Publications by authors named "Thomas G Beach"

345 Publications

A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies.

Acta Neuropathol 2021 Jul 26. Epub 2021 Jul 26.

Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103, Leipzig, Germany.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may-in analogy to pGlu-Aβ peptides in Alzheimer's disease-act as a seed for pathogenic protein aggregation.
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http://dx.doi.org/10.1007/s00401-021-02349-5DOI Listing
July 2021

Vagus Nerve and Stomach Synucleinopathy in Parkinson's Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the "Body-First" Hypothesis.

J Parkinsons Dis 2021 Jun 14. Epub 2021 Jun 14.

Banner Sun Health Research Institute, Sun City, AZ, USA.

Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson's disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla.

Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD.

Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology.

Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive.

Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.
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http://dx.doi.org/10.3233/JPD-212733DOI Listing
June 2021

A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with and CNOT3.

Genes (Basel) 2021 May 26;12(6). Epub 2021 May 26.

Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in . The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 ( = -0.27, 95% CI = (-0.35, -0.19), = 1.29 × 10) and rs10881463 ( = -0.20, 95% CI = (-0.27, -0.13), = 3.40 × 10). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4-NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis.
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http://dx.doi.org/10.3390/genes12060815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228534PMC
May 2021

Cell-Type Specific Changes in DNA Methylation of Intron 1 in Synucleinopathy Brains.

Front Neurosci 2021 28;15:652226. Epub 2021 Apr 28.

Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, United States.

Parkinson's disease (PD) and dementia with Lewy body (DLB) are the most common synucleinopathies. gene is a major genetic risk factor for these diseases group, and dysregulation of its expression has been implicated in the genetic etiologies of several synucleinopathies. DNA methylation at CpG island (CGI) within intron 1 has been suggested as a regulatory mechanism of expression, and changes in methylation levels at this region were associated with PD and DLB. However, the role of DNA methylation in the regulation of expression in a cell-type specific manner and its contribution to the pathogenesis of PD and DLB remain poorly understood, and the data are conflicting. Here, we employed a bisulfite pyrosequencing technique to profile the DNA methylation across intron 1 CGI in PD and DLB compared to age- and sex-matched normal control subjects. We analyzed homogenates of bulk frozen frontal cortex samples and a subset of neuronal and glia nuclei sorted by the fluorescence-activated nuclei sorting (FANS) method. Bulk brain tissues showed no significant difference in the overall DNA methylation across intron 1 CGI region between the neuropathological groups. Sorted neuronal nuclei from PD frontal cortex showed significant lower levels of DNA methylation at this region compared to normal controls, but no differences between DLB and control, while sorted glia nuclei exhibited trends of decreased overall DNA methylation in DLB only. In conclusion, our data suggested disease-dependent cell-type specific differential DNA methylation within intron 1 CGI. These changes may affect dysregulation that presumably mediates disease-specific risk. Our results can be translated into the development of the intron 1 CGI region as an attractive therapeutics target for gene therapy in patients who suffer from synucleinopathies due to dysregulation.
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http://dx.doi.org/10.3389/fnins.2021.652226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113398PMC
April 2021

Identification of retinoblastoma binding protein 7 (Rbbp7) as a mediator against tau acetylation and subsequent neuronal loss in Alzheimer's disease and related tauopathies.

Acta Neuropathol 2021 Aug 12;142(2):279-294. Epub 2021 May 12.

Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute, Arizona State University, Tempe, AZ, USA.

Evidence indicates that tau hyper-phosphorylation and subsequent neurofibrillary tangle formation contribute to the extensive neuronal death in Alzheimer's disease (AD) and related tauopathies. Recent work has identified that increased tau acetylation can promote tau phosphorylation. Tau acetylation occurs at lysine 280 resulting from increased expression of the lysine acetyltransferase p300. The exact upstream mechanisms mediating p300 expression remain elusive. Additional work highlights the role of the epigenome in tau pathogenesis, suggesting that dysregulation of epigenetic proteins may contribute to acetylation and hyper-phosphorylation of tau. Here, we identify and focus on the histone-binding subunit of the Nucleosome Remodeling and Deacetylase (NuRD) complex: Retinoblastoma-Binding Protein 7 (Rbbp7). Rbbp7 chaperones chromatin remodeling proteins to their nuclear histone substrates, including histone acetylases and deacetylases. Notably, Rbbp7 binds to p300, suggesting that it may play a role in modulating tau acetylation. We interrogated Rbbp7 in post-mortem brain tissue, cell lines and mouse models of AD. We found reduced Rbbp7 mRNA expression in AD cases, a significant negative correlation with CERAD (neuritic plaque density) and Braak Staging (pathogenic tau inclusions) and a significant positive correlation with post-mortem brain weight. We also found a neuron-specific downregulation of Rbbp7 mRNA in AD patients. Rbbp7 protein levels were significantly decreased in 3xTg-AD and PS19 mice compared to NonTg, but no decreases were found in APP/PS1 mice that lack tau pathology. In vitro, Rbbp7 overexpression rescued TauP301L-induced cytotoxicity in immortalized hippocampal cells and primary cortical neurons. In vivo, hippocampal Rbbp7 overexpression rescued neuronal death in the CA1 of PS19 mice. Mechanistically, we found that increased Rbbp7 reduced p300 levels, tau acetylation at lysine 280 and tau phosphorylation at AT8 and AT100 sites. Collectively, these data identify a novel role of Rbbp7, protecting against tau-related pathologies, and highlight its potential as a therapeutic target in AD and related tauopathies.
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http://dx.doi.org/10.1007/s00401-021-02323-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270842PMC
August 2021

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.

Nat Genet 2021 06 6;53(6):787-793. Epub 2021 May 6.

Translational Genomics Core of Partners HealthCare Personalized Medicine, Cambridge, MA, USA.

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10) and WWOX (HR = 2.12, P = 2.37 × 10) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
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http://dx.doi.org/10.1038/s41588-021-00847-6DOI Listing
June 2021

Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau.

EMBO Mol Med 2021 Jun 5;13(6):e14022. Epub 2021 May 5.

Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.

Alzheimer's disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer's disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer's disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging ("BioFINDER-2", N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.
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http://dx.doi.org/10.15252/emmm.202114022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185545PMC
June 2021

Brain proteome-wide association study implicates novel proteins in depression pathogenesis.

Nat Neurosci 2021 Jun 12;24(6):810-817. Epub 2021 Apr 12.

Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA.

Depression is a common condition, but current treatments are only effective in a subset of individuals. To identify new treatment targets, we integrated depression genome-wide association study (GWAS) results (N = 500,199) with human brain proteomes (N = 376) to perform a proteome-wide association study of depression followed by Mendelian randomization. We identified 19 genes that were consistent with being causal in depression, acting via their respective cis-regulated brain protein abundance. We replicated nine of these genes using an independent depression GWAS (N = 307,353) and another human brain proteomic dataset (N = 152). Eleven of the 19 genes also had cis-regulated mRNA levels that were associated with depression, based on integration of the depression GWAS with human brain transcriptomes (N = 888). Meta-analysis of the discovery and replication proteome-wide association study analyses identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously implicated in depression by GWAS. Together, these findings provide promising brain protein targets for further mechanistic and therapeutic studies.
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http://dx.doi.org/10.1038/s41593-021-00832-6DOI Listing
June 2021

Acute Brain Ischemia, Infarction and Hemorrhage in Subjects Dying with or Without Autopsy-Proven Acute Pneumonia.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

Stroke is one of the most serious complications of Covid-19 disease but it is still unclear whether stroke is more common with Covid-19 pneumonia as compared to non-Covid-19 pneumonia. We investigated the concurrence rate of autopsy-confirmed acute brain ischemia, acute brain infarction and acute brain hemorrhage with autopsy-proven acute non-Covid pneumonia in consecutive autopsies in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study of normal aging and neurodegenerative diseases. Of 691 subjects with a mean age of 83.4 years, acute pneumonia was histopathologically diagnosed in 343 (49.6%); the concurrence rates for histopathologically-confirmed acute ischemia, acute infarction or subacute infarction was 14% and did not differ between pneumonia and non-pneumonia groups while the rates of acute brain hemorrhage were 1.4% and 2.0% of those with or without acute pneumonia, respectively. In comparison, in reviews of Covid-19 publications, reported clinically-determined rates of acute brain infarction range from 0.5% to 20% while rates of acute brain hemorrhage range from 0.13% to 2%. In reviews of Covid-19 autopsy studies, concurrence rates for both acute brain infarction and acute brain hemorrhage average about 10%. Covid-19 pneumonia and non-Covid-19 pneumonia may have similar risks tor concurrent acute brain infarction and acute brain hemorrhage when pneumonia is severe enough to cause death. Additionally, acute brain ischemia, infarction or hemorrhage may not be more common in subjects dying of acute pneumonia than in subjects dying without acute pneumonia.
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http://dx.doi.org/10.1101/2021.03.22.21254139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010760PMC
March 2021

Olfaction in Neuropathologically Defined Progressive Supranuclear Palsy.

Mov Disord 2021 07 23;36(7):1700-1704. Epub 2021 Mar 23.

Banner Sun Health Research Institute, Sun City, Arizona, USA.

Background: Hyposmia is characteristic of idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLBs), whereas progressive supranuclear palsy (PSP) typically has normal sense of smell. However, there is a lack of pathologically confirmed data.

Objective: The objective is to study hyposmia in pathologically confirmed PSP patients and compare to PD patients and nondegenerative controls.

Methods: We studied autopsied subjects in the Arizona Study of Aging and Neurodegenerative Disorders who had antemortem olfactory testing and a neuropathological diagnosis of either PD, PSP, or control.

Results: This study included 281 cases. Those with neuropathologically confirmed PSP (N = 24) and controls (N = 174) had significantly better sense of smell than those with PD (N = 76). Although most PSP patients had normal olfaction, there were some with hyposmia, resulting in an overall reduced sense of smell in PSP compared to controls. The sensitivity of having PSP pathologically in those presenting with parkinsonism and normosmia was 93.4% with a specificity of 64.7%. Cases with both PSP and PD pathologically had reduced sense of smell similar to PD alone (N = 7). Hyposmic PSP patients had significantly higher Lewy body burden not meeting criteria for additional PD/DLB diagnosis.

Conclusions: Pathologically confirmed PD had reduced olfaction compared with PSP or controls. In the setting of parkinsonism in this sample, the presence of normosmia had high sensitivity for PSP. Hyposmia in PSP suggests the presence of additional Lewy body pathology. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28568DOI Listing
July 2021

Clinicopathological Correlation: Dopamine and Amyloid PET Imaging with Neuropathology in Three Subjects Clinically Diagnosed with Alzheimer's Disease or Dementia with Lewy Bodies.

J Alzheimers Dis 2021 ;80(4):1603-1612

Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, USA.

Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer's disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker.

Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND).

Methods: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared.

Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD.

Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.
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http://dx.doi.org/10.3233/JAD-200323DOI Listing
January 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

Vascular Lesions, APOE ε4, and Tau Pathology in Alzheimer Disease.

J Neuropathol Exp Neurol 2021 Feb;80(3):240-246

Banner Sun Health Research Institute, Sun City, Arizona, USA.

We sought to determine the associations among cerebral amyloid angiopathy (CAA), white matter rarefaction (WMR), circle of Willis atherosclerosis (CWA), and total microinfarct number with Braak neurofibrillary stage in postmortem individuals with and without Alzheimer disease (AD). Data from 355 cases of autopsied individuals with Braak stage I-VI who had antemortem consensus diagnoses of cognitively unimpaired (n = 183), amnestic mild cognitive impairment (n = 31), and AD dementia (n = 141) were used. The association between Braak stage and vascular lesions were individually assessed using multivariable linear regression that adjusted for age at death, APOE ε4 carrier status, sex, education, and neuritic plaque density. CAA (p = 0.007) and WMR (p < 0.001) were associated with Braak stage, independent of amyloid load; microinfarct number and CWA showed no association. Analyses of the interactions between APOE ε4 carrier status and vascular lesions found that greater WMR and positive ε4 carrier status were associated with higher Braak stages. These results suggest that CAA and WMR are statistically linked to the severity of AD-related NFT pathology. The statistical link between WMR and NFT load may be strengthened by the presence of APOE ε4 carrier status. An additional finding was that Lewy body pathology was most prevalent in higher Braak stages.
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http://dx.doi.org/10.1093/jnen/nlaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899190PMC
February 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

Genetic control of the human brain proteome.

Am J Hum Genet 2021 03 10;108(3):400-410. Epub 2021 Feb 10.

Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008492PMC
March 2021

Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis.

Nat Genet 2021 02 28;53(2):143-146. Epub 2021 Jan 28.

Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD), but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.
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http://dx.doi.org/10.1038/s41588-020-00773-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130821PMC
February 2021

Increased Risk of Autopsy-Proven Pneumonia with Sex, Season and Neurodegenerative Disease.

medRxiv 2021 Jan 8. Epub 2021 Jan 8.

There has been a markedly renewed interest in factors associated with pneumonia, a leading cause of death worldwide, due to its frequent concurrence with pandemics of influenza and Covid-19 disease. Reported predisposing factors to both bacterial pneumonia and pandemic viral lower respiratory infections are wintertime occurrence, older age, obesity, pre-existing cardiopulmonary conditions and diabetes. Also implicated are age-related neurodegenerative diseases that cause parkinsonism and dementia. We investigated the prevalence of autopsy-proven pneumonia in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study, between the years 2006 and 2019 and before the beginning of the Covid-19 pandemic. Of 691 subjects dying at advanced ages (mean 83.4), pneumonia was diagnosed postmortem in 343 (49.6%). There were 185 subjects without dementia or parkinsonism while clinicopathological diagnoses for the other subjects included 319 with Alzheimer's disease dementia, 127 with idiopathic Parkinson's disease, 72 with dementia with Lewy bodies, 49 with progressive supranuclear palsy and 78 with vascular dementia. Subjects with one or more of these neurodegenerative diseases all had higher pneumonia rates, ranging between 50 and 61%, as compared to those without dementia or parkinsonism (40%). In multivariable logistic regression models, male sex and a non-summer death both had independent contributions (ORs of 1.67 and 1.53) towards the presence of pneumonia at autopsy while the absence of parkinsonism or dementia was a significant negative predictor of pneumonia (OR 0.54). Male sex, dementia and parkinsonism may also be risk factors for Covid-19 pneumonia. The apolipoprotein E4 allele, as well as obesity, chronic obstructive pulmonary disease, diabetes, hypertension, congestive heart failure, cardiomegaly and cigarette smoking history, were not significantly associated with pneumonia, in contradistinction to what has been reported for Covid-19 disease.
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http://dx.doi.org/10.1101/2021.01.07.21249410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805471PMC
January 2021

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

J Neuropathol Exp Neurol 2021 01;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

Alzheimer's Disease Neuropathological Comorbidities are Common in the Younger-Old.

J Alzheimers Dis 2021 ;79(1):389-400

Banner Alzheimer's Institute, Phoenix, AZ, USA.

Background: Clinicopathological studies have demonstrated that Alzheimer's disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the rate of cognitive decline. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics.

Objective: As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown; our objective is to provide this information.

Methods: We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer's Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer's Association intermediate or high AD Neuropathological Change levels, excluding those with known autosomal dominant AD-related mutations.

Results: Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where "pure" ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20%in the 70s and beyond. Lewy body disease is the most common comorbidity at younger ages but actually is less common at later ages, while for most others, their prevalence increases with age.

Conclusion: Alzheimer's disease neuropathological comorbidities are highly prevalent even in the younger-old.
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http://dx.doi.org/10.3233/JAD-201213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034496PMC
January 2021

Immunohistochemical Detection of Synuclein Pathology in Skin in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinsonism.

Mov Disord 2021 04 24;36(4):895-904. Epub 2020 Nov 24.

Department of Neurology, McGill University-Montreal General Hospital, Montreal, Quebec, Canada.

Background: Recent studies reported abnormal alpha-synuclein deposition in biopsy-accessible sites of the peripheral nervous system in Parkinson's disease (PD). This has considerable implications for clinical diagnosis. Moreover, if deposition occurs early, it may enable tissue diagnosis of prodromal PD.

Objective: The aim of this study was to develop and test an automated bright-field immunohistochemical assay of cutaneous pathological alpha-synuclein deposition in patients with idiopathic rapid eye movement sleep behavior disorder, PD, and atypical parkinsonism and in control subjects.

Methods: For assay development, postmortem skin biopsies were taken from 28 patients with autopsy-confirmed Lewy body disease and 23 control subjects. Biopsies were stained for pathological alpha-synuclein in automated stainers using a novel dual-immunohistochemical assay for serine 129-phosphorylated alpha-synuclein and pan-neuronal marker protein gene product 9.5. After validation, single 3-mm punch skin biopsies were taken from the cervical 8 paravertebral area from 79 subjects (28 idiopathic rapid eye movement sleep behavior disorder, 20 PD, 10 atypical parkinsonism, and 21 control subjects). Raters blinded to clinical diagnosis assessed the biopsies.

Results: The immunohistochemistry assay differentiated alpha-synuclein pathology from nonpathological-appearing alpha-synuclein using combined phosphatase and protease treatments. Among autopsy samples, 26 of 28 Lewy body samples and none of the 23 controls were positive. Among living subjects, punch biopsies were positive in 23 (82%) subjects with idiopathic rapid eye movement sleep behavior disorder, 14 (70%) subjects with PD, 2 (20%) subjects with atypical parkinsonism, and none (0%) of the control subjects. After a 3-year follow-up, eight idiopathic rapid eye movement sleep behavior disorder subjects phenoconverted to defined neurodegenerative syndromes, in accordance with baseline biopsy results.

Conclusion: Even with a single 3-mm punch biopsy, there is considerable promise for using pathological alpha-synuclein deposition in skin to diagnose both clinical and prodromal PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28399DOI Listing
April 2021

Deep Profiling of Microgram-Scale Proteome by Tandem Mass Tag Mass Spectrometry.

J Proteome Res 2021 01 11;20(1):337-345. Epub 2020 Nov 11.

Departments of Structural Biology and Developmental Neurobiology, Saint Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States.

Tandem mass tag (TMT)-based mass spectrometry (MS) enables deep proteomic profiling of more than 10,000 proteins in complex biological samples but requires up to 100 μg protein in starting materials during a standard analysis. Here, we present a streamlined protocol to quantify more than 9000 proteins with 0.5 μg protein per sample by 16-plex TMT coupled with two-dimensional liquid chromatography and tandem mass spectrometry (LC/LC-MS/MS). In this protocol, we optimized multiple conditions to reduce sample loss, including processing each sample in a single tube to minimize surface adsorption, increasing digestion enzymes to shorten proteolysis and function as carriers, eliminating a desalting step between digestion and TMT labeling, and developing miniaturized basic pH LC for prefractionation. By profiling 16 identical human brain tissue samples of Alzheimer's disease (AD), vascular dementia (VaD), and non-dementia controls, we directly compared this new microgram-scale protocol to the standard-scale protocol, quantifying 9116 and 10,869 proteins, respectively. Importantly, bioinformatics analysis indicated that the microgram-scale protocol had adequate sensitivity and reproducibility to detect differentially expressed proteins in disease-related pathways. Thus, this newly developed protocol is of general application for deep proteomics analysis of biological and clinical samples at sub-microgram levels.
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http://dx.doi.org/10.1021/acs.jproteome.0c00426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262114PMC
January 2021

Human Autopsy-Derived Scalp Fibroblast Biobanking for Age-Related Neurodegenerative Disease Research.

Cells 2020 10 30;9(11). Epub 2020 Oct 30.

Banner Sun Health Research Institute, Sun City, AZ 85351, USA.

The Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program at Banner Sun Health Research Institute (BSHRI) is a longitudinal clinicopathological study with a current enrollment of more than 900 living subjects for aging and neurodegenerative disease research. Annual clinical assessments are done by cognitive and movement neurologists and neuropsychologists. Brain and body tissues are collected at a median postmortem interval of 3.0 h for neuropathological diagnosis and banking. Since 2018, the program has undertaken banking of scalp fibroblasts derived from neuropathologically characterized donors with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Here, we describe the procedure development and cell characteristics from 14 male and 15 female donors (mean ± SD of age: 83.6 ± 12.2). Fibroblasts from explant cultures were banked at passage 3. The results of mRNA analysis showed positive expression of fibroblast activation protein, vimentin, fibronectin, and THY1 cell surface antigen. We also demonstrated that the banked fibroblasts from a postmortem elderly donor were successfully reprogramed to human-induced pluripotent stem cells (hiPSCs). Taken together, we have demonstrated the successful establishment of a human autopsy-derived fibroblast banking program. The cryogenically preserved cells are available for request at the program website of the BSHRI.
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http://dx.doi.org/10.3390/cells9112383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692621PMC
October 2020

Blinded RT-QuIC Analysis of α-Synuclein Biomarker in Skin Tissue From Parkinson's Disease Patients.

Mov Disord 2020 12 22;35(12):2230-2239. Epub 2020 Sep 22.

Department of Biomedical Sciences, Parkinson's Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.

Background: An unmet clinical need in Parkinson's disease (PD) is to identify biomarkers for diagnosis, preferably in peripherally accessible tissues such as skin. Immunohistochemical studies have detected pathological α-synuclein (αSyn) in skin biopsies from PD patients albeit sensitivity needs to be improved.

Objective: Our study provides the ultrasensitive detection of pathological αSyn present in the skin of PD patients, and thus, pathological αSyn in skin could be a potential biomarker for PD.

Methods: The real-time quaking-induced conversion assay was used to detect pathological αSyn present in human skin tissues. Further, we optimized this ultra-sensitive and specific assay for both frozen and formalin-fixed paraffin-embedded sections of skin tissues. We determined the seeding kinetics of the αSyn present in the skin from autopsied subjects consisting of frozen skin tissues from 25 PD and 25 controls and formalin-fixed paraffin-embedded skin sections from 12 PD and 12 controls.

Results: In a blinded study of skin tissues from autopsied subjects, we correctly identified 24/25 PD and 24/25 controls using frozen skin tissues (96% sensitivity and 96% specificity) compared to 9/12 PD and 10/12 controls using formalin-fixed paraffin-embedded skin sections (75% sensitivity and 83% specificity).

Conclusions: Our blinded study results clearly demonstrate the feasibility of using skin tissues for clinical diagnosis of PD by detecting pathological αSyn. Moreover, this peripheral biomarker discovery study may have broader translational value in detecting misfolded proteins in skin samples as a longitudinal progression marker. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749035PMC
December 2020

Dopaminergic Retinal Cell Loss and Visual Dysfunction in Parkinson Disease.

Ann Neurol 2020 11 19;88(5):893-906. Epub 2020 Sep 19.

Department of Physiology, Genetics, and Microbiology, University of Alicante, Alicante, Spain.

Objective: Considering the demonstrated implication of the retina in Parkinson disease (PD) pathology and the importance of dopaminergic cells in this tissue, we aimed to analyze the state of the dopaminergic amacrine cells and some of their main postsynaptic neurons in the retina of PD.

Methods: Using immunohistochemistry and confocal microscopy, we evaluated morphology, number, and synaptic connections of dopaminergic cells and their postsynaptic cells, AII amacrine and melanopsin-containing retinal ganglion cells, in control and PD eyes from human donors.

Results: In PD, dopaminergic amacrine cell number was reduced between 58% and 26% in different retinal regions, involving a decline in the number of synaptic contacts with AII amacrine cells (by 60%) and melanopsin cells (by 35%). Despite losing their main synaptic input, AII cells were not reduced in number, but they showed cellular alterations compromising their adequate function: (1) a loss of mitochondria inside their lobular appendages, which may indicate an energetic failure; and (2) a loss of connexin 36, suggesting alterations in the AII coupling and in visual signal transmission from the rod pathway.

Interpretation: The dopaminergic system impairment and the affection of the rod pathway through the AII cells may explain and be partially responsible for the reduced contrast sensitivity or electroretinographic response described in PD. Also, dopamine reduction and the loss of synaptic contacts with melanopsin cells may contribute to the melanopsin retinal ganglion cell loss previously described and to the disturbances in circadian rhythm and sleep reported in PD patients. These data support the idea that the retina reproduces brain neurodegeneration and is highly involved in PD pathology. ANN NEUROL 2020;88:893-906.
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http://dx.doi.org/10.1002/ana.25897DOI Listing
November 2020

Cerebrovascular medin is associated with Alzheimer's disease and vascular dementia.

Alzheimers Dement (Amst) 2020 25;12(1):e12072. Epub 2020 Aug 25.

Banner Sun Health Research Institute Sun City Arizona USA.

Introduction: Medin, an aging-associated amyloidogenic protein, induces cerebrovascular dysfunction and inflammation. We investigated the relationship between cerebrovascular medin and Alzheimer's disease (AD) and vascular dementia (VaD).

Methods: Cerebral arteriole medin was quantified from 91 brain donors with no dementia (ND), AD, VaD, or combined AD and VaD. Correlation analyses evaluated the relationship between arteriole medin, and plaques, tangles, or white matter lesions (WML). Receiver operating characteristic and regression analyses assessed whether medin is predictive of AD or VaD versus other cerebrovascular pathologies (circle of Willis [CoW] atherosclerosis and cerebral amyloid angiopathy [CAA]).

Results: Arteriole medin was higher in those with AD, VaD, or combined AD/VaD versus ND ( < .05), and correlated with tangle, plaque, and WML, but not CAA or CoW atherosclerosis. Among cerebrovascular pathologies, medin was the strongest predictor of AD diagnosis, whereas CoW atherosclerosis and arteriole medin were predictors of VaD.

Discussion: Cerebral arteriole medin is associated with and could be a potential novel risk factor or biomarker for AD and VaD.
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http://dx.doi.org/10.1002/dad2.12072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447901PMC
August 2020

ACValidator: A novel assembly-based approach for verification of circular RNAs.

Biol Methods Protoc 2020 10;5(1):bpaa010. Epub 2020 Aug 10.

Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.

Circular RNAs (circRNAs) are evolutionarily conserved RNA species that are formed when exons "back-splice" to each other. Current computational algorithms to detect these back-splicing junctions produce divergent results, and hence there is a need for a method to distinguish true-positive circRNAs. To this end, we developed Assembly based CircRNA Validator (ACValidator) for verification of circRNAs. ACValidator extracts reads from a user-defined window on either side of a circRNA junction and assembles them to generate contigs. These contigs are aligned against the circRNA sequence to find contigs spanning the back-spliced junction. When evaluated on simulated datasets, ACValidator achieved over ∼80% sensitivity on datasets with an average of 10 circRNA-supporting reads and with read lengths of at least 100 bp. In experimental datasets, ACValidator produced higher verification percentages for samples treated with ribonuclease R compared to nontreated samples. Our workflow is applicable to non-polyA-selected RNAseq datasets and can also be used as a candidate selection strategy for prioritizing experimental validations. All workflow scripts are freely accessible on our GitHub page https://github.com/tgen/ACValidator along with detailed instructions to set up and run ACValidator.
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http://dx.doi.org/10.1093/biomethods/bpaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415914PMC
August 2020

In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease.

Neurology 2020 09 3;95(9):e1267-e1284. Epub 2020 Aug 3.

From the Department of Neurology (L.M.C., S.M.), University of Pittsburgh, PA; Banner Sun Health Research Institute (T.G.B., G.E.S.), Sun City, AZ; University of Iowa (M.C.B., C.S.C., C.C.-G.), Iowa City; Department of Neurology (C.H.A.), Mayo Clinic College of Medicine, Scottsdale, AZ; St. Michael's Hospital (D.G.M.), Toronto, Canada; University of Texas Southwestern Medical School (C.L.W.), Dallas; Icahn School of Medicine at Mount Sinai (J.F.C.), New York, NY; Institute for Neurodegenerative Disorders (D.J.), New Haven, CT; BioLegend Inc. (P.T.), Dedham, MA; Indiana University (T.F.), Indianapolis; The Michael J. Fox Foundation for Parkinson's Research (V.A., C.M.K., L.R., K.D.D.), New York, NY; and Department of Neurology (B.M.), Center of Parkinsonism and Movement Disorders Paracelsus-Elena Klinik Kassel and University Medical Center Göttingen, Germany.

Objective: The Systemic Synuclein Sampling Study (S4) measured α-synuclein in multiple tissues and biofluids within the same patients with Parkinson disease (PD) vs healthy controls (HCs).

Methods: S4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and nonmotor measures and dopamine transporter SPECT were obtained. Biopsies of skin, colon, submandibular gland (SMG), CSF, saliva, and blood were collected. Tissue biopsy sections were stained with 5C12 monoclonal antibody against pathologic α-synuclein; digital images were interpreted by neuropathologists blinded to diagnosis. Biofluid total α-synuclein was quantified using ELISA.

Results: The final cohort included 59 patients with PD and 21 HCs. CSF α-synuclein was lower in patients with PD vs HCs; sensitivity/specificity of CSF α-synuclein for PD diagnosis was 87.0%/63.2%, respectively. Sensitivity of α-synuclein immunoreactivity for PD diagnosis was 56.1% for SMG and 24.1% for skin; specificity was 92.9% and 100%, respectively. There were no significant relationships between different measures of α-synuclein within participants.

Conclusions: S4 confirms lower total α-synuclein levels in CSF in patients with PD compared to HCs, but specificity is low. In contrast, α-synuclein immunoreactivity in skin and SMG is specific for PD but sensitivity is low. Relationships within participants across different tissues and biofluids could not be demonstrated. Measures of pathologic forms of α-synuclein with higher accuracy are critically needed.

Classification Of Evidence: This study provides Class III evidence that total CSF α-synuclein does not accurately distinguish patients with PD from HCs, and that monoclonal antibody staining for SMG and skin total α-synuclein is specific but not sensitive for PD diagnosis.
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http://dx.doi.org/10.1212/WNL.0000000000010404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538226PMC
September 2020

Cell death and survival pathways in Alzheimer's disease: an integrative hypothesis testing approach utilizing -omic data sets.

Neurobiol Aging 2020 11 3;95:15-25. Epub 2020 Jul 3.

ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.

Whether a cell lives or dies is controlled by an array of intercepting and dynamic molecular pathways. Although there is evidence of neuronal loss in Alzheimer's disease (AD) and multiple programmed cell death (PCD) pathways have been implicated in this process, there has been no comprehensive evaluation of the dominant pathway responsible for cell death in AD. Likewise, the relative dominance of survival and PCD pathways in AD remains unclear. Here, we present the results of hypothesis-driven bioinformatic analysis of PCD and survival pathway activation in paired methylation and expression data from the middle temporal gyrus (MTG) as well as expression from laser-captured cells from the MTG and hippocampus. The results not only indicate activation of cell death pathways in AD-of which apoptosis is responsible for the largest fraction of upregulated genes-but also of cell survival pathways. These results are indicative of a complex balance between survival and death pathways in AD that future studies should work to delineate at a single cell level.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609561PMC
November 2020

Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.

JAMA 2020 08;324(8):772-781

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).

Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD.

Design, Setting, And Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017).

Exposures: Plasma P-tau217.

Main Outcomes And Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]).

Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22).

Conclusions And Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.
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http://dx.doi.org/10.1001/jama.2020.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388060PMC
August 2020
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