All brain areas affected in Parkinson's disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A- expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

Huntington's disease (HD) is an autosomal dominantly inherited, and currently untreatable, neuropsychiatric disorder. This progressive and ultimately fatal disease is named after the American physician George Huntington and according to the underlying molecular biological mechanisms is assigned to the human polyglutamine or CAG-repeat diseases. In the present article we give an overview of the currently known neurodegenerative hallmarks of the brains of HD patients. Subsequent to recent pathoanatomical studies the prevailing reductionistic concept of HD as a human neurodegenerative disease, which is primarily and more or less exclusively confined to the striatum (ie, caudate nucleus and putamen) has been abandoned. Many recent studies have improved our neuropathological knowledge of HD; many of the early groundbreaking findings of neuropathological HD research have been rediscovered and confirmed. The results of this investigation have led to the stepwise revision of the simplified pathoanatomical and pathophysiological HD concept and culminated in the implementation of the current concept of HD as a multisystem degenerative disease of the human brain. The multisystem character of the neuropathology of HD is emphasized by a brain distribution pattern of neurodegeneration (i) which apart from the striatum includes the cerebral neo-and allocortex, thalamus, pallidum, brainstem and cerebellum, and which (ii) therefore, shares more similarities with polyglutamine spinocerebellar ataxias than previously thought.

The phenotype of early-onset Alzheimer Disease, associated with Presenilin 1 (PSEN1) gene mutations, may present with clinical and neuropathological heterogeneity. In some instances, the clinical presentation and evolution of the disorder may suggest other neurodegenerative disorders. The proband has been followed clinically during the past two years; magnetic resonance imaging (MRI) studies were carried out. Family history indicates that the proband's mother died at 39 with a neurodegenerative disease. The proband's DNA was isolated, and the Huntingtin and Prion Protein genes were sequenced. Archival brain tissue from the proband's mother was traced and reexamined by histology and immunohistochemistry. For histology, hematoxylin and eosin-Luxol fast blue and Thioflavin S methods were used; for immunohistochemistry, sections were labeled with antibodies against tau, β-amyloid, and α-synuclein. Following the brain studies, the PSEN1 gene was sequenced. The proband, a 38 year-old woman, presented with impaired memory and lack of insight. Neurological evaluation showed dysarthria, truncal myoclonus, increased muscle tone, and ataxia with a wide-based gait. MRI revealed marked cerebral atrophy with hydrocephalus. Review of records documented early onset dementia, suspected to be Huntington disease (HD), affecting the proband's mother and grandmother. Genetic analysis at the National Prion Disease Pathology Surveillance Center ruled out familial prion disease. HD had been ruled out previously. Review of the mother's brain autopsy revealed cerebral atrophy. Histologically, the cerebral cortex showed numerous amyloid plaques and neurofibrillary tangles. Lewy bodies were noted in amygdala. Aβ and tau deposits were numerous in cerebral cortex, amygdala, hippocampus, and entorhinal cortex. Aβ-immunolabeled plaques without cores (“cotton wool plaques”) were present. Amyloid angiopathy was observed. DNA analysis revealed a TTG to TTT nucleotide mutation, resulting in leucine to phenylalanine substitution (L418F) in the PSEN1 gene. This is the first study of the phenotypic and neuropathological features associated with the PSEN1 L418F mutation. Clinical presentation and family history had suggested various neurodegenerative disorders, including HD and prion disease as possible diagnoses. Retrospective neuropathological studies of the mother's brain were informative and paved the way for screening for familial AD genes and a definitive diagnosis. (P30AG35982; P30AG010133; HBTRC HHSN-271-2013-0030C; CDC UR8/CCU515004.)

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

OBJECTIVE: We investigated protein levels and expression patterns of excitatory amino acid transporter 1 (EAAT1) and EAAT2 in the cerebellar cortex of essential tremor (ET) cases and controls. BACKGROUND: SLC1A2 genetic polymorphisms have been linked to ET. The SLC1A2 gene encodes EAAT2, the major glutamate transporter that clears glutamate from the synaptic cleft. One postulated mechanism of ET is the over-excitation of glutamatergic olivo-cerebellar climbing fibers, which leads to the excitotoxic destruction of Purkinje cells (PCs). Therefore, the levels of EAATs could be important in ET pathogenesis. DESIGN/METHODS: We compared the levels of EAAT1 and EAAT2 in postmortem cerebellar cortex from 16 ET cases and 13 age-matched controls using Western blotting. We also studied the expression patterns of EAAT1 and EAAT2 in the cerebellar cortex by immunohistochemistry. RESULTS: We found that the EAAT1 levels were similar in ET cases and in controls (1.16 ± 1.13 in ET cases vs. 1.00 ± 0.78 in controls, p = 0.67). The average EAAT2 level was three times higher in controls than in ET cases (1.00 ± 0.62 in controls vs. 0.35 ± 0.23 in ET cases, p = 0.001). EAAT1 was expressed mostly in the Bergmann glia radial processes whereas EAAT2 was expressed not only in the Bergman glia but also in the protoplasmic astrocytes. EAAT2, but not EAAT1, was selectively expressed in the astrocytic processes surrounding the PC axonal initial segment, a region of other ET pathology such as PC axonal torpedoes and "hairy" basket cell processes. EAAT1 and EAAT2 expression patterns did not differ between ET cases and controls. CONCLUSIONS: These results indicated that the EAAT2 levels were selectively decreased in the astrocytes in the ET cerebellar cortex. Decreased EAAT2 levels could support the excitotoxicity hypothesis of ET. Study Supported by: NINDS R01 NS042859, NINDS K08 NS08738

Background: Huntington's disease (HD) is a progressive polyglutamine disease which is characterized neuropathologically by severe neuronal loss in the striatum and select layers of the neo- /INS;and allocortex. The cerebellum and brainstem are among the brain sites whose neuropathological state in and relevance for the clinical picture of HD is still controversial.

(Neuron 78, 440–455; May 8, 2013) The original version of Figure 6 contained incorrect sequences for the two CGG KI mouse lines used in this study. This typographical error does not affect our interpretation of the data. We apologize for any inconvenience that this error has caused. The corrected figure is below and has also been corrected in the online version of the paper. CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia SyndromeTodd et al.NeuronApril 18, 2013In BriefCGG repeat expansions underlie the neurodegenerative disorder fragile X-associated tremor ataxia syndrome. Todd et al. describe how CGG repeats trigger non-AUG-initiated translation, producing a polyglycine protein that accumulates in FXTAS brains and contributes to toxicity in model systems. Full-Text PDF Open Archive

Objective: Multiple system atrophy (MSA), the most common of the atypical parkinsonian disorders, is characterized by the presence of an abnormal spatial covariance pattern in resting state metabolic brain images from patients with this disease. Nonetheless, the potential utility of this pattern as a MSA biomarker is contingent upon its specificity for this disorder and its relationship to clinical disability in individual patients. Methods: We used [18F]fluorodeoxyglucose PET to study 33 patients with MSA, 20 age- and severity-matched patients with idiopathic Parkinson disease (PD), and 15 healthy volunteers. For each subject, we computed the expression of the previously characterized metabolic covariance patterns for MSA and PD (termed MSARP and PDRP, respectively) on a prospective single-case basis. The resulting network values for the individual patients were correlated with clinical motor ratings and disease duration. Results: In the MSA group, disease-related pattern (MSARP) values were elevated relative to the control and PD groups (p < 0.001 for both comparisons). In this group, MSARP values correlated with clinical ratings of motor disability (r = 0.57, p = 0.0008) and with disease duration (r = −0.376, p = 0.03). By contrast, MSARP expression in the PD group did not differ from control values (p = 1.0). In this group, motor ratings correlated with PDRP (r = 0.60, p = 0.006) but not with MSARP values (p = 0.88). Conclusions: MSA is associated with elevated expression of a specific disease-related metabolic pattern. Moreover, differences in the expression of this pattern in patients with MSA correlate with clinical disability. The findings suggest that the MSARP may be a useful biomarker in trials of new therapies for this disorder.