Publications by authors named "Thomas D Bird"

176 Publications

Familial Idiopathic Basal Ganglia Calcification: A Father-Son Dyad Demonstrate Heterogeneity of Presentation and Disease Progression.

Arch Clin Neuropsychol 2021 Apr 23. Epub 2021 Apr 23.

VA Puget Sound Health Care System, Geriatric Research Education and Clinical Center, Seattle, Washington 98144, USA.

Objective: Familial idiopathic basal ganglia calcification (FIBGC) is a rare, heritable disease characterized by calcium deposition in the basal ganglia and other brain regions. Clinical presentations are diverse, featuring an array of neurologic, psychiatric, and/or cognitive symptoms. This dyad report presents neurogenetic, neuroimaging, neurological, and serial neuropsychological data from a father (S1) and son (S2) with FIBGC.

Method/results: The SLC20A2 genetic mutation c.1828-1831delTCCC was identified for each patient, both of whom evidenced similar patterns of brain calcification mainly in the basal ganglia and cerebellum on neuroimaging. S1's onset was in his late 60s with primary motor abnormalities followed by cognitive decline; S2's younger onset (late 30s) was characterized by predominant psychiatric symptoms and mild cognitive changes. Our unique, detailed longitudinal study revealed that both subjects demonstrated largely stable performance across most neuropsychological domains assessed.

Conclusions: The subjects' differences in presentation demonstrate the variable expressivity in FIBGC even with the same pathogenic variant within a single family. Distinct phenotypes may be associated with age of onset even in persons with the same mutation, consistent with past research. Disease progression may feature an initial period of notable change from baseline followed by relative stability, as seen both on imaging and neuropsychological evaluation.
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http://dx.doi.org/10.1093/arclin/acab026DOI Listing
April 2021

Hexanucleotide Repeat in Huntington-Like Patients: Systematic Review and Meta-Analysis.

Front Genet 2020 2;11:551780. Epub 2020 Nov 2.

Neurogenetics Research Center, Instituto Nacional de Ciencias Neurológicas, Lima, Peru.

Patients with Huntington-Like disorders (HLD) comprise a variety of allelic disorders sharing a Huntington phenotype. The hexanucleotide repeat expansion of the gene could explain part of the HLD etiology. We aimed to conduct a systematic review and meta-analysis looking for the frequency of the hexanucleotide repeat expansion of the gene in HLD patients. The protocol was registered on the International Prospective Register of Systematic Reviews database (PROSPERO) (registration number: CRD42018105465). The search was carried out in Medline, Scopus, Web of Science, and Embase in April 2018, and updated in July 2020. Observational studies reporting patients with HLD carrying the hexanucleotide repeat expansion in the gene were selected and reviewed; this process was duplicated. The cutoff threshold for considering the hexanucleotide expansion as a pathogenic variant was equal to or >30 GC repeats. Cases with intermediate alleles with 20-29 repeat are also analyzed. Pooled frequency and 95% CI were calculated using random-effects models. Nine out of 219 studies were selected, reporting 1,123 affected individuals with HLD. Among them, 18 individuals carried expansion, representing 1% (95% CI: 0-2%, = 0%) of the pooled frequency. Seven selected studies came from European centers, one was reported at a US center, and one came from a South-African center. We identified five individuals carrying intermediate alleles representing 3% (95% CI: 0-14%, = 78.5%). The frequency of unstable hexanucleotide repeat expansion in HLD patients is very low. Further studies with more accurate clinical data and from different ethnic backgrounds are needed to confirm this observation.
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http://dx.doi.org/10.3389/fgene.2020.551780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667021PMC
November 2020

Adult onset pan-neuronal human tau tubulin kinase 1 expression causes severe cerebellar neurodegeneration in mice.

Acta Neuropathol Commun 2020 11 23;8(1):200. Epub 2020 Nov 23.

Geriatrics Research Education and Clinical Center, Seattle Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA.

The kinase TTBK1 is predominantly expressed in the central nervous system and has been implicated in neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis through its ability to phosphorylate the proteins tau and TDP-43. Mutations in the closely related gene TTBK2 cause spinocerebellar ataxia, type 11. However, it remains unknown whether altered TTBK1 activity alone can drive neurodegeneration. In order to characterize the consequences of neuronal TTBK1 upregulation in adult brains, we have generated a transgenic mouse model with inducible pan-neuronal expression of human TTBK1. We find that these inducible TTBK1 transgenic mice (iTTBK1 Tg) exhibit motor and cognitive phenotypes, including decreased grip strength, hyperactivity, limb-clasping, and spatial memory impairment. These behavioral phenotypes occur in conjunction with progressive weight loss, neuroinflammation, and severe cerebellar degeneration with Purkinje neuron loss. Phenotype onset begins weeks after TTBK1 induction, culminating in average mortality around 7 weeks post induction. The iTTBK1 Tg animals lack any obvious accumulation of pathological tau or TDP-43, indicating that TTBK1 expression drives neurodegeneration in the absence of detectable pathological protein deposition. In exploring TTBK1 functions, we identified the autophagy related protein GABARAP to be a novel interacting partner of TTBK1 and show that GABARAP protein levels increase in the brain following induction of TTBK1. These iTTBK1 Tg mice exhibit phenotypes reminiscent of spinocerebellar ataxia, and represent a new model of cerebellar neurodegeneration.
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http://dx.doi.org/10.1186/s40478-020-01073-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684928PMC
November 2020

Triggering Receptor Expressed on Myeloid Cell 2 R47H Exacerbates Immune Response in Alzheimer's Disease Brain.

Front Immunol 2020 25;11:559342. Epub 2020 Sep 25.

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States.

The R47H variant in the microglial triggering receptor expressed on myeloid cell 2 (TREM2) receptor is a strong risk factor for Alzheimer's disease (AD). To characterize processes affected by R47H, we performed an integrative network analysis of genes expressed in brains of AD patients with R47H, sporadic AD without the variant, and patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), systemic disease with early-onset dementia caused by loss-of-function mutations in TREM2 or its adaptor TYRO protein tyrosine kinase-binding protein (TYROBP). Although sporadic AD had few perturbed microglial and immune genes, TREM2 R47H AD demonstrated upregulation of interferon type I response and pro-inflammatory cytokines accompanied by induction of NKG2D stress ligands. In contrast, PLOSL had distinct sets of highly perturbed immune and microglial genes that included inflammatory mediators, immune signaling, cell adhesion, and phagocytosis. TREM2 knockout (KO) in THP1, a human myeloid cell line that constitutively expresses the TREM2- TYROBP receptor, inhibited response to the viral RNA mimetic poly(I:C) and phagocytosis of amyloid-beta oligomers; overexpression of ectopic TREM2 restored these functions. Compared with wild-type protein, R47H TREM2 had a higher stimulatory effect on the interferon type I response signature. Our findings point to a role of the TREM2 receptor in the control of the interferon type I response in myeloid cells and provide insight regarding the contribution of R47H TREM2 to AD pathology.
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http://dx.doi.org/10.3389/fimmu.2020.559342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546799PMC
April 2021

Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1.

Hum Mol Genet 2020 08;29(15):2551-2567

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.
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http://dx.doi.org/10.1093/hmg/ddaa139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471505PMC
August 2020

Mutations in the SIGMAR1 gene cause a distal hereditary motor neuropathy phenotype mimicking ALS: Report of two novel variants.

Neuromuscul Disord 2020 07 23;30(7):572-575. Epub 2020 May 23.

Department of Neurology, University of Washington, 1660 S. Columbian way S127, Seattle WA, United States; Department of Medicine, University of Washington, United States; Department of Psychiatry and Behavioral Sciences, United States; GRECC, VA Medical Center, United States.

Distal hereditary motor neuropathy (dHMN) is an inherited neuromuscular disease characterized by symmetric distal weakness and atrophy without sensory changes. There are about thirty known genes associated with dHMN, but together they explain only about a third of cases. Mutations in the sigma non-opioid intracellular receptor 1 gene (SIGMAR1) has been linked to autosomal recessive dHMN with pyramidal signs in several families. This phenotype can mimic amyotrophic lateral sclerosis (ALS). We report a 39-year-old man who was referred to our ALS clinic with distal motor weakness and hyperreflexia. Whole exome sequencing identified two novel variants in the SIGMAR1 gene in the proband. Targeted Sanger sequencing of asymptomatic family members confirmed that each carried one of these two variants. Our findings expand the number of known SIGMAR1 pathogenic variants associated with dHMN, which should be clinically distinguished from ALS.
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http://dx.doi.org/10.1016/j.nmd.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387213PMC
July 2020

Heterozygous missense variants cause ataxia, cognitive decline, and STUB1 mislocalization.

Neurol Genet 2020 Apr 10;6(2):1-13. Epub 2020 Feb 10.

Department of Neurology (D.-H.C., E.H., S.J., T.D.B.), University of Washington, Seattle; Department of Pathology (C.L., C.D.K.), Neuropathology Division, University of Washington, Seattle; Geriatric Research, Education, and Clinical Center (GRECC) (M.Y., D.G.C., W.H.R., T.D.B.), VA Puget Sound Health Care System, Seattle, WA; Department of Medicine (M.K.N.-K., W.H.R., T.D.B.), Division of Medical Genetics, University of Washington, Seattle; Mental Illness Research, Education, and Clinical Center (MIRECC) (J.S.M., W.H.R.), VA Puget Sound Health Care System, Seattle, WA; Department of Psychiatry and Behavioral Sciences (J.S.M., W.H.R.), University of Washington, Seattle; Department of Neurology (C.M.G.), University of Chicago, IL; Department of Medicine (D.G.C.), Division of Gerontology and Geriatric Medicine, University of Washington, Seattle; and Department of Pharmacology (D.G.C.), University of Washington, Seattle.

Objective: To identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant -related ataxia and investigate the effects of pathogenic variants on localization.

Methods: Clinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.

Results: Mutations in have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.

Conclusions: This study confirms a dominant inheritance pattern in -ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.
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http://dx.doi.org/10.1212/NXG.0000000000000397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073456PMC
April 2020

Hyperphosphorylated Tau, Increased Adenylate Cyclase 5 (ADCY5) Immunoreactivity, but No Neuronal Loss in ADCY5-Dyskinesia.

Mov Disord Clin Pract 2020 Jan 14;7(1):70-77. Epub 2019 Dec 14.

Department of Medicine, Division of Medical Genetics University of Washington Seattle Washington USA.

Background: Adenylate cyclase 5 (ADCY5)-related dyskinesia is a childhood-onset movement disorder. Manifestations vary in frequency and severity and may include chorea, tremor, dystonia, facial twitches, myoclonus, axial hypotonia, and limb hypertonia. Psychosis is likely part of the broader spectrum. ADCY5 is widely expressed in the brain, especially in the striatum. Previous reports of brain autopsies of 2 subjects with likely ADCY5-dyskinesia were limited by the absence of a molecular diagnosis. In 1 case, normal gross pathology was reported. In the other case, ADCY5 expression was not examined and neuropathological findings were confounded by age and comorbidities.

Objectives: To examine ADCY5 expression and neuropathological changes in ADCY5-dyskinesia.

Methods: An extensive brain autopsy, including immunohistochemical analyses with antibodies to paired helical filament tau, α-synuclein, amyloid-β, microtubule-associated protein 2, and ADCY5, was performed.

Results: The patient, with a p.M1029K ADCY5 variant, had severe dyskinesias from early childhood, later recurrent episodes of psychosis, and died at age 46. Gross pathology was unremarkable, but we detected increased immunoreactivity for ADCY5 in neurons in multiple brain regions. Despite no history of brain trauma to suggest chronic traumatic encephalopathy, we found tau deposits in the deep cortical sulci, midbrain, and hippocampus with minimal amyloid pathology and no Lewy bodies.

Conclusions: We present the first brain autopsy findings in a molecularly proven case of ADCY5-dyskinesia, showing increased ADCY5 immunoreactivity in neurons and evidence of tau deposition. Additional patients will need to be studied to determine whether increased immunoreactivity for ADCY5 is a signature for ADCY5-dyskinesia and whether this disease has a tauopathy component.
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http://dx.doi.org/10.1002/mdc3.12873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962666PMC
January 2020

Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy.

PLoS Genet 2019 12 13;15(12):e1008526. Epub 2019 Dec 13.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.

Pathological phosphorylated TDP-43 protein (pTDP) deposition drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the cellular and genetic mechanisms at work in pathological TDP-43 toxicity are not fully elucidated. To identify genetic modifiers of TDP-43 neurotoxicity, we utilized a Caenorhabditis elegans model of TDP-43 proteinopathy expressing human mutant TDP-43 pan-neuronally (TDP-43 tg). In TDP-43 tg C. elegans, we conducted a genome-wide RNAi screen covering 16,767 C. elegans genes for loss of function genetic suppressors of TDP-43-driven motor dysfunction. We identified 46 candidate genes that when knocked down partially ameliorate TDP-43 related phenotypes; 24 of these candidate genes have conserved homologs in the human genome. To rigorously validate the RNAi findings, we crossed the TDP-43 transgene into the background of homozygous strong genetic loss of function mutations. We have confirmed 9 of the 24 candidate genes significantly modulate TDP-43 transgenic phenotypes. Among the validated genes we focused on, one of the most consistent genetic modifier genes protecting against pTDP accumulation and motor deficits was the heparan sulfate-modifying enzyme hse-5, the C. elegans homolog of glucuronic acid epimerase (GLCE). We found that knockdown of human GLCE in cultured human cells protects against oxidative stress induced pTDP accumulation. Furthermore, expression of glucuronic acid epimerase is significantly decreased in the brains of FTLD-TDP cases relative to normal controls, demonstrating the potential disease relevance of the candidate genes identified. Taken together these findings nominate glucuronic acid epimerase as a novel candidate therapeutic target for TDP-43 proteinopathies including ALS and FTLD-TDP.
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http://dx.doi.org/10.1371/journal.pgen.1008526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934317PMC
December 2019

Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort.

Acta Neuropathol Commun 2019 06 7;7(1):91. Epub 2019 Jun 7.

Division of Neuropathology, Department of Pathology, University of Washington, Seattle, WA, 98104, USA.

Alzheimer's disease neuropathologic change (ADNC) is defined by progressive accumulation of β-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.
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http://dx.doi.org/10.1186/s40478-019-0743-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556006PMC
June 2019

Aβ and tau prion-like activities decline with longevity in the Alzheimer's disease human brain.

Sci Transl Med 2019 05;11(490)

Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

The hallmarks of Alzheimer's disease (AD) are the accumulation of Aβ plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of Aβ in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological Aβ conformers. Individuals over 80 years of age had the lowest amounts of prion-like Aβ and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.
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http://dx.doi.org/10.1126/scitranslmed.aat8462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640844PMC
May 2019

Alternative splicing in a presenilin 2 variant associated with Alzheimer disease.

Ann Clin Transl Neurol 2019 Apr 10;6(4):762-777. Epub 2019 Mar 10.

Department of Neurology University of Washington Seattle Washington.

Objective: Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (), presenilin 2 (), and amyloid precursor protein (). Previously, we reported a rare frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates.

Methods: We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families.

Results: Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less A compared to controls, indicating abnormal -secretase activity. Analysis of transcript levels in brain tissue revealed alternatively spliced products in patient brain as well as in sporadic AD and age-matched control brain.

Interpretation: These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel alternative transcripts in addition to previously reported splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.
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http://dx.doi.org/10.1002/acn3.755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469258PMC
April 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Correction: Genetic data and cognitively defined late-onset Alzheimer's disease subgroups.

Mol Psychiatry 2020 Nov;25(11):3100

Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA.

This article was originally published under standard licence, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.
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http://dx.doi.org/10.1038/s41380-019-0348-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962581PMC
November 2020

Genetic data and cognitively defined late-onset Alzheimer's disease subgroups.

Mol Psychiatry 2020 11 4;25(11):2942-2951. Epub 2018 Dec 4.

Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA.

Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer's disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10 and odds ratios more extreme than those previously reported for Alzheimer's disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.
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http://dx.doi.org/10.1038/s41380-018-0298-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548676PMC
November 2020

Trends over 42 years in the Adult Medical Genetics Clinic at the University of Washington.

Genet Med 2019 06 16;21(6):1457-1461. Epub 2018 Oct 16.

Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

Purpose: We analyzed the patients served by the University of Washington Adult Genetic Medicine Clinic (UWAGMC) over a 42-year period to determine how clinical services have changed and to evaluate the contributing factors.

Methods: We conducted a retrospective survey of patients seen by UWAGMC that included patients seen from 1975 to 2016. Variables considered included referral indication, disease status, and clinic visit date. Indications for referral were then binned into clinical categories for descriptive analysis.

Results: Of 30,780 patient visits during the 39 years for which data were available, 57.3% occurred in the last decade. Referrals for breast/ovarian cancer or colon/endometrial cancer account for 74.8% of cancer referrals since 1998. Huntington disease patients made up 46% of neurological referral indications. Telephone screening implemented in 2013 has reduced the number of referrals for hypermobile Ehlers-Danlos syndrome.

Conclusion: Referral indications increased with clinical testing availability and because of the academic programs of UWAGMC providers. With increased public awareness of heritable conditions, prescreening self-referrals were used to allocate limited resources. These trends demonstrate the need for more geneticists in adult medicine to expand centers of excellence for rare diseases and to serve the increasing numbers of adult patients with genetic conditions.
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http://dx.doi.org/10.1038/s41436-018-0329-5DOI Listing
June 2019

Molecular genetic testing for hereditary ataxia: What every neurologist should know.

Neurol Clin Pract 2018 Feb;8(1):27-32

Division of Genetic Medicine, Department of Pediatrics (SEW), and Departments of Neurology and Medicine (TDB), University of Washington, Seattle.

Purpose Of Review: Because of extensive clinical overlap among many forms of hereditary ataxia, molecular genetic testing is often required to establish a diagnosis. Interrogation of multiple genes has become a popular diagnostic approach as the cost of sequence analysis has decreased and the number of genes associated with overlapping phenotypes has increased. We describe the benefits and limitations of molecular genetic tests commonly used to determine the etiology of hereditary ataxia.

Recent Findings: There are more than 300 hereditary disorders associated with ataxia. The most common causes of hereditary ataxia are expansion of nucleotide repeats within 7 genes: , , , , , (spinocerebellar ataxia type 6), and (Friedreich ataxia). Recent reports describing the use of clinical exome sequencing to identify causes of hereditary ataxia may lead neurologists to start their clinical investigation with a less sensitive molecular test providing a misleading "negative" result.

Summary: The majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia.
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http://dx.doi.org/10.1212/CPJ.0000000000000421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839675PMC
February 2018

A Genetic Study of Psychosis in Huntington's Disease: Evidence for the Involvement of Glutamate Signaling Pathways.

J Huntingtons Dis 2018 ;7(1):51-59

Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.

Background: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD.

Objective: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD.

Methods: DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups.

Results: Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling.

Conclusions: This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.
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http://dx.doi.org/10.3233/JHD-170277DOI Listing
October 2019

Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration.

Mol Neurodegener 2018 02 6;13(1). Epub 2018 Feb 6.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA.

Background: Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients. Both TTBK1 and TTBK2 were initially identified as tau kinases and TTBK1 has been shown to phosphorylate tau epitopes commonly observed in Alzheimer's disease and other tauopathies.

Methods: To further elucidate how TTBK1/2 activity contributes to both TDP-43 and tau phosphorylation in the context of the neurodegeneration seen in FTLD, we examined the consequences of elevated human TTBK1/2 kinase expression in transgenic animal models of disease.

Results: We show that C. elegans co-expressing tau/TTBK1 tau/TTBK2, or TDP-43/TTBK1 transgenes in combination exhibit synergistic exacerbation of behavioral abnormalities and increased pathological protein phosphorylation. We also show that C. elegans co-expressing tau/TTBK1 or tau/TTBK2 transgenes in combination exhibit aberrant neuronal architecture and neuron loss. Surprisingly, the TTBK2/TDP-43 transgenic combination showed no exacerbation of TDP-43 proteinopathy related phenotypes. Additionally, we observed elevated TTBK1/2 protein expression in cortical and hippocampal neurons of FTLD-tau and FTLD-TDP cases relative to normal controls.

Conclusions: Our findings suggest a possible etiology for the two most common FTLD subtypes through a kinase activation driven mechanism of neurodegeneration.
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http://dx.doi.org/10.1186/s13024-018-0237-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802059PMC
February 2018

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing.

Sci Rep 2018 01 17;8(1):975. Epub 2018 Jan 17.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.

Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults. These drugs act rapidly to inhibit C. elegans feeding within minutes of exposure. Sertraline, paroxetine, and chlorpromazine also decrease motility of adult Trichuris muris whipworms, prevent hatching and development of Ancylostoma caninum hookworms and kill Schistosoma mansoni flatworms, three widely divergent parasitic helminth species. C. elegans mutants with resistance to known anthelmintic drugs such as ivermectin are equally or more susceptible to these three drugs, suggesting that they may act on novel targets to kill worms. Sertraline, paroxetine, and chlorpromazine have long histories of use clinically as antidepressant or antipsychotic medicines. They may represent new classes of anthelmintic drug that could be used in combination with existing front-line drugs to boost effectiveness of anti-parasite treatment as well as offset the development of parasite drug resistance.
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http://dx.doi.org/10.1038/s41598-017-18457-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772060PMC
January 2018

Clinical approach to the patient with neurogenetic disease.

Handb Clin Neurol 2018 ;147:3-9

Department of Neurology, University of Washington, Seattle, WA, United States.

Neurogenetic diseases are surprisingly common. This chapter reviews a systematic approach to the evaluation of a patient thought to have such a disease. The emphasis is on first recognizing potential clues to the diagnosis contained in the family history and presentation of symptoms. Ataxia, neuropathy, muscle weakness, dementia, epilepsy, and cognitive delay are all "reservoirs" of neurogenetic disease. A high index of suspicion for genetic causes and a thoughtful evaluation of simplex (sporadic) cases is often necessary. Then the physician can proceed to the differential diagnosis, genetic testing, and genetic counseling. A team approach including a genetic counselor is usually the best strategy.
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http://dx.doi.org/10.1016/B978-0-444-63233-3.00001-4DOI Listing
July 2018

Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease.

Proc Natl Acad Sci U S A 2018 01 8;115(4):E782-E791. Epub 2018 Jan 8.

Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158;

Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aβ deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT Aβ, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aβ40 fibrils into transgenic mice expressing only WT Aβ induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aβ40 prions induce a conformation of WT Aβ similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aβ prion conformations, which kinetically dominate the spread of prions in the brain.
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http://dx.doi.org/10.1073/pnas.1714966115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789926PMC
January 2018

An 8-generation family with X-linked Charcot-Marie-Tooth: Confirmation Of the pathogenicity Of a 3' untranslated region mutation in GJB1 and its clinical features.

Muscle Nerve 2018 05 28;57(5):859-862. Epub 2017 Dec 28.

Department of Neurology, University of Washington, Seattle, Washington, USA.

Introduction: Mutations in gap junction protein beta 1 (GJB1) on the X chromosome represent one of the most common causes of hereditary neuropathy. We assessed manifestations associated with a rare 3' untranslated region mutation (UTR) of GJB1 in a large family with X-linked Charcot-Marie-Tooth disease (CMTX).

Methods: Clinical, electrophysiological, and molecular genetic analyses were performed on an 8-generation family with CMTX.

Results: There were 22 affected males and 19 symptomatic females, including an 83-year-old woman followed for 40 years. Electrophysiological studies showed a primarily axonal neuropathy. The c.*15C>T mutation in the GJB1 3' UTR was identified in 4 branches of the family with a log of odds (LOD) of 4.91. This created a BstE II enzyme recognition site that enabled detection by restriction digestion.

Discussion: The c.*15C>T mutation in the GJB1 3' UTR segregates with CMTX1 in 8 generations. Penetrance in males and females is essentially complete. A straightforward genetic method to detect this mutation is described. Muscle Nerve 57: 859-862, 2018.
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http://dx.doi.org/10.1002/mus.26037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910283PMC
May 2018