Structures of α-synuclein filaments from human brains with Lewy pathology.

Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms1. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra2. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis3. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset4. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy5. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.

MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration.

The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site3. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies4. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies5 and Parkinson's disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces-whereas silencing MAPT-AS1 expression increases-neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs6, with particular relevance for proteostasis in neurodegeneration.

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.

The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression.

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.

Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue.

AIMS: Epigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter. METHODS: We analysed the performances of two DNA methylation-based clocks, DNAmClockMulti and DNAmClockCortical , in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α-synuclein aggregates in oligodendrocytes. RESULTS: Estimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClockCortical , r = [0.80-0.97], p < 0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClockMulti significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClockCortical tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte-enriched cohorts (e.g., oligodendrocyte-enriched nuclei, p = 6.1 × 10-5 ) suggested that this cell type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClockCortical (r > 0.31, p < 0.05), and similar trends were obtained with DNAmClockMulti . Although increased age acceleration was observed in MSA compared with controls, no significant differences were detected upon adjustment for possible confounders (e.g., cell-type proportions). CONCLUSIONS: Our findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration.

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. Medical records were systematically reviewed, and clinical diagnosis was documented by retrospectively applying the MDS-MSA criteria, second consensus criteria, and diagnosis according to treating clinicians at early (within 3 years of symptom onset) and final stages. Diagnostic parameters (sensitivity, specificity, positive/negative predictive value, and accuracy) were calculated using neuropathological diagnosis as gold standard and compared between different criteria. RESULTS: Three hundred eighteen patients (103 MSA and 215 non-MSA) were included, comprising 248 patients with parkinsonism and 70 with cerebellar ataxia. Clinically probable MDS-MSA showed excellent sensitivity (95.1%), specificity (94.0%), and accuracy (94.3%), although their sensitivity at early stages was modest (62.1%). Clinically probable MDS-MSA outperformed diagnosis by clinicians and by second consensus criteria. Clinically established MDS-MSA showed perfect specificity (100%) even at early stages although to the detriment of low sensitivity. MDS-MSA diagnostic accuracy did not differ according to clinical presentation (ataxia vs. parkinsonism). CONCLUSIONS: MDS-MSA criteria demonstrated excellent diagnostic performance against neuropathological diagnosis and are useful diagnostic tools for clinical practice and research. © 2023 International Parkinson and Movement Disorder Society.

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. OBJECTIVES: This study aims to provide up-to-date clinical diagnostic accuracy data and validate current clinical diagnostic criteria for PD against neuropathology. METHODS: A retrospective review of medical records of consecutive patients with parkinsonism from the Queen Square Brain Bank was performed between 2009 and 2019. Clinical diagnosis was documented at early (within 5 years of motor symptom onset) and final stages and categorized by movement disorder experts or regular clinicians. Movement Disorder Society Parkinson's disease (MDS-PD) diagnostic criteria were retrospectively applied. Diagnostic accuracy parameters (sensitivity, specificity, positive/negative predictive value, and accuracy) were calculated using neuropathological diagnosis as the gold standard. RESULTS: A total of 267 patients (141 PD and 126 non-PD parkinsonism) were included. Clinical diagnostic accuracy was 97.2% for experts, 92.5% for the MDS clinically probable PD criteria, and 90.3% for clinicians. Similar figures were obtained when applied at an early stage (91.5%, 89.5%, and 84.2% diagnostic accuracy, respectively). MDS clinically established early PD criteria demonstrated very high specificity (98.4%) at early stages. CONCLUSIONS: Our results showed an important improvement in PD clinical diagnostic accuracy in clinical practice over the past decade, more marked at early stages of the disease. MDS-PD diagnostic criteria is a valid tool in clinical practice and research for the identification of PD patients showing excellent sensitivity and specificity, although movement disorder experts' diagnosis remains the gold standard PD diagnosis during life. © 2023 International Parkinson and Movement Disorder Society.

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. Although there is considerable evidence that processes such as insulin signaling, mitochondrial function, autophagy, and inflammation are involved in the pathogenesis of both PD and T2D, the primary aim of this review is to highlight the evidence showing that T2D-associated dysregulation of these pathways occurs not only in the periphery but also in the brain and how this may facilitate neurodegeneration in PD. We also discuss the challenges involved in disentangling the complex relationship between T2D, insulin resistance, and PD, as well as important questions for further research. © 2022 International Parkinson and Movement Disorder Society.

Neuroimaging correlates of brain injury in Wilson's disease: a multimodal, whole-brain MRI study.

Wilson's disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focused on specific sequences or regions of interest, often stratifying chronically treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively recruited patients with Wilson's disease (age range 16-68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding 6 months as having 'active' disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound ('free') copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson's disease.

Globular glial tauopathy type II.

The globular glial tauopathies (GGTs) are a rare group of neurodegenerative diseases with fewer than 90 autopsy-confirmed cases reported in the literature. Although there has been some uncertainty about whether GGT is entirely distinct from progressive supranuclear palsy, a recent study of tau filament structures supports the definition of GGT as a separate neuropathological entity. We present a sporadic case of GGT type II presenting with a progressive corticobasal-primary lateral sclerosis overlap syndrome in a 74-year-old woman. Neuropathological examination identified neuronal and glial tau inclusions, including globular astrocytic and oligodendroglial inclusions. We also discuss the clinical features and molecular pathophysiology of GGT. Increased awareness of this condition could become more important as patients with GGT may be candidates for anti-tau therapies currently undergoing clinical evaluation in patients with other tauopathies.

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. However, beyond 300 days culture, 10+16 neurons showed less marked increase of this 4R:3R-tau transcript ratio compared to astrocytes. Interestingly, throughout maturation, both 10+16 carriers consistently displayed different 4R:3R-tau transcript and protein ratios. These elevated levels of 4R-tau in astrocytes implicate glial cells in the pathogenic process and also suggests a cell-type-specific regulation and may inform and help on treatment of pre-clinical tauopathies.

Pathological substrate of memory impairment in multiple system atrophy.

AIMS: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic α-synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal α-synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of α-synuclein-positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal α-synuclein in the hippocampus can lead to memory impairment. METHODS: We performed pathological and biochemical analyses using a mouse model of adult-onset MSA and human cases (MSA, N = 25; Parkinson's disease, N = 3; Alzheimer's disease, N = 2; normal controls, N = 11). In addition, the MSA model mice were examined behaviourally and physiologically. RESULTS: In the MSA model, inducible human α-synuclein was first expressed in oligodendrocytes and subsequently accumulated in the cytoplasm of excitatory hippocampal neurons (NCI-like structures) and their presynaptic nerve terminals with the development of memory impairment. α-Synuclein oligomers increased simultaneously in the hippocampus of the MSA model. Hippocampal dendritic spines also decreased in number, followed by suppression of long-term potentiation. Consistent with these findings obtained in the MSA model, post-mortem analysis of human MSA brain tissues showed that cases of MSA with memory impairment developed more NCIs in excitatory hippocampal neurons along with α-synuclein oligomers than those without. CONCLUSIONS: Our results provide new insights into the role of α-synuclein oligomers as a possible pathological cause of memory impairment in MSA.

Neuroimaging Correlates of Cognitive Deficits in Wilson's Disease.

BACKGROUND: Cognitive impairment is common in neurological presentations of Wilson's disease (WD). Various domains can be affected, and subclinical deficits have been reported in patients with hepatic presentations. Associations with imaging abnormalities have not been systematically tested. OBJECTIVE: The aim was to determine the neuroanatomical basis for cognitive deficits in WD. METHODS: We performed a 16-item neuropsychological test battery and magnetic resonance brain imaging in 40 patients with WD. The scores for each test were compared between patients with neurological and hepatic presentations and with normative data. Associations with Unified Wilson's Disease Rating Scale neurological examination subscores were examined. Quantitative, whole-brain, multimodal imaging analyses were used to identify associations with neuroimaging abnormalities in chronically treated stable patients. RESULTS: Abstract reasoning, executive function, processing speed, calculation, and visuospatial function scores were lower in patients with neurological presentations than in those with hepatic presentations and correlated with neurological examination subscores. Deficits in abstract reasoning and phonemic fluency were associated with lower putamen volumes even after controlling for neurological severity. About half of patients with hepatic presentations had poor performance in memory for faces, cognitive flexibility, or associative learning relative to normative data. These deficits were associated with widespread cortical atrophy and/or white matter diffusion abnormalities. CONCLUSIONS: Subtle cognitive deficits in patients with seemingly hepatic presentations represent a distinct neurological phenotype associated with diffuse cortical and white matter pathology. This may precede the classical neurological phenotype characterized by movement disorders and executive dysfunction and be associated with basal ganglia damage. A binary phenotypic classification for WD may no longer be appropriate. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson's disease (i.e. Parkinson's disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson's disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson's disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson's disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson's disease mimic versus typical Parkinson's disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson's disease or progressive supranuclear palsy (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson's disease or progressive supranuclear palsy.

Faster disease progression in Parkinson's disease with type 2 diabetes is not associated with increased α-synuclein, tau, amyloid-ß 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. Time to disability milestones (recurrent falls, wheelchair dependence, dementia and care home placement) and survival were compared to assess disease progression and their risk estimated using Cox hazard regression models. Correlation with pathological data was performed, including quantification of α-synuclein in key brain regions and staging of vascular, Lewy and Alzheimer's pathologies. RESULTS: Patients with PD and diabetes (male 76%; age at death 78.6 ± 6.2 years) developed earlier falls (p < 0.001), wheelchair dependence (p = 0.004), dementia (p < 0.001), care home admission (p < 0.001) and had reduced survival (p < 0.001). Predating diabetes was independently associated with a two to three-fold increase in the risk of disability and death. Neuropathological assessment did not show any differences in global or regional vascular pathology, α-synuclein load in key brain areas, staging of Lewy pathology or Alzheimer's disease pathology. CONCLUSIONS: Pre-existing type 2 diabetes contributes to faster disease progression and reduced survival in Parkinson's disease which is not driven by increased vascular, Lewy or Alzheimer's pathologies. Additional non-specific neurodegeneration related to chronic brain insulin resistance may be involved.

MOBP and HIP1 in multiple system atrophy: New α-synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis.

AIMS: Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α-synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α-synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin-associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation. METHODS: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays. RESULTS: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA. CONCLUSIONS: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.

Wilson's disease: update on pathogenesis, biomarkers and treatments.

Wilson's disease is an autosomal-recessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. Decoppering treatments are used to prevent disease progression and reduce symptoms, but neurological outcomes remain mixed. In this article, we review the current understanding of pathogenesis, biomarkers and treatments for Wilson's disease from the neurological perspective, with a focus on recent advances. The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotype-phenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilson's disease. Delayed diagnoses continue to be a major problem for patients with neurological presentations. We highlight limitations in our current approach to making a diagnosis and novel diagnostic biomarkers, including the potential for newborn screening programmes. We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilson's disease, before discussing future directions for translational research.

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. At postmortem, neurodegenerative pathologies were systematically evaluated following consensus criteria. Degeneration of the substantia nigra was assessed as a marker of presynaptic dopaminergic parkinsonism using semiquantitative methods. RESULTS: A total of 55 patients (35 men [64%]) were included with median (interquartile range) age at diagnosis of 58.8 (52.6-63.9) years and a disease duration of 9.6 (6.2-12.9) years. Movement disorders were present in 19 (35%) patients without differences among disease subtypes. The most common syndromes were parkinsonism (9 patients [16%]), usually as an additional late feature, and corticobasal syndrome (CBS, 7 patients [13%]), commonly as a presenting feature. Substantia nigra degeneration was present in 37 (67%) patients although it did not show a good clinical correlation with movement disorders. Those with Pick's disease showed milder substantia nigra degeneration and better response to levodopa. CONCLUSIONS: Movement disorders can present in all FTLD subtypes, more commonly as a late additional feature (parkinsonism) or as a presenting symptom (CBS). The underlying pathophysiology is complex and likely to involve structures outside the presynaptic striatonigral system. © 2020 International Parkinson and Movement Disorder Society.

Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease.

BACKGROUND: Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end-organ damage. OBJECTIVE: To identify a biomarker for neurological involvement in WD. METHODS: Neuronal and glial-specific proteins were measured in plasma samples from 40 patients and 38 age-matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non-adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded. RESULTS: Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients. CONCLUSION: NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Hippocampal α-synuclein pathology correlates with memory impairment in multiple system atrophy.

Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1-4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal-subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in multiple system atrophy.