DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson's disease, and progressive supranuclear palsy: a cross-comparative investigation.

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by neuronal loss and gliosis, with oligodendroglial cytoplasmic inclusions (GCIs) containing α-synuclein being the primary pathological hallmark. Clinical presentations of MSA overlap with other parkinsonian disorders, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported alterations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP.

Neuropathologic Validation and Diagnostic Accuracy of Presynaptic Dopaminergic Imaging in the Diagnosis of Parkinsonism.

Background And Objectives: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism.

Pathology of neurodegenerative disease for the general neurologist.

Neurodegeneration refers to progressive dysfunction or loss of selectively vulnerable neurones from brain and spinal cord regions. Despite important advances in fluid and imaging biomarkers, the definitive diagnosis of most neurodegenerative diseases still relies on neuropathological examination. Not only has careful clinicopathological correlation shaped current clinical diagnostic criteria and informed our understanding of the natural history of neurodegenerative diseases, but it has also identified conditions with important public health implications, including variant Creutzfeldt-Jakob disease, iatrogenic amyloid-β and chronic traumatic encephalopathy.

Late Presentation of Chronic Traumatic Encephalopathy in a Former Association Football Player.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people who have suffered repetitive head impacts. To date, very few cases have been reported in association football players.

Objectives: To describe the clinicopathological features of a case of CTE in an 84-year-old former football player who was clinically diagnosed as having dementia with Lewy bodies (DLB).

Pathological Validation of the MDS Criteria for the Diagnosis of Multiple System Atrophy.

Background: The recent International Parkinson and Movement Disorder Society diagnostic criteria for multiple system atrophy (MDS-MSA) have been developed to improve diagnostic accuracy although their diagnostic properties have not been evaluated.

Objectives: The aims were to validate the MDS-MSA diagnostic criteria against neuropathological diagnosis and compare their diagnostic performance to previous criteria and diagnosis in clinical practice.

Methods: Consecutive patients with sporadic, progressive, adult-onset parkinsonism, or cerebellar ataxia from the Queen Square Brain Bank between 2009 and 2019 were selected and divided based on neuropathological diagnosis into MSA and non-MSA.

Clinical Diagnostic Accuracy of Parkinson's Disease: Where Do We Stand?

Background: Clinical diagnostic accuracy of Parkinson's disease (PD) remains suboptimal. Changes in disease concept may have improved clinical diagnostic accuracy in the past decade. However, current clinical diagnostic criteria have not been validated against neuropathological confirmation.

Type 2 Diabetes and Parkinson's Disease: A Focused Review of Current Concepts.

Highly reproducible epidemiological evidence shows that type 2 diabetes (T2D) increases the risk and rate of progression of Parkinson's disease (PD), and crucially, the repurposing of certain antidiabetic medications for the treatment of PD has shown early promise in clinical trials, suggesting that the effects of T2D on PD pathogenesis may be modifiable. The high prevalence of T2D means that a significant proportion of patients with PD may benefit from personalized antidiabetic treatment approaches that also confer neuroprotective benefits. Therefore, there is an immediate need to better understand the mechanistic relation between these conditions and the specific molecular pathways affected by T2D in the brain.

Association Between Orthostatic Hypotension and Dementia in Patients With Parkinson Disease and Multiple System Atrophy.

Background And Objectives: Orthostatic hypotension (OH) increases dementia risk in patients with Parkinson disease (PD), although the underlying mechanisms and whether a similar association between OH and cognitive impairment exists in other synucleinopathies remain unknown. The aim is to evaluate the association between OH and dementia risk in patients with PD, and cognitive impairment risk in patients with multiple system atrophy (MSA), and to explore relevant clinical and neuropathologic factors to understand underlying pathogenic mechanisms.

Methods: This is a retrospective cohort study.

Diagnosing Premotor Multiple System Atrophy: Natural History and Autonomic Testing in an Autopsy-Confirmed Cohort.

Background And Objectives: Nonmotor features precede motor symptoms in many patients with multiple system atrophy (MSA). However, little is known about differences between the natural history, progression, and prognostic factors for survival in patients with MSA with nonmotor vs motor presentations. We aimed to compare initial symptoms, disease progression, and clinical features at final evaluation and investigate differences in survival and natural history between patients with MSA with motor and nonmotor presentations.

The faecal metabolome and mycobiome in Parkinson's disease.

Background: Gut fungal composition and its metabolites have not been assessed simultaneously in Parkinson's disease (PD) despite their potential pathogenic contribution.

Objective: To evaluate the faecal metabolome and mycobiome in PD by assessing volatile organic compounds (VOCs) and fungal rRNA.

Methods: Faecal VOCs from 35 PD patients and two control groups (n = 35; n = 15) were assessed using gas chromatography and mass spectrometry.

Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation.

The microtubule-associated protein tau gene (MAPT) 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four-repeat (4R)-tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R-tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10+16 carriers which, compared to controls, showed persistently increased 4R:3R-tau transcript and protein ratios in both cell types.

Hypothalamic α-synuclein and its relation to autonomic symptoms and neuroendocrine abnormalities in Parkinson disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder presenting with defining motor features and a variable combination of nonmotor symptoms. There is growing evidence suggesting that hypothalamic involvement in PD may contribute to the pathogenesis of nonmotor symptoms. Initial neuropathologic studies demonstrated histologic involvement of hypothalamic nuclei by Lewy pathology, i.

Faster disease progression in Parkinson's disease with type 2 diabetes is not associated with increased α-synuclein, tau, amyloid-β or vascular pathology.

Aims: Growing evidence suggests a shared pathogenesis between Parkinson's disease and diabetes although the underlying mechanisms remain unknown. The aim of this study was to evaluate the effect of type 2 diabetes on Parkinson's disease progression and to correlate neuropathological findings to elucidate pathogenic mechanisms.

Methods: In this cohort study, medical records were retrospectively reviewed of cases with pathologically confirmed Parkinson's disease with and without pre-existing type 2 diabetes.

Identification of multiple system atrophy mimicking Parkinson's disease or progressive supranuclear palsy.

We studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson's disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.

A Clinicopathologic Study of Movement Disorders in Frontotemporal Lobar Degeneration.

Background: Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking.

Objective: The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD.

Methods: In this cohort study, movement disorder clinical data were retrospectively collected from medical records of consecutive patients with a postmortem diagnosis of FTLD from the Queen Square Brain Bank between January 2010 and December 2018.

The Association Between Type 2 Diabetes Mellitus and Parkinson's Disease.

In recent years, an emerging body of evidence has forged links between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). In observational studies, those with T2DM appear to be at increased risk of developing PD, as well as experiencing faster progression and a more severe phenotype of PD, with the effects being potentially mediated by several common cellular pathways. The insulin signalling pathway, for example, may be responsible for neurodegeneration via insulin dysregulation, aggregation of amyloids, neuroinflammation, mitochondrial dysfunction and altered synaptic plasticity.

Colonic transit, high-resolution anorectal manometry and MRI defecography study of constipation in Parkinson's disease.

Introduction: Despite clinical relevance and potential role on the disease pathogenesis, underlying mechanisms of constipation in Parkinson's disease (PD) remain poorly understood. A systematic assessment using complementary physiological investigations was performed to elucidate constipation pathophysiology in order to improve its symptomatic management.

Methods: PD patients with constipation were evaluated with clinical questionnaires, colonic transit, high-resolution anorectal manometry and MRI defecography.

Prognosis and Neuropathologic Correlation of Clinical Subtypes of Parkinson Disease.

Importance: Clinical subtyping of Parkinson disease at diagnosis is useful in estimating disease course and survival. Severity and rate of progression of neuropathologies are important determinants of clinical Parkinson subtypes.

Objective: To provide longitudinal clinical disease-course data and neuropathologic correlation for newly proposed Parkinson disease subtypes.

Association of autonomic symptoms with disease progression and survival in progressive supranuclear palsy.

Background: Development of autonomic failure is associated with more rapid disease course and shorter survival in patients with Parkinson's disease and multiple system atrophy. However, autonomic symptoms have not been specifically assessed as a prognostic factor in progressive supranuclear palsy (PSP). We evaluated whether development of autonomic symptoms is associated with disease progression and survival in PSP.