (principally alpha-synuclein in insoluble plaques) deposited in the central nervous system throughout the lifespan of patients are responsible for PD and related diseases. The clinical presentation of PD varies among individuals with differences in symptoms, severity, progression, and prognosis. In addition, PD bears a social stigma that presents a number of difficulities in disease management. Recent changes in PD management have created further challenges for general internal medicine providers. The goal of this review is to update general practitioners on current state-of-the-art diagnostic tools and practice strategies for PD.

Delayed gastric emptying is a well-recognized non-motor feature of Parkinson's disease (PD) and a critical determinant of levodopa pharmacokinetics. Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly prescribed for metabolic disorders and weight loss and are under investigation as potential disease-modifying therapies in PD. However, GLP-1 signaling exerts a potent inhibitory effect on gastric motility. This creates a mechanistic convergence whereby PD-related gastrointestinal dysfunction and GLP-1-mediated gastric slowing may synergistically impair transmission of levodopa and other dopaminergic drugs to the gut and thereby limit its efficacy. Here, we synthesize current evidence on the shared neuro-gastroenterological pathways linking PD and GLP-1 signaling, and we propose a conceptual "double-hit" model of delayed gastric emptying. We further examine the implications of this interaction for levodopa pharmacokinetics and motor fluctuations, highlighting a clinically relevant trade-off between the potential benefits of GLP-1 receptor agonists and their immediate negative impact on dopaminergic therapy.

Abstract Cognitive impairment is among the most common non-motor symptoms in parkinsonism and Parkinson’s disease, ranging from subjective complaints to dementia. Although several predictive factors have been described, their prognostic relevance remains uncertain. This study aimed to examine the predictive association between clinical features and the risk of dementia and determine the incidence of dementia in a population-based cohort of incident Parkinsonism cases. Patients with parkinsonism onset between 1991 and 2020 were identified using the Rochester Epidemiology Project records-linkage system. Subjects with cognitive impairment preceding motor symptoms onset or concomitant Alzheimer’s disease were excluded. Diagnoses of dementia and mild cognitive impairment were established using neuropsychological testing or brief cognitive screening. Development of dementia was assessed using a Cox proportional hazards regression model. Associations between dementia and each risk factor were individually estimated in adjusted Cox models. All risk factors were also included in a least absolute shrinkage and selection operator penalized multivariable Cox model. A total of 1104 patients were included: 153 (13.9%) developed mild cognitive impairment, and 543 (49.2%) developed dementia during follow-up. The cumulative incidence of dementia was 30.3% at 5 years, 48.6% at 10 years, 61.4% at 15 years and 69.3% at 20 years, indicating that a considerable portion of patients remained free of dementia after a prolonged follow-up. The majority of patients with dementia were males (61.5%), and older age at disease onset was associated with risk of dementia (hazard ratio [HR] = 1.32, P < 0.001 per 5-year increment). In the penalized model, dementia risk was significantly higher among individuals presenting with impaired postural reflexes (HR = 1.26, P = 0.014), consistent with a poorer prognosis in akinetic-rigid-predominant parkinsonism. Eye movement abnormalities, including reduced ocular range of motion (HR = 1.86, P < 0.001) and smooth pursuit alterations (HR = 1.34, P = 0.024), were also associated with dementia. Non-motor symptoms, including rapid eye movement sleep behaviour disorder (HR = 1.51, P < 0.001), orthostatic hypotension (HR = 1.30, P = 0.009) and constipation (HR = 1.24, P = 0.022), were linked to dementia risk, supporting a potential involvement of non-dopaminergic and central autonomic pathways in cognitive decline. These findings were largely confirmed in the Parkinson’s disease/Parkinson’s disease with dementia group, in which 77 (13.5%) developed mild cognitive impairment and 249 (43.5%) developed dementia. Among these patients, smooth pursuit alterations, reduced ocular range of motion, orthostatic hypotension and constipation were associated with dementia.

INTRODUCTION: The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal-to-noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS: Fifty-seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS: Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non-AD tauopathies. DISCUSSION: These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non-AD tauopathies.

Quantitative susceptibility mapping (QSM) on MRI quantifies tissue magnetic susceptibility, which increases with iron accumulation, myelin loss, and neuroinflammation. Elevated QSM in the substantia nigra (SN) has been reported in Lewy body disease and other parkinsonian disorders, but from existing literature it remains unclear whether these findings are driven by neurodegeneration-related iron deposition or other neuropathologic features. We studied 59 autopsied participants who underwent antemortem 3 T MRI with QSM (median age at death, 78.5 years; MRI-to-death interval, 2.0 years), including clinical diagnoses of 18 with Alzheimer’s-type dementia, 15 cognitively unimpaired, 9 with mild cognitive impairment, and 9 with dementia with Lewy bodies. A machine learning-incorporated digital histopathology pipeline quantified tau burden, iron deposition, and neuronal densities. The SN was divided into geometric quadrants, and QSM values were analyzed in relation to corresponding neuropathologic measures within each quadrant. Iron deposition correlated with QSM in all quadrants (ρ = 0.41–0.56, all P < 0.005). Tau burden correlated with QSM in the ventromedial (VM) quadrant (ρ = 0.45, P = 0.002), whereas lower pigmented neuron density was associated with higher QSM in the dorsomedial quadrant (ρ = – 0.35, P = 0.007). Rank regression analysis confirmed iron as the strongest predictor of QSM across all quadrants (β = 0.35–1.06, P ≤ 0.026), with tau independently associated with QSM in the VM (β = 0.45, P = 0.015). Mediation analysis demonstrated that tau exerted direct (0.45, P = 0.018) and indirect effects via iron (0.12, P = 0.046) on QSM in the VM, with 80

OBJECTIVES:Early-onset Parkinson disease (EOPD) is associated with stronger genetic contributions than late-onset Parkinson disease (LOPD). However, the complex interplay between genetic susceptibility, family history, and environmental factors remains incompletely understood. This study assesses familial aggregation of PD and essential tremor (ET) among relatives of patients with EOPD and compares it with patients with LOPD. METHODS:Patients with EOPD evaluated at the Mayo Clinic were identified, whereas patients with LOPD were identified through the Rochester Epidemiology Project record-linkage system. All cases with symptom onset between 1991 and 2020 were included. RESULTS:A total of 732 cases with EOPD and 469 with LOPD were included. EOPD patients were significantly more likely to have a positive family history of PD in parents (proportion ratio [PR] = 1.67, p = 0.049), second-degree relatives (PR = 2.54, p < 0.001), and all family members (PR = 1.63, p < 0.001). Similarly, they had higher frequency of family history of ET (PR = 1.47, p = 0.029). By contrast, patients with EOPD were less likely to have siblings with PD (PR = 0.38, p = 0.009). DISCUSSION:The higher prevalence of PD and ET family history in the EOPD cohort supports a stronger genetic contribution and may reflect enrichment for high-penetrance monoallelic variants. Conversely, the higher frequency of affected siblings in the LOPD cohort suggests a polygenic inheritance pattern with greater environmental contribution.

Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer's disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time-course 123 I-FP-CIT SPECT (DaT-SPECT) findings in autopsy-confirmed DLB are not well characterized. We previously reported that the DaTQUANT z-score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z-score of −1 as the cutoff value. We sought to examine how DaT-SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT-SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age-adjusted z-scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT-SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z-score <-1.0 at their initial scan including in MCI+RBD (-1.76) and iRBD (-1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z-score <-2.0 and one (17%) had z-score of -1.55. All patients (100%) showed DaTQUANT putamen z-score <-2.0 at their last scans. DaTQUANT using cut-off putamen z-score of -1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z-score <-2 at their last scans.

Abstract INTRODUCTION Visual perceptual difficulties occur in dementia with Lewy bodies (DLB). Normative data and cut scores for DLB and mild cognitive impairment with Lewy bodies (MCI‐LB) are needed for the 20‐item Noise Pareidolia Task. METHODS Participants included 344 cognitively unimpaired (CU), 112 DLB, and 105 MCI‐LB. Cumulative percentile ranking was used for normative classification. Receiver operating characteristic analyses, convergent validity, and associations with visual hallucinations (VH) were assessed. RESULTS In CU participants, a perfect score was average, one error was low average, and two or more errors fell below average. A cut score of one or more errors optimally distinguished CU participants from DLB (Total score area under the curve [AUC]: 0.82, Noise score AUC: 0.77) and MCI‐LB (Total score AUC: 0.75, Noise score AUC: 0.74). A cut score of two or more errors lowered sensitivity but increased specificity to 94%. Performance was associated with VH in DLB, but not MCI‐LB. DISCUSSION Results establish normative data for the 20‐item Noise Pareidolia Task and support its use in DLB and MCI‐LB.