Publications by authors named "Dennis W Dickson"

739 Publications

A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech.

Nat Commun 2021 06 8;12(1):3452. Epub 2021 Jun 8.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment.
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http://dx.doi.org/10.1038/s41467-021-23687-8DOI Listing
June 2021

Clinical, Imaging, and Pathologic Characteristics of Patients With Right Versus Left Hemisphere-Predominant Logopenic Progressive Aphasia.

Neurology 2021 Jun 4. Epub 2021 Jun 4.

Department of Neurology, Rochester, MN, USA

Objective: To assess and compare demographic, clinical, neuroimaging and pathologic characteristics of a cohort of patients with right versus left hemisphere-predominant logopenic progressive aphasia (LPA).

Methods: This is a case-control study of patients with LPA who were prospectively followed at Mayo Clinic and underwent an [F]-fluorodeoxyglucose (FDG)-PET scan. Patients were classified as rLPA if right temporal lobe metabolism was ≥1 standard deviation lower than left temporal lobe metabolism. Patients with rLPA were frequency-matched 3:1 to typical left-predominant LPA based on degree of asymmetry and severity of temporal lobe metabolism. Patients were compared on clinical, imaging (MRI, FDG-PET, amyloid-beta- and tau-PET) and pathologic characteristics.

Results: Of 103 prospectively recruited LPA patients 8 (4 females) were classified as rLPA (7.8%); all rLPA cases were right-handed. rLPA patients had milder aphasia based on the Western Aphasia Battery-Aphasia Quotient (=0.04) and less frequent phonologic errors (=0.015). rLPA had shorter survival compared to typical LPA: hazard ratio 4.0(1.2- 12.9), =0.02. There were no other differences in demographics, handedness, genetics, neurological or neuropsychological tests. Compared to the 24 frequency-matched typical LPA patients, rLPA showed greater frontotemporal hypometabolism of the non-dominant hemisphere on FDG-PET and less atrophy in amygdala and hippocampus of the dominant hemisphere. Autopsy evaluation revealed a similar distribution of pathologic findings in both groups, with Alzheimer's disease pathologic changes being the most frequent pathology.

Conclusions: Right LPA is associated with less severe aphasia but has shorter survival from reported symptom onset than typical LPA, possibly related to greater involvement of the non-dominant hemisphere.
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http://dx.doi.org/10.1212/WNL.0000000000012322DOI Listing
June 2021

MRI quantitative susceptibility mapping of the substantia nigra as an early biomarker for Lewy body disease.

J Neuroimaging 2021 May 25. Epub 2021 May 25.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Background And Purpose: Neurodegeneration of the substantia nigra in Lewy body disease is associated with iron deposition, which increases the magnetic susceptibility of the substantia nigra on MRI. Our objective was to measure iron deposition in the substantia nigra in patients with probable dementia with Lewy bodies (pDLB) and patients who are at risk for pDLB by quantitative susceptibility mapping (QSM).

Methods: Participants included pDLB (n = 36), mild cognitive impairment with at least one core feature of DLB (MCI-LB; n = 15), idiopathic rapid eye movement sleep behavior disorder (iRBD; n = 11), and an age-and gender-matched clinically unimpaired control group (n = 102). QSM was derived from multi-echo 3D gradient recalled echo MRI at 3T, and groups were compared on mean susceptibility values of the substantia nigra and its relation to parkinsonism severity.

Results: Patients with pDLB had higher susceptibility in the substantia nigra compared to controls (p< 0.001) and MCI-LB (p = 0.043). The susceptibility of substantia nigra showed an increasing trend from controls to iRBD and MCI-LB, and to pDLB (p< 0.001). Parkinsonism severity was not associated with the mean susceptibility in the substantia nigra in the patient groups.

Conclusions: Our data suggested that QSM is sensitive to the increased magnetic susceptibility due to higher iron content in the substantia nigra in pDLB. The trend of increasing susceptibility from controls to iRBD and MCI-LB, and to pDLB suggests that iron deposition in the substantia nigra starts to increase as early as the prodromal stage in DLB and continues to increase as the disease progresses, independent of parkinsonism severity.
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http://dx.doi.org/10.1111/jon.12878DOI Listing
May 2021

Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer's disease.

Acta Neuropathol Commun 2021 05 21;9(1):93. Epub 2021 May 21.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.

Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer's disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = -3.70 [95% CI -0.49--0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.
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http://dx.doi.org/10.1186/s40478-021-01199-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147512PMC
May 2021

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer's disease.

Acta Neuropathol Commun 2021 05 12;9(1):86. Epub 2021 May 12.

VA Boston Healthcare System, 150 S. Huntington Ave, Boston, MA, 02130, USA.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer's disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.
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http://dx.doi.org/10.1186/s40478-021-01189-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114683PMC
May 2021

Old age genetically confirmed frontotemporal lobar degeneration with TDP-43 has limbic predominant TDP-43 deposition.

Neuropathol Appl Neurobiol 2021 May 9. Epub 2021 May 9.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Aims: To assess the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions in a unique cohort of old-age patients with genetic frontotemporal lobar degeneration (gFTLD-TDP) and compare these patients with sporadic old-age individuals with TDP-43, either in the presence of Alzheimer's disease (AD-TDP) or in isolation (pure-TDP).

Methods: The brain bank at Mayo Clinic-Jacksonville was searched for cases ≥75 years old at death with TDP-43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD-TDP (n = 15) with progranulin (GRN)/C9ORF72 mutations; (2) AD-TDP (n = 10)-cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure-TDP (n = 10)-cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP-43 burden was calculated using digital pathology.

Results: Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP-43 burden in gFTLD-TDP and AD-TDP, but not pure-TDP, was limbic-predominant targeting CA1 and subiculum. Patients with gFTLD-TDP had higher burden in entorhinal cortex compared to AD-TDP. TDP-43 burden in middle frontal cortex did not differ between the three groups.

Conclusions: In old age it is challenging to clinically and pathologically differentiate gFTLD-TDP from AD-TDP and pure-TDP-43 based on burden. Like AD-TDP, old age gFTLD-TDP have a limbic predominant TDP-43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.
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http://dx.doi.org/10.1111/nan.12727DOI Listing
May 2021

Underlying pathology identified after 20 years of disease course in two cases of slowly progressive frontotemporal dementia syndromes.

Neurocase 2021 Apr 27;27(2):212-222. Epub 2021 Apr 27.

Departments of Neurology, Mayo Clinic Rochester, Minnesota, USA.

We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed a benign course over 26 years, his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated slowly over 22 years, his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.
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http://dx.doi.org/10.1080/13554794.2021.1918723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189252PMC
April 2021

Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases.

Brain 2021 May;144(4):1082-1088

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10-4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10- 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.
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http://dx.doi.org/10.1093/brain/awab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105038PMC
May 2021

Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer's disease.

Nat Commun 2021 04 19;12(1):2311. Epub 2021 Apr 19.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.
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http://dx.doi.org/10.1038/s41467-021-22399-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055900PMC
April 2021

Analysis of intraoperative human brain tissue transcriptome reveals putative risk genes and altered molecular pathways in glioma-related seizures.

Epilepsy Res 2021 Jul 18;173:106618. Epub 2021 Mar 18.

Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Background: The pathogenesis of glioma-related seizures (GRS) is poorly understood. Here in, we aim to identify putative molecular pathways that lead to the development of GRS.

Methods: We determined brain transcriptome from intraoperative human brain tissue of patients with either GRS, glioma without seizures (non-GRS), or with idiopathic temporal lobe epilepsy (iTLE). We performed transcriptome-wide comparisons between disease groups tissue from non-epileptic controls (non-EC) to identify differentially-expressed genes (DEG). We compared DEGs to identify those that are specific or common to the groups. Through a gene ontology analysis, we identified molecular pathways enriched for genes with a Log-fold change ≥1.5 or ≤-1.5 and p-value <0.05 compared to non-EC.

Results: We identified 110 DEGs that are associated with GRS vs. non-GRS: 80 genes showed high and 30 low expression in GRS. There was significant overexpression of genes involved in cell-to-cell and glutamatergic signaling (CELF4, SLC17A7, and CAMK2A) and down-regulation of genes involved immune-trafficking (CXCL8, H19, and VEGFA). In the iTLE vs GRS analysis, there were 1098 DEGs: 786 genes were overexpressed and 312 genes were underexpressed in the GRS samples. There was significant enrichment for genes considered markers of oncogenesis (GSC, MYBL2, and TOP2A). Further, there was down-regulation of genes involved in the glutamatergic neurotransmission (vesicular glutamate transporter-2) in the GRS vs. iTLE samples.

Conclusions: We identified a number of altered processes such as cell-to-cell signaling and interaction, inflammation-related, and glutamatergic neurotransmission in the pathogenesis of GRS. Our findings offer a new landscape of targets to further study in the fields of brain tumors and seizures.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106618DOI Listing
July 2021

Machine learning-based decision tree classifier for the diagnosis of progressive supranuclear palsy and corticobasal degeneration.

Neuropathol Appl Neurobiol 2021 Mar 24. Epub 2021 Mar 24.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Aims: This study aimed to clarify the different topographical distribution of tau pathology between progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and establish a machine learning-based decision tree classifier.

Methods: Paraffin-embedded sections of the temporal cortex, motor cortex, caudate nucleus, globus pallidus, subthalamic nucleus, substantia nigra, red nucleus, and midbrain tectum from 1020 PSP and 199 CBD cases were assessed by phospho-tau immunohistochemistry. The severity of tau lesions (i.e., neurofibrillary tangle, coiled body, tufted astrocyte or astrocytic plaque, and tau threads) was semi-quantitatively scored in each region. Hierarchical cluster analysis was performed using tau pathology scores. A decision tree classifier was made with tau pathology scores using 914 cases. Cross-validation was done using 305 cases. An additional ten cases were used for a validation study.

Results: Cluster analysis displayed two distinct clusters; the first cluster included only CBD, and the other cluster included all PSP and six CBD cases. We built a decision tree, which used only seven decision nodes. The scores of tau threads in the caudate nucleus were the most decisive factor for predicting CBD. In a cross-validation, 302 out of 305 cases were correctly diagnosed. In the pilot validation study, three investigators made a correct diagnosis in all cases using the decision tree.

Conclusion: Regardless of the morphology of astrocytic tau lesions, semi-quantitative tau pathology scores in select brain regions are sufficient to distinguish PSP and CBD. The decision tree simplifies neuropathologic differential diagnosis of PSP and CBD.
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http://dx.doi.org/10.1111/nan.12710DOI Listing
March 2021

The AD tau core spontaneously self-assembles and recruits full-length tau to filaments.

Cell Rep 2021 Mar;34(11):108843

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA. Electronic address:

Tau accumulation is a major pathological hallmark of Alzheimer's disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, we demonstrate that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology. The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay. Finally, we show that the filament cores in corticobasal degeneration (CBD) and Pick's disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.
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http://dx.doi.org/10.1016/j.celrep.2021.108843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094113PMC
March 2021

Cerebral Amyloid Angiopathy Burden and Cerebral Microbleeds: Pathological Evidence for Distinct Phenotypes.

J Alzheimers Dis 2021 ;81(1):113-122

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.

Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia.

Objective: To determine whether CMBs on antemortem MRI correlate with CAA.

Methods: We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs.

Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs.

Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOEɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.
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http://dx.doi.org/10.3233/JAD-201536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113155PMC
January 2021

Loss of Tmem106b leads to cerebellum Purkinje cell death and motor deficits.

Brain Pathol 2021 May 11;31(3):e12945. Epub 2021 Mar 11.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

TMEM106B has been recently implicated in multiple neurodegenerative diseases. Here, Rademakers et al. report a late-onset cerebellar Purkinje cell loss and progressive decline in motor function and gait deficits in a conventional Tmem106b-/- mouse model. By using high-power microscopy and bulk RNA sequencing, the authors further identify lysosomal and immune dysfunction as potential underlying mechanisms of the Purkinje cell loss.
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http://dx.doi.org/10.1111/bpa.12945DOI Listing
May 2021

Latent trait modeling of tau neuropathology in progressive supranuclear palsy.

Acta Neuropathol 2021 05 26;141(5):667-680. Epub 2021 Feb 26.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
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http://dx.doi.org/10.1007/s00401-021-02289-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043857PMC
May 2021

Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease.

medRxiv 2021 Feb 18. Epub 2021 Feb 18.

The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal β-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.
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http://dx.doi.org/10.1101/2021.02.15.21251511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899461PMC
February 2021

The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy.

J Neuropathol Exp Neurol 2021 Feb;80(3):210-219

VA Boston Healthcare System, Boston, Massachusetts.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.
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http://dx.doi.org/10.1093/jnen/nlab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899277PMC
February 2021

Investigating ELOVL7 coding variants in multiple system atrophy.

Neurosci Lett 2021 04 15;749:135723. Epub 2021 Feb 15.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Mayo Graduate School Neuroscience Track, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Multiple system atrophy (MSA) is a rare sporadic, progressive parkinsonism characterised by autonomic dysfunction. A recent genome-wide association study reported an association at the Elongation of Very Long Fatty Acids Protein 7 (ELOVL7) locus with MSA risk. In the current study four independent and unrelated cohorts were assessed, consisting of pathologically confirmed MSA cases, Parkinson's disease (PD) cases, and two unrelated, healthy control groups. All exons of ELOVL7 were sequenced in pathologically confirmed MSA cases; data for PPMI samples and Biobank controls was extracted from whole genome sequence. Coding variants in ELOVL7 were extremely rare, and we observed no significant association of ELOVL7 coding variants with risk of MSA.
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http://dx.doi.org/10.1016/j.neulet.2021.135723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983070PMC
April 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

TAR DNA-Binding Protein 43 Is Associated with Rate of Memory, Functional and Global Cognitive Decline in the Decade Prior to Death.

J Alzheimers Dis 2021 ;80(2):683-693

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline.

Objective: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain.

Methods: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline.

Results: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations.

Conclusion: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.
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http://dx.doi.org/10.3233/JAD-201166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020877PMC
January 2021

Deep Learning-Based Image Classification in Differentiating Tufted Astrocytes, Astrocytic Plaques, and Neuritic Plaques.

J Neuropathol Exp Neurol 2021 Mar;80(4):306-312

From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

This study aimed to develop a deep learning-based image classification model that can differentiate tufted astrocytes (TA), astrocytic plaques (AP), and neuritic plaques (NP) based on images of tissue sections stained with phospho-tau immunohistochemistry. Phospho-tau-immunostained slides from the motor cortex were scanned at 20× magnification. An automated deep learning platform, Google AutoML, was used to create a model for distinguishing TA in progressive supranuclear palsy (PSP) from AP in corticobasal degeneration (CBD) and NP in Alzheimer disease (AD). A total of 1500 images of representative tau lesions were captured from 35 PSP, 27 CBD, and 33 AD patients. Of those, 1332 images were used for training, and 168 images for cross-validation. We tested the model using 100 additional test images taken from 20 patients of each disease. In cross-validation, precision and recall for each individual lesion type were 100% and 98.0% for TA, 98.5% and 98.5% for AP, and 98.0% and 100% for NP, respectively. In a test set, all images of TA and NP were correctly predicted. Only eleven images of AP were predicted to be TA or NP. Our data indicate the potential usefulness of deep learning-based image classification methods to assist in differential diagnosis of tauopathies.
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http://dx.doi.org/10.1093/jnen/nlab005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985829PMC
March 2021

Association of Mitochondrial DNA Genomic Variation With Risk of Pick Disease.

Neurology 2021 03 10;96(13):e1755-e1760. Epub 2021 Feb 10.

From the Department of Neuroscience (R.R.V., M.C.B., A.I.S.-B., R.L.W., S.K., S.F.R., R.R., D.W.D., O.A.R.), Division of Biomedical Statistics and Informatics (M.G.H., P.W.J.), Department of Neurology (R.J.U., Z.K.W.), and Department of Clinical Genomics (O.A.R.), Mayo Clinic, Jacksonville, FL; Perelman School of Medicine (E.S., J.Q.T., V.M.V.D.) and Department of Neurology (M.G.), University of Pennsylvania, Philadelphia; and VIB-UAntwerp Center for Molecular Neurology (R.R.), University of Antwerp, Belgium.

Objective: To determine whether stable polymorphisms that define mitochondrial haplogroups in mitochondrial DNA (mtDNA) are associated with Pick disease risk, we genotyped 52 pathologically confirmed cases of Pick disease and 910 neurologically healthy controls and performed case-control association analysis.

Methods: Fifty-two pathologically confirmed cases of Pick disease from Mayo Clinic Florida (n = 38) and the University of Pennsylvania (n = 14) and 910 neurologically healthy controls collected from Mayo Clinic Florida were genotyped for unique mtDNA haplogroup-defining variants. Mitochondrial haplogroups were determined, and in a case-control analysis, associations of mtDNA haplogroups with risk of Pick disease were evaluated with logistic regression models that were adjusted for age and sex.

Results: No individual mtDNA haplogroups or superhaplogroups were significantly associated with risk of Pick disease after adjustment for multiple testing ( < 0.0021, considered significant). However, nominally significant ( < 0.05) associations toward an increased risk of Pick disease were observed for mtDNA haplogroup W (5.8% cases vs 1.6% controls, odds ratio [OR] 4.78, = 0.020) and subhaplogroup H4 (5.8% cases vs 1.2% controls, OR 4.82, = 0.021).

Conclusion: Our findings indicate that mtDNA variation is not a disease driver but may influence disease susceptibility. Ongoing genetic assessments in larger cohorts of Pick disease are currently underway.
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http://dx.doi.org/10.1212/WNL.0000000000011649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055308PMC
March 2021

Frequency of spinocerebellar ataxia mutations in patients with multiple system atrophy.

Clin Auton Res 2021 Feb 27;31(1):117-125. Epub 2021 Jan 27.

Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Purpose: Investigate single nucleotide variants and short tandem repeats in 39 genes related to spinocerebellar ataxia in clinical and pathologically defined cohorts of multiple system atrophy.

Methods: Exome sequencing was conducted in 28 clinical multiple system atrophy patients to identify single nucleotide variants in spinocerebellar ataxia-related genes. Novel variants were validated in two independent disease cohorts: 86 clinically diagnosed multiple system atrophy patients and 166 pathological multiple system atrophy cases. Expanded repeat alleles in spinocerebellar ataxia genes were evaluated in 36 clinically diagnosed multiple system atrophy patients, and CAG/CAA repeats in TATA-Box Binding Protein (TBP, causative of SCA17) were screened in 216 clinical and pathological multiple system atrophy patients and 346 controls.

Results: No known pathogenic spinocerebellar ataxia single nucleotide variants or pathogenic range expanded repeat alleles of ATXN1, ATXN2, ATXN3, CACNA1A, AXTN7, ATXN8OS, ATXN10, PPP2R2B, and TBP were detected in any clinical multiple system atrophy patients. However, four novel variants were identified in four spinocerebellar ataxia-related genes across three multiple system atrophy patients. Additionally, four multiple system atrophy patients (1.6%) and one control (0.3%) carried an intermediate length 41 TBP CAG/CAA repeat allele (OR = 4.11, P = 0.21). There was a significant association between the occurrence of a repeat length of longer alleles (> 38 repeats) and an increased risk of multiple system atrophy (OR = 1.64, P = 0.03).

Conclusion: Occurrence of TBP CAG/CAA repeat length of longer alleles (> 38 repeats) is significantly associated with increased multiple system atrophy risk. This discovery warrants further investigation and supports a possible genetic overlap of multiple system atrophy with SCA17.
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http://dx.doi.org/10.1007/s10286-020-00759-1DOI Listing
February 2021

Progressive Supranuclear Palsy and Corticobasal Degeneration.

Adv Exp Med Biol 2021 ;1281:151-176

UC San Diego Department of Neurosciences, La Jolla, CA, USA.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative tauopathies with neuronal and glial lesions composed of tau that is composed predominantly of isomers with four repeats in the microtubule-binding domain (4R tau). The brain regions vulnerable to pathology in PSP and CBD overlap, but there are differences, particularly with respect to distribution of neuronal loss, the relative abundance of neuronal and glial lesions, the morphologic features of glial lesions, and the frequency of comorbid pathology. Both PSP and CBD have a wide spectrum of clinical manifestations, including disorders of movement and cognition. Recognition of phenotypic diversity in PSP and CBD may improve antemortem diagnostic accuracy, which tends to be very good for the most common presentation of PSP (Richardson syndrome), but poor for the most characteristic presentation of CBD (corticobasal syndrome: CBS). Development of molecular and imaging biomarkers may improve antemortem diagnostic accuracy. Currently, multidisciplinary symptomatic and supportive treatment with pharmacological and non-pharmacological strategies remains the standard of care. In the future, experimental therapeutic trials will be important to slow disease progression.
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http://dx.doi.org/10.1007/978-3-030-51140-1_11DOI Listing
February 2021

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

J Neuropathol Exp Neurol 2021 Jan;80(2):102-111

Institute of Neurology, Medical University of Vienna, Vienna, Austria.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.
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http://dx.doi.org/10.1093/jnen/nlaa153DOI Listing
January 2021

Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study.

Lancet Neurol 2021 02 17;20(2):107-116. Epub 2020 Dec 17.

Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, University College London Queen Square Institute of Neurology, London, UK. Electronic address:

Background: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP).

Methods: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets.

Findings: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant.

Interpretation: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies.

Funding: PSP Association, CBD Solutions, Medical Research Council (UK).
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http://dx.doi.org/10.1016/S1474-4422(20)30394-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116626PMC
February 2021

MAPT subhaplotypes in corticobasal degeneration: assessing associations with disease risk, severity of tau pathology, and clinical features.

Acta Neuropathol Commun 2020 12 7;8(1):218. Epub 2020 Dec 7.

Division of Biomedical Statistics and Informatics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After correcting for multiple testing (P < 0.0026 considered as significant), we confirmed the strong association between the MAPT H2 haplotype and decreased risk of CBD (Odds ratio = 0.26, P = 2 × 10), and also observed a novel association between the H1d subhaplotype and an increased CBD risk (Odds ratio = 1.76, P = 0.002). Additionally, although not statistically significant after correcting for multiple testing, the H1c haplotype was associated with a higher risk of CBD (Odds ratio = 1.49, P = 0.009). No MAPT haplotypes were significantly associated with any tau pathology measures, age of CBD onset, or disease duration. Though replication will be important and there is potential that population stratification could have influenced our findings, these results suggest that several MAPT H1 subhaplotypes are primarily responsible for the strong association between MAPT H1 and risk of CBD, but that H1 subhaplotypes are unlikely to play a major role in driving tau pathology or clinical features. Our findings also indicate that similarities in MAPT haplotype risk-factor profile exist between CBD and the related tauopathy progressive supranuclear palsy, with H2, H1d, and H1c displaying associations with both diseases.
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http://dx.doi.org/10.1186/s40478-020-01097-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720600PMC
December 2020

Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype.

Ann Neurol 2021 03 17;89(3):520-533. Epub 2020 Dec 17.

Department of Neurology, Mayo Clinic, Rochester, MN.

Objective: The objective of this study was to describe clinical features, [ F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB).

Methods: This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD).

Results: All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD.

Interpretation: Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520-533.
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http://dx.doi.org/10.1002/ana.25979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040336PMC
March 2021

Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation.

Acta Neuropathol Commun 2020 12 1;8(1):210. Epub 2020 Dec 1.

Department of Neuroscience, Mayo Clinic, Collaborative Research Building CR03-010 13400 E. Shea Blvd, Scottsdale, AZ, 85259, USA.

The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer's disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD.
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http://dx.doi.org/10.1186/s40478-020-01079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708249PMC
December 2020

Astrocyte-derived clusterin suppresses amyloid formation in vivo.

Mol Neurodegener 2020 11 27;15(1):71. Epub 2020 Nov 27.

Department of Neuroscience, Mayo Clinic, Collaborative Research Building CR03-010, 13400 E. Shea Blvd, Scottsdale, AZ, 85259, USA.

Background: Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer's disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased expression. Although there is strong evidence implicating CLU in amyloid metabolism, the exact mechanism underlying the CLU involvement in AD is not fully understood or whether physiologic alterations of CLU levels in the brain would be protective.

Results: We used a gene delivery approach to overexpress CLU in astrocytes, the major source of CLU expression in the brain. We found that CLU overexpression resulted in a significant reduction of total and fibrillar amyloid in both cortex and hippocampus in the APP/PS1 mouse model of AD amyloidosis. CLU overexpression also ameliorated amyloid-associated neurotoxicity and gliosis. To complement these overexpression studies, we also analyzed the effects of haploinsufficiency of Clu using heterozygous (Clu) mice and control littermates in the APP/PS1 model. CLU reduction led to a substantial increase in the amyloid plaque load in both cortex and hippocampus in APP/PS1; Clu mice compared to wild-type (APP/PS1; Clu) littermate controls, with a concomitant increase in neuritic dystrophy and gliosis.

Conclusions: Thus, both physiologic ~ 30% overexpression or ~ 50% reduction in CLU have substantial impacts on amyloid load and associated pathologies. Our results demonstrate that CLU plays a major role in Aβ accumulation in the brain and suggest that efforts aimed at CLU upregulation via pharmacological or gene delivery approaches offer a promising therapeutic strategy to regulate amyloid pathology.
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http://dx.doi.org/10.1186/s13024-020-00416-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694353PMC
November 2020