Neurodegenerative movement disorders: An epigenetics perspective and promise for the future

Neurodegenerative movement disorders (NMDs) are age dependent disorders that are characterised by the degeneration and loss of neurons, typically accompanied by pathological accumulation of different protein aggregates in the brain, which lead to motor symptoms. NMDs include Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and Huntington's disease, among others. Epigenetic modifications are responsible for functional gene regulation during development, adult life, and ageing, and have progressively been implicated in complex diseases such as cancer, and more recently in neurodegenerative diseases, such as NMDs. DNA methylation is by far the most widely studied epigenetic modification and consists of the reversible addition of a methyl group to the DNA without changing the DNA sequence. Although this research field is still in its infancy in relation to NMDs, an increasing number of studies point towards a role for DNA methylation in disease processes. This review addresses recent advances in epigenetic and epigenomic research in NMDs, with a focus on human brain DNA methylation studies. We discuss the current understanding of the DNA methylation changes underlying these disorders, the potential for use of these DNA modifications in peripheral tissues as biomarkers in early disease detection, classification, and progression as well as a promising role in future disease management and therapy

Hierarchical Joint Registration of Tissue Blocks With Soft Shape Constraints For Large-Scale Histology of The Human Brain

Large-scale 3D histology reconstruction of the human brain with MRI as volumetric reference generally requires reassembling the tissue blocks into the MRI space, prior to any further reconstruction of the histology of the individual blocks. This is a challenging registration problem, particularly in the frequent case that blockface photographs of paraffin embedded tissue are used as intermediate modality, as their contrast between white and gray matter is rather low. Here we propose a registration framework to address this problem, relying on two key components. First, blocks are simultaneously aligned to the MRI while exploiting the spatial constraints that they impose on each other, by means of a customized soft shape constraint (similarly to a jigsaw puzzle). And second, we adopt a hierarchical optimization strategy that capitalizes on our prior knowledge on the slicing and blocking procedure. Our framework is validated quantitatively on synthetic data, and qualitatively on the histology of a whole human hemisphere

Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan

Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aβ in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble Aβ in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-Aβ interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms – all known pathogenic features of these protein folding disorders – suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms

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 is 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

A case of TDP-43 type C pathology presenting as nonfluent variant primary progressive aphasia

We report a case of rapidly progressive nonfluent variant PPA (nfvPPA), age at onset 77 years old and disease duration 3.3 years, who came to post mortem and was found to have TDP-43 type C pathology, an unusual finding for nfvPPA. All prior TDP-43 type C cases from the UCL FTD cohort (n=25) had a semantic variant PPA (svPPA) phenotype, with all having a younger age at onset and longer disease duration than the nfvPPA case. Volumetric analysis of MRI from the nfvPPA case, twelve of the svPPA cases and ten age-matched controls was performed. Whilst left frontal and insular volumes were lower in the nfvPPA case compared with svPPA, cortical and medial temporal lobe volumes were lower (particularly on the right) in the svPPA group compared with the nfvPPA patient. Such anatomical involvement is likely to be consistent with the presence of a nonfluent aphasia (left frontal lobe and insula), and only mild semantic deficit early in the illness (left but not right temporal lobe). Such unique cases add to the heterogeneity of the FTD spectrum

Coenzyme Q10 Levels Are Decreased in the Cerebellum of Multiple-System Atrophy Patients

BACKGROUND: The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases. METHODS: Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography. RESULTS: We detected a statistically significant decrease (by 3-5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)]. CONCLUSION: Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated

Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired Association football (soccer) players

In retired professional Association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career and concussion history were prospectively collected. Next-of-kin consented for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer’s disease (N=6), TDP-43 (N=6), cerebral amyloid angiopathy (N=5), hippocampal sclerosis (N=2), corticobasal degeneration (N=1), dementia with Lewy bodies (N=1) and vascular pathology (N=1), all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer’s disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association Football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation including large scale case-control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies

Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognised for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. RESULTS: CAA was more common in DLB than in PDD (p = 0.003). The severity of CAA was greater in DLB than in PDD (p = 0.009), with significantly higher CAA scores in the parietal lobe (p = 0.043), and the occipital lobe (p = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. CONCLUSIONS: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD