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. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate genome-wide DNA methylation patterns in the frontal lobe white matter of individuals with MSA (n = 17), PD (n = 17), and PSP (n = 16) along with controls (n = 15) using the Illumina EPIC array, to identify shared and disease-specific DNA methylation alterations. Genome-wide DNA methylation profiling of frontal lobe white matter in the three parkinsonian disorders revealed substantial commonalities in DNA methylation alterations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport to be shared between these parkinsonian disorders. Our overall analysis points toward more similarities in DNA methylation patterns between MSA and PD, both synucleinopathies, compared to that between MSA and PD with PSP, which is a tauopathy. Our results also highlight several shared DNA methylation changes and pathways indicative of converging molecular mechanisms in the white matter contributing toward neurodegeneration in all three parkinsonian disorders.

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-ß and chronic traumatic encephalopathy. Neuropathological examination may also point to previously unsuspected genetic diagnoses with potential implications for living relatives. Moreover, detailed neuropathological assessment is crucial for research studies that rely on curated postmortem tissue to investigate the molecular mechanisms responsible for neurodegeneration and for biomarker discovery and validation. This review aims to elucidate the hallmark pathological features of neurodegenerative diseases commonly seen in general neurology clinics, such as Alzheimer's disease and Parkinson's disease; rare but well-known diseases, including progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy and more recently described entities such as chronic traumatic encephalopathy and age-related tau astrogliopathy.

Stiff person syndrome.

Stiff Person syndrome (SPS) is a rare autoimmune disorder of the central nervous system characterized by stiffness and spasms in the lumbar and proximal lower limb muscles. Nonmotor symptoms include phobias, anxiety, and depression. SPS exists on a spectrum ranging from a focal disease known as the stiff limb syndrome to progressive encephalomyelitis with rigidity and myoclonus. Collectively, these conditions may be referred to as stiff person spectrum disorders, as they share similar core clinical features and autoantibodies against several neuronal proteins, which are involved in modulating central hyperexcitability. Antibodies against the glutamic acid decarboxylase enzyme are most frequently associated with SPS but their role in disease pathogenesis remains uncertain. Other antibodies associated with SPS now include those against the glycine receptor, amphiphysin, dipeptidyl-peptidase-like protein 6, gephyrin, γ-aminobutyric acid receptor A (GABAAR), and the GABAAR-associated protein. First-line treatments for SPS include diazepam and baclofen. Patients who do not respond adequately may benefit from immunotherapy. Intravenous immunoglobulin has the most supporting evidence, and while several other immunotherapies are used, further trials are required to determine their efficacy. Further studies to establish the precise role of autoantibodies in the pathogenesis of SPS are also needed to better understand and manage this disabling condition.

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. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.

Intranasal administration of trehalose reduces α-synuclein oligomers and accelerates α-synuclein aggregation.

Abnormal α-synuclein (αSyn), including an oligomeric form of αSyn, accumulates and causes neuronal dysfunction in the brains of patients with multiple system atrophy. Neuroprotective drugs that target abnormal αSyn aggregation have not been developed for the treatment of multiple system atrophy. In addition, treating diseases at an early stage is crucial to halting the progress of neuronal damage in neurodegeneration. In this study, using early-stage multiple system atrophy mouse model and in vitro kinetic analysis, we investigated how intranasal and oral administration of trehalose can improve multiple system atrophy pathology and clinical symptoms. The multiple system atrophy model showed memory impairment at least four weeks after αSyn induction. Behavioural and physiological analyses showed that intranasal and oral administration of trehalose reversed memory impairments to near-normal levels. Notably, trehalose treatment reduced the amount of toxic αSyn and increased the aggregated form of αSyn in the multiple system atrophy model brain. In vitro kinetic analysis confirmed that trehalose accelerated the aggregate formation of αSyn. Based on our findings, we propose a novel strategy whereby accelerated αSyn aggregate formation leads to reduced exposure to toxic αSyn oligomers, particularly during the early phase of disease progression.