Publications by authors named "Carlos Cruchaga"

202 Publications

Undetected Neurodegenerative Disease Biases Estimates of Cognitive Change in Older Adults.

Psychol Sci 2021 May 27:956797620985518. Epub 2021 May 27.

Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis.

Neurodegenerative disease is highly prevalent among older adults and, if undetected, may obscure estimates of cognitive change among aging samples. Our aim in this study was to determine the nature and magnitude of cognitive change in the absence of common neuropathologic markers of neurodegenerative disease. Cognitively normal older adults (ages 65-89 years, = 199) were classified as normal or abnormal using neuroimaging and cerebrospinal-fluid biomarkers of β-amyloid, tau, and neurodegeneration. When cognitive change was modeled without accounting for biomarker status, significant decline was evident for semantic memory, processing speed, and working memory. However, after adjusting for biomarker status, we found that the rate of change was attenuated and that the biomarker-normal group demonstrated no decline for any cognitive domain. These results indicate that estimates of cognitive change in otherwise healthy older adults will be biased toward decline when the presence of early neurodegenerative disease is not accounted for.
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http://dx.doi.org/10.1177/0956797620985518DOI Listing
May 2021

Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.

Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.

Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.

Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
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http://dx.doi.org/10.1002/alz.12333DOI Listing
May 2021

Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri, USA.

Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation.

Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography.

Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P = .02), with significant weighting on linear regression toward CSF total tau (P = .03) and CSF phosphorylated tau at codon 181 (P = .03), but not CSF Aβ .

Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau.
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http://dx.doi.org/10.1002/alz.12375DOI Listing
May 2021

Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.

Nature 2021 May 28;593(7858):255-260. Epub 2021 Apr 28.

Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.

Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
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http://dx.doi.org/10.1038/s41586-021-03489-0DOI Listing
May 2021

Causal Effect of MMP-1 (Matrix Metalloproteinase-1), MMP-8, and MMP-12 Levels on Ischemic Stroke: A Mendelian Randomization Study.

Stroke 2021 Apr 27:STROKEAHA120033041. Epub 2021 Apr 27.

Stroke Pharmacogenomics and Genetics Laboratory, Sant Pau Research Institute, Barcelona, Spain (J.C.-M., N.C., E.M., C.G.-F., M.L., I.F.-C.).

Background And Purpose: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain.

Methods: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791).

Results: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86-0.94]; value=7.43×10), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92-0.98]; value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65-0.77]; value=5.11×10); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06-1.45]; value=0.03). No associations were found in relation to stroke outcome.

Conclusions: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.
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http://dx.doi.org/10.1161/STROKEAHA.120.033041DOI Listing
April 2021

The Dystonia Coalition: A Multicenter Network for Clinical and Translational Studies.

Front Neurol 2021 8;12:660909. Epub 2021 Apr 8.

Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of international consensus for the definition and classification of all dystonias, diagnostic criteria for specific subtypes of dystonia, standardized evaluation strategies, development of clinimetrically sound measurement tools, and large multicenter studies that document the phenotypic heterogeneity and evolution of specific types of dystonia.
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http://dx.doi.org/10.3389/fneur.2021.660909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060489PMC
April 2021

African Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants.

Neurol Genet 2021 Apr 4;7(2):e571. Epub 2021 Mar 4.

Department of Neurology (S.E.S., A.J., R.L.H., R.J.M., L.P., J.J.L.-G., K.L.M., A.M.F., D.M.H., J.C.M.), Department of Psychiatry (C.C., F.H.G.F.), and Division of Biostatistics (L.M., C.X.), Washington University School of Medicine, St. Louis, MO; Office of Health Equity and Department of Medicine (C.H.W.), Division of Geriatrics, Vanderbilt University Medical Center, Nashville, TN; Department of Internal Medicine (C.H.W.), Meharry Medical College, Nashville, TN; Alzheimers Disease Research Center (Y.D.), University of Wisconsin School of Medicine and Public Health, Madison; Brain and Mind Centre (L.P.), University of Sydney, NSW, Australia; and Mallinckrodt Institute of Radiology (B.M.A., T.L.S.B.), Washington University School of Medicine, St. Louis, MO.

Objective: To evaluate for racial differences in triggering receptor expressed on myeloid cells 2 (TREM2), a key immune mediator in Alzheimer disease, the levels of CSF soluble TREM2 (sTREM2), and the frequency of associated genetic variants were compared in groups of individuals who self-reported their race as African American (AA) or non-Hispanic White (NHW).

Methods: Community-dwelling older research participants underwent measurement of CSF sTREM2 concentrations and genetic analyses.

Results: The primary cohort included 91 AAs and 868 NHWs. CSF sTREM2 levels were lower in the AA compared with the NHW group (1,336 ± 470 vs 1,856 ± 624 pg/mL, < 0.0001). AAs were more likely to carry coding variants (15% vs 3%, < 0.0001), which were associated with lower CSF sTREM2. AAs were less likely to carry the rs1582763 minor allele (8% vs 37%, < 0.0001), located near , which was associated with higher CSF sTREM2. These findings were replicated in an independent cohort of 23 AAs and 917 NHWs: CSF sTREM2 levels were lower in the AA group ( = 0.03), AAs were more likely to carry coding variants (22% vs 4%, = 0.002), and AAs were less likely to carry the rs1582763 minor allele (16% vs 37%, = 0.003).

Conclusions: On average, AAs had lower CSF sTREM2 levels compared with NHWs, potentially because AAs are more likely to carry genetic variants associated with lower CSF sTREM2 levels. Importantly, CSF sTREM2 reflects TREM2-mediated microglial activity, a critical step in the immune response to amyloid plaques. These findings suggest that race may be associated with risk for genetic variants that influence Alzheimer disease-related inflammation.
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http://dx.doi.org/10.1212/NXG.0000000000000571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054965PMC
April 2021

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer's disease.

Hum Mol Genet 2021 May;30(9):811-822

Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China.

To identify novel risk genes and better understand the molecular pathway underlying Alzheimer's disease (AD), whole-exome sequencing was performed in 215 early-onset AD (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.
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http://dx.doi.org/10.1093/hmg/ddab090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161517PMC
May 2021

Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25.

Neurobiol Aging 2021 Feb 11;102:64-72. Epub 2021 Feb 11.

Department of Neurology, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA. Electronic address:

Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.008DOI Listing
February 2021

Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease.

Brain 2021 Mar 16. Epub 2021 Mar 16.

Dementia Research Centre, University College London, Queen Square, London, UK.

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal aging, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state-fMRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: First, we included 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls. Second, we included 156 amyloid-PET positive subjects across the spectrum of sporadic Alzheimer's disease as well as 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal-lobe tau-PET (i.e. composite across Braak stage I & III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher fMRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (p = 0.007). Similarly, for sporadic Alzheimer's disease patients, higher fMRI-assessed system segregation was associated with less decrement in global cognition (p = 0.001) and episodic memory (p = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awab112DOI Listing
March 2021

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma.

Brain 2021 Mar 16. Epub 2021 Mar 16.

Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.

Hemorrhagic transformation is a complication of recombinant tissue-plasminogen activator (rtPA) treatment. The most severe form, parenchymal hematoma, can result in neurological deterioration, disability, and death. Our objective is to identify single nucleotide variations associated with a risk of parenchymal hematoma following thrombolytic therapy in acute ischemic stroke patients. A fixed-effect genome-wide metanalysis was performed combining two-stage Genome Wide Association studies (GWAs) (n = 1,904). The Discovery Stage (3 cohorts) comprised 1,324 ischemic stroke individuals, of whom 5.4% had a parenchymal hematoma. Genetic variants yielding a p-value <1x10-5 were analyzed in the Validation Stage (6 cohorts), formed by 580 ischemic stroke patients with 12.1% hemorrhagic events. All the participants received rtPA; cases were parenchymal hematoma type 1 or 2 as defined by the ECASS criteria. Genome-wide significant findings (p < 5x10-8) were characterized by in-silico functional annotation, gene expression, and DNA regulatory elements. We analyzed 7,989,272 single nucleotide polymorphisms (SNPs) and identified a Genome-wide association locus on chromosome 20 in the Discovery Cohort; functional annotation indicated that the ZBTB46 gene was driving the association for Chrosome 20. The top SNP was rs76484331 in the ZBTB46 gene (p = 2.49x10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55). In the Replication Cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal hematoma (p = 0.01), and the overall association after meta-analysis increased (p = 1.61x10-8; OR: 5.84; 95%CI: 3.16-10.76). ZBTB46 codes the Zinc Finger and BTB domain-containing protein 46 that acts as a transcription factor. In-silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conculsion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal hematoma following rtPA treatment.
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http://dx.doi.org/10.1093/brain/awab090DOI Listing
March 2021

Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression.

Alzheimers Dement 2021 Mar 2. Epub 2021 Mar 2.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.

Introduction: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain.

Methods: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes.

Results: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia.

Discussion: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.
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http://dx.doi.org/10.1002/alz.12310DOI Listing
March 2021

Long runs of homozygosity are associated with Alzheimer's disease.

Transl Psychiatry 2021 Feb 24;11(1):142. Epub 2021 Feb 24.

Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
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http://dx.doi.org/10.1038/s41398-020-01145-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904832PMC
February 2021

Lack of evidence supporting a role for DPP6 sequence variants in Alzheimer's disease in the European American population.

Acta Neuropathol 2021 04 16;141(4):623-624. Epub 2021 Feb 16.

Department Psychiatry, Washington University School of Medicine (WUSM), 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.

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http://dx.doi.org/10.1007/s00401-021-02271-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952336PMC
April 2021

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

Neurology 2021 03 25;96(12):e1632-e1645. Epub 2021 Jan 25.

From the Departments of Radiology (N.J.-M., T.M.B., B.A.G., G.C., P.M., R.C.H., T.L.S.B.), Neurology (E.M., J.H., B.M.A., R.J.P., J.C.M., R.J.B.), Psychological and Brain Sciences (J.H.), Psychiatry (C.C., C.M.K.), and Pathology and Immunology (R.J.P.) and Division of Biostatistics (G.W., C.X.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimers Institute (Y.S.), Phoenix, AZ; Department of Cognitive Neurology and Neuropsychology (R.F.A.), Instituto de Investigaciones Neurológicas Fleni, Buenos Aires, Argentina; Departments of Neurology and Clinical and Translational Science (S.B.B.), University of Pittsburgh School of Medicine, PA; Department of Neurology (A.M.B.), Taub Institute for Research on Alzheimers Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY; Neuroscience Research Australia (W.S.B., P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales (W.S.B.), Sydney, Australia; Dementia Research Centre and UK Dementia Research Institute (D.M.C., N.C.F., A.O.), UCL Queen Square Institute of Neurology, London, UK; Departments of Neurology (J.P.C., K.A.J.) and Radiology (K.A.J.), Massachusetts General Hospital, Boston; Department of Neurology (H.C.C., J.M.R.), Keck School of Medicine of USC, Los Angeles, CA; Department of Psychiatry and Human Behavior (S.C., A.K.W.L., S.S.), Memory and Aging Program, Butler Hospital, Brown University Alpert Medical School, Providence, RI; Center for Neuroimaging, Department of Radiology and Imaging Science (M.R.F., A.J.S.), Department of Pathology and Laboratory Medicine (B.G.), and Indiana Alzheimers Disease Research Center (A.J.S.), Indiana University School of Medicine, Indianapolis; Departments of Molecular Imaging and Neurology (M.F.), Royal Prince Alfred Hospital, University of Sydney, Australia; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; German Center for Neurodegenerative Diseases (DZNE) (C.L., J.L., I.Y.); Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy (C.L.), University of Tübingen; Department of Neurology (J.L., I.Y.), Ludwig-Maximilians-Universität München; Munich Cluster for Systems Neurology (SyNergy) (J.L., I.Y.), Germany; Florey Institute and The University of Melbourne (C.L.M.), Australia; Department of Neurology (J.M.N.), Columbia University Irving Medical Center, New York, NY; Department of Radiology (K.K., C.R.J., G.M.P.), Mayo Clinic, Rochester, MN; Department of Molecular Imaging and Therapy (C.C.R., V.L.V.), Austin Health, University of Melbourne, Heidelberg, Australia; Clinical Research Center for Dementia (H.S.), Osaka City University; Department of Neurology (M.S.), Hirosaki University Graduate School of Medicine; and Department of Neurology (K.S.), The University of Tokyo, Japan.

Objective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).

Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.

Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).

Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.
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http://dx.doi.org/10.1212/WNL.0000000000011542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032370PMC
March 2021

Modeling autosomal dominant Alzheimer's disease with machine learning.

Alzheimers Dement 2021 Jun 21;17(6):1005-1016. Epub 2021 Jan 21.

German Center for Neurodegenerative Diseases, Munich, Germany.

Introduction: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease.

Methods: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status.

Results: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R  = 0.95), fluorodeoxyglucose (R  = 0.93), and atrophy (R  = 0.95) in mutation carriers compared to non-carriers.

Discussion: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.
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http://dx.doi.org/10.1002/alz.12259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195816PMC
June 2021

Quantitative endophenotypes as an alternative approach to understanding genetic risk in neurodegenerative diseases.

Neurobiol Dis 2021 Apr 8;151:105247. Epub 2021 Jan 8.

Department of Psychiatry, Washington University, St. Louis, MO 63110, United States of America; NeuroGenomics and Informatics, Washington University, St. Louis, MO 63110, United States of America; Hope Center for Neurologic Diseases, Washington University, St. Louis, MO 63110, United States of America; The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, 63110, United States of America; Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, United States of America. Electronic address:

Endophenotypes, as measurable intermediate features of human diseases, reflect underlying molecular mechanisms. The use of quantitative endophenotypes in genetic studies has improved our understanding of pathophysiological changes associated with diseases. The main advantage of the quantitative endophenotypes approach to study human diseases over a classic case-control study design is the inferred biological context that can enable the development of effective disease-modifying treatments. Here, we summarize recent progress on biomarkers for neurodegenerative diseases, including cerebrospinal fluid and blood-based, neuroimaging, neuropathological, and clinical studies. This review focuses on how endophenotypic studies have successfully linked genetic modifiers to disease risk, disease onset, or progression rate and provided biological context to genes identified in genome-wide association studies. Finally, we review critical methodological considerations for implementing this approach and future directions.
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http://dx.doi.org/10.1016/j.nbd.2020.105247DOI Listing
April 2021

Rare and de novo coding variants in chromodomain genes in Chiari I malformation.

Am J Hum Genet 2021 01 21;108(1):100-114. Epub 2020 Dec 21.

Department of Pediatrics, Washington University, St. Louis, MO 63110, USA; Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA; Department of Neurology, Washington University, St. Louis, MO 63110, USA.

Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820723PMC
January 2021

/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer's disease pathogenesis.

Sci Transl Med 2020 12;12(574)

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer's disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene , is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of /YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, knockdown increased phagocytosis of zymosan particles and of β-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal expression, whereas deletion of the negative clock regulators PER1/PER2 increased expression. Basal mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of was gated by the clock. Our findings reveal /YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory induction.
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http://dx.doi.org/10.1126/scitranslmed.aax3519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808313PMC
December 2020

Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome.

Stroke 2021 01 15;52(1):132-141. Epub 2020 Dec 15.

Department of Neurology, Son Espases University Hospital, IdISBa, Palma de Mallorca, Spain (C.V.-B., R.D.-N., S.T., C.J.).

Background And Purpose: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSS - NIHSS = ΔNIHSS), to examine its relevance to AIS mechanisms and long-term outcomes.

Methods: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS was examined. Finally, the association of ΔNIHSS with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA).

Results: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS (R=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R=0.27), but much of the variance remained unexplained. ΔNIHSS had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS was similarly associated with 90-day outcomes.

Conclusions: The dynamic phenotype, ΔNIHSS, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.
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http://dx.doi.org/10.1161/STROKEAHA.119.028687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769959PMC
January 2021

Exome-wide rare variant analysis in familial essential tremor.

Parkinsonism Relat Disord 2021 01 24;82:109-116. Epub 2020 Nov 24.

Saskatchewan Movement Disorders Program, University of Saskatchewan/Saskatchewan Health Authority, Saskatoon, Saskatchewan, Canada.

Introduction: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing.

Methods: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes.

Results: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders.

Conclusions: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.
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http://dx.doi.org/10.1016/j.parkreldis.2020.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856267PMC
January 2021

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease.

Acta Neuropathol Commun 2020 11 19;8(1):196. Epub 2020 Nov 19.

Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA.

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta, total tau, and phosphorylated tau as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta levels (effect = - 0.5, p = 9.2 × 10). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta (R = 2.29%; p = 2.5 × 10). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta levels (p = 7.3 × 10). Two-sample Mendelian Randomization revealed that CSF amyloid beta plays a role in Parkinson's disease (p = 1.4 × 10) and age at onset (p = 7.6 × 10), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta (p = 3.8 × 10), higher mean cortical binding potentials (p = 5.8 × 10), and higher Braak amyloid beta score (p = 4.4 × 10). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta, and APOE.
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http://dx.doi.org/10.1186/s40478-020-01072-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678051PMC
November 2020

Biphasic cortical macro- and microstructural changes in autosomal dominant Alzheimer's disease.

Alzheimers Dement 2021 04 16;17(4):618-628. Epub 2020 Nov 16.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Introduction: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials.

Methods: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network.

Results: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations.

Discussion: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.
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http://dx.doi.org/10.1002/alz.12224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043974PMC
April 2021

Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

During the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated (LBF=5.30) and (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of and is enriched in neurons. , a pre-synaptic protein, and , a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke.

Research Into Context: No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke. This is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry. The findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.
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http://dx.doi.org/10.1101/2020.10.29.20222257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654887PMC
November 2020

Socioeconomic Status Mediates Racial Differences Seen Using the AT(N) Framework.

Ann Neurol 2021 02 7;89(2):254-265. Epub 2020 Nov 7.

Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.

Objectives: African Americans are at greater risk for developing Alzheimer's disease (AD) dementia than non-Hispanic whites. In addition to biological considerations (eg, genetic influences and comorbid disorders), social and environmental factors may increase the risk of AD dementia. This paper (1) assesses neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences and (2) considers mediating effects of socioeconomic status (SES) and measures of small vessel and cardiovascular disease on observed race differences.

Methods: Imaging measures of AT(N) (amyloid and tau positron emission tomography [PET]) structural magnetic resonance imaging (MRI), and resting state functional connectivity (rs-fc) were collected from African American (n = 131) and white (n = 685) cognitively normal participants age 45 years and older. Measures of small vessel and cardiovascular disease (white matter hyperintensities [WMHs] on MRI, blood pressure, and body mass index [BMI]) and area-based SES were included in mediation analyses.

Results: Compared to white participants, African American participants had greater neurodegeneration, as measured by decreased cortical volumes (Cohen's f = 0.05, p < 0.001). SES mediated the relationship between race and cortical volumes. There were no significant race effects for amyloid, tau, or rs-fc signature.

Interpretation: Modifiable factors, such as differences in social contexts and resources, particularly area-level SES, may contribute to observed racial differences in AD. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies. ANN NEUROL 2021;89:254-265.
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http://dx.doi.org/10.1002/ana.25948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903892PMC
February 2021

Single-subject grey matter network trajectories over the disease course of autosomal dominant Alzheimer's disease.

Brain Commun 2020 15;2(2):fcaa102. Epub 2020 Jul 15.

Department of Neurology, Amsterdam Neuroscience, Alzheimer Center Amsterdam, Amsterdam, UMC, VU University, Netherlands.

Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer's disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer's disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset -9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer's disease, which is alike sporadic Alzheimer's disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer's disease.
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http://dx.doi.org/10.1093/braincomms/fcaa102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475695PMC
July 2020

, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

Neurology 2020 12 17;95(24):e3288-e3302. Epub 2020 Sep 17.

From the Institute of Neurology (B.C., D.A.K., J.H., P.A.L., R.F.), School of Pharmacy (C.M.), and UCL Movement Disorders Centre (J.H.), University College London; School of Pharmacy (C.M., P.A.L.), University of Reading, Whiteknights; Neurogenetics Laboratory (M.B.-Q., C.W., J.M.P.), National Hospital for Neurology and Neurosurgery, London, UK; Aptima Clinic (Miquel Aguilar), Terrassa; Memory Disorders Unit, Department of Neurology (I.A., M.D.-F., P.P.), University Hospital Mutua de Terrassa, Barcelona; Hospital Universitario Central de Asturias (V.A., M.M.-G.), Oviedo, Spain; NORMENT (O.A.), Institute of Clinical Medicine, University of Oslo, Norway; Regional Neurogenetic Centre (Maria Anfossi, Livia Bernardi, A.C.B., M.E.C., Chiara Cupidi, F.F., Maura Gallo, R.M., N.S.), ASPCZ, Lamezia Terme; Department of Neuroscience, Psychology, Drug Research and Child Health (S.B., B.N., I.P., S.S.), University of Florence; Molecular Markers Laboratory (Luisa Benussi, Giuliano Binetti, R.G.), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience (D.B.), University of Sheffield, UK; Research Center and Memory Clinic (M.B., I.H., S.M.-G., Agustín Ruiz), Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain; Centre for Neurodegenerative Disorders (B.B., A.P.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Clinical Neurosciences (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neurology (Geir Bråthen, S.B.S.), University Hospital of Trondheim, Norway; Dept NVS, Division of Neurogeriatrics (H.-H.C., C.G., B.K., L.Ö.), Karolinska Institutet, Bioclinicum Solna, Sweden; Department of Neurology (J.C., O.D.-I., I.I.-G., A.L.), IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; Anne Rowling Regenerative Neurology Clinic (S.C., G.J.T.H., S.P.) and Centre for Clinical Brain Sciences (S.P.), University of Edinburgh, UK; NeuroGenomics and Informatics, Department of Psychiatry (Carlos Cruchaga), Washington University, St. Louis, MO; Cognitive Impairment Center (M.E.D.B., Maurizio Gallucci) and Immunohematology and Transfusional Medicine Service (E.D., A.V.), Local Health Authority n.2 Marca Trevigiana, Treviso, Italy; Department of Psychiatry and Psychotherapy (J.D.-S., C.R.), School of Medicine, Technical University of Munich, Germany; Department of Neurology (D.F., M.G.K.) and Clinical Institute of Medical Genetics (A.M., B.P.), University Medical Center Ljubljana, Slovenia; Dino Ferrari Center (D.G., Elio Scarpini, M.S.), University of Milan, Italy; Cognitive Neuroscience Lab, Think and Speak Lab (J.H.G.), Shirley Ryan Ability Lab, Chicago, IL; Department of Pathology and Laboratory Medicine (Murray Grossman, EunRan Suh, J.Q.T., V.M.V.D.), Center for Neurodegenerative Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; UCL Dementia Research Institute (J.H.), London; Reta Lila Weston Institute (J.H.), UCL Queen Square Institute of Neurology, UK; Institute for Advanced Study (J.H.), The Hong Kong University of Science and Technology, China; Royal Edinburgh Hospital (G.J.T.H.), UK; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (E.D.H.), Columbia University, New York, NY; Department of Neurology, Memory and Aging Center (A.K., B.M., J.Y.), University of California, San Francisco; UCL Genomics (M.K., G.K.M., Y.P.), UCL Great Ormond Street Institute of Child Health, London, UK; Geriatric Center Frullone ASL Napoli 1 Centro (G.M.), Napoli, Italy; Department of Neurology (M.O.M., J.v.R., J.C.V.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Rona Holdings (P.M.), Silicon Valley, CA; Newcastle Brain Tissue Resource, Institute of Neuroscience (C.M.M.), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK; Department of Neurology (C.N.), Skåne University Hospital, Malmö, Sweden; Fondazione Policlinico Universitario A. Gemelli IRCCS (V.N.), Rome, Italy; Division of Neuroscience & Experimental Psychology (S.P.-B., A.M.T.R., S.R., J.C.T.), University of Manchester, UK; Amsterdam University Medical Center (Y.A.L.P.), VU University Medical Center, the Netherlands; Cardiovascular Research Unit (A.A.P.), IRCCS Multimedica, Milan; Neurology I, Department of Neuroscience (I.R., Elisa Rubino), University of Torino; NeurOMICS laboratory (G.M., Antonella Rendina, E.V.), Institute of Biochemistry and Cell Biology (IBBC), CNR Napoli, Italy; Manchester Centre for Clinical Neurosciences (A.M.T.R., J.S., J.C.T.), Salford Royal NHS Trust, Manchester, UK; Tanz Centre for Research in Neurodegenerative Diseases (Ekaterina Rogaeva), University of Toronto, Canada; Department of Biotechnology (B.R.), Jožef Stefan Institute, Ljubljana, Slovenia; Division of Neurology V and Neuropathology (G.R., F.T.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Hospital Clínic of Barcelona, Spain; Clinical Memory Research Unit, Department of Clinical Sciences Malmö (C.N., A.F.S.), and Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund (M.L.W.), Lund University, Sweden; Neurodegenerative Brain Diseases Group (J.V.d.Z., C.V.B.), Center for Molecular Neurology, VIB, Antwerp, Belgium; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (V.E.-P.), Division of Psychological Medicine and Clinical Neurosciences and Dementia Research Institute, Cardiff University, UK; Instituto de Investigación Sanitaria del Principado de Asturias (V.A.), Oviedo, Asturias; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (I.A., M.D.-F., P.P.), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (M.B., J.C., O.D.-I., I.H., I.I.-G., A.L., S.M.-G., Agustín Ruiz), Instituto de Salud Carlos III, Madrid, Spain; MRC Cognition and Brain Sciences Unit (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neuromedicine and Movement Science (Geir Bråthen, S.B.S.), Norwegian University of Science and Technology, Trondheim, Norway; Unit for Hereditary Dementias (H.-H.C., C.G., B.K., L.Ö.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Medical Faculty (D.F., M.G.K.), University of Ljubljana, Slovenia; Fondazione IRCCS Ca'Granda (D.G., Elio Scarpini, M.S.), Ospedale Policlinico, Milan, Italy; Penn Center for Frontotemporal Degeneration (Murray Grossman), Philadelphia, PA; Universidad de Oviedo (M.M.-G.), Asturias, Spain; IRCCS Fondazione Don Carlo Gnocchi (B.N., S.S.), Florence; Istituto di Medicina Genomica (V.N.), Università Cattolica del sacro Cuore, Rome, Italy; Amsterdam Neuroscience (Y.A.L.P.), the Netherlands; Department of Medicine and Surgery (A.A.P.), University of Salerno, Baronissi (SA), Italy; Faculty of Chemistry and Chemical Technology (B.R.), University of Ljubljana, Slovenia; Institud d'Investigacions Biomèdiques August Pi i Sunyer (R.S.-V.), Barcelona, Spain; Department of Biomedical Sciences (J.V.d.Z., C.V.B.), University of Antwerp, Belgium; and Department of Comparative Biomedical Sciences (P.A.L.), The Royal Veterinary College, London, UK.

Objective: We sought to characterize expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.

Methods: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.

Results: We found pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [ = 2.17 × 10; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [ = 1.1 × 10; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.

Conclusions: Our results indicate correlation between pathogenic expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.
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http://dx.doi.org/10.1212/WNL.0000000000010914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836664PMC
December 2020

Examination of the Effect of Rare Variants in TREM2, ABI3, and PLCG2 in LOAD Through Multiple Phenotypes.

J Alzheimers Dis 2020 ;77(4):1469-1482

Neurogenomics and Informatics Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

Background: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer's disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype.

Objective: In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease.

Methods: We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline).

Results: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes.

Conclusion: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.
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http://dx.doi.org/10.3233/JAD-200019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927150PMC
January 2020