Relationship between MRI brain-age heterogeneity, cognition, genetics and Alzheimer’s disease neuropathology
(2024) eBioMedicine, 109, art. no. 105399, .
Antoniades, M.a , Srinivasan, D.a , Wen, J.a q , Erus, G.a , Abdulkadir, A.a p , Mamourian, E.a , Melhem, R.a , Hwang, G.a r , Cui, Y.a , Govindarajan, S.T.a , Chen, A.A.b , Zhou, Z.a , Yang, Z.a , Chen, J.a , Pomponio, R.c , Sotardi, S.d , An, Y.e , Bilgel, M.e , LaMontagne, P.f , Singh, A.g , Benzinger, T.f , Beason-Held, L.e , Marcus, D.S.f , Yaffe, K.h , Launer, L.i , Morris, J.C.j , Tosun, D.k , Ferrucci, L.l , Bryan, R.N.m , Resnick, S.M.e , Habes, M.a n , Wolk, D.o , Fan, Y.m , Nasrallah, I.M.m , Shou, H.g , Davatzikos, C.a
a AI<sup>2</sup>D, Center for AI and Data Science for Integrated Diagnostics, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, United States
b Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104, United States
c Department of Biostatistics, Colorado School of Public Health, Aurora, CO 80045, United States
d Department of Radiology, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, United States
e Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, United States
h University of California, San Francisco, CA, United States
i Neuroepidemiology Section, Intramural Research Program, National Institute on Aging, Bethesda, MD, United States
j Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
k Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
l National Institute on Aging, National Institute of Health, Baltimore, MD 21224, United States
m Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
n Neuroimage Analytics Laboratory (NAL) and the Biggs Institute Neuroimaging Core (BINC), Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
o Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
p Department of Clinical Neuroscience, Center for Research in Neuroscience, Lausanne University Hospital, Lausanne, Switzerland
q Laboratory of AI and Biomedical Science (LABS), University of Southern California, Los Angeles, CA, United States
r Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
Abstract
Background: Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer’s disease (AD). Methods: Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42–85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer’s Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task). Findings: Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits. Interpretation: The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life. Funding: The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute. © 2024 The Authors
Author Keywords
Ageing; Alzheimer’s disease; Brain age; Cognition; Multimodal
Document Type: Article
Publication Stage: Final
Source: Scopus
Sensory-Motor Neuropathy in Mfn2 T105M Knock-in Mice and Its Reversal by a Novel Piperine-Derived Mitofusin Activator
(2024) The Journal of Pharmacology and Experimental Therapeutics, 391 (2), pp. 361-374.
Weigele, J., Zhang, L., Franco, A., Cartier, E., Dorn, G.W., 2nd
Department of Internal Medicine (Pharmacogenomics), Washington University School of Medicine (J.W., L.Z., A.F., E.C., St. Louis Missouri, Inc. (J.W.
Abstract
Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of preclinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2 A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurologic phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has subnanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is widespread and broadly contributory in neurodegeneration, but difficult to target therapeutically. Here, we describe 8015-P2, a new small molecule mitofusin activator with ∼10-fold greater potency and improved in vivo pharmacokinetics versus comparators, and demonstrate its rapid reversal of sensory and motor neuron dysfunction in an Mfn2 T105M knock-in mouse model of Charcot-Marie-Tooth disease type 2 A. These findings further support the therapeutic approach of targeting mitochondrial dysdynamism in neurodegeneration. Copyright © 2024 by The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Inhibitory Actions of Potentiating Neuroactive Steroids in the Human α1β3γ2L γ-Aminobutyric Acid Type A Receptor
(2024) Molecular Pharmacology, 106 (5), pp. 264-277.
Pierce, S.R., Germann, A.L., Covey, D.F., Evers, A.S., Steinbach, J.H., Akk, G.
Departments of Anesthesiology (S.R.P., A.L.G., D.F.C., Developmental Biology (D.F.C., the Taylor Family Institute for Innovative Psychiatric Research (D.F.C., A.S.E., Washington University School of Medicine, St Louis, MO, United States
Abstract
The γ-aminobutyric acid type A (GABAA) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3β-hydroxy steroids inhibit, while 3α-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the α1β3γ2L GABAA receptor by the endogenous neurosteroid 3α-hydroxy-5β-pregnan-20-one (3α5βP) and the synthetic neuroactive steroid 3α-hydroxy-5α-androstane-17β-carbonitrile (ACN). The receptors were expressed in Xenopus oocytes. All experiments were done using two-electrode voltage-clamp electrophysiology. In the presence of low concentrations of GABA, 3α5βP and ACN potentiate the GABAA receptor. To reveal inhibition, we conducted the experiments on receptors activated by the combination of a saturating concentration of GABA and propofol to fully activate the receptors and mask potentiation, or on mutant receptors in which potentiation is ablated. Under these conditions, both steroids inhibited the receptor with IC50s of ∼13 μM and maximal inhibitory effects of 70-90%. Receptor inhibition by 3α5βP was sensitive to substitution of the α1 transmembrane domain (TM) 2-2′ residue, previously shown to ablate inhibition by pregnenolone sulfate. However, results of coapplication studies and the apparent lack of state dependence suggest that pregnenolone sulfate and 3α5βP inhibit the GABAA receptor independently and through distinct mechanisms. Mutations to the neurosteroid binding sites in the α1 and β3 subunits statistically significantly, albeit weakly and incompletely, reduced inhibition by 3α5βP and ACN. SIGNIFICANCE STATEMENT: The heteromeric GABAA receptor is inhibited by sulfated steroids and 3β-hydroxy steroids, while 3α-hydroxy steroids are considered to potentiate the receptor. We show here that 3α-hydroxy steroids have inhibitory effects on the α1β3γ2L receptor, which are observed in specific experimental settings and are expected to manifest under different physiological conditions. Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.
Document Type: Article
Publication Stage: Final
Source: Scopus
Novel SGCE Mutation in a Patient With Myoclonus-Dystonia
(2024) Neurology: Genetics, 10 (2), art. no. e200128, .
Klinman, E.a , Gooch, C.b , Perlmutter, J.S.a , Davis, A.A.a , Maiti, B.a
a The Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
Abstract
Objectives Characterize the presentation, workup, and management of SGCE myoclonus-dystonia, a rare genetic condition, in a patient with atypical presenting symptoms and no family history of movement abnormalities. Methods A woman with myoclonus and dystonia was identified based on clinical history and physical examination. Workup was conducted to determine the cause of her symptoms, including whole-exome sequencing. Myoclonus-dystonia is associated with more than 100 distinct mutations in MYC/DYT-SGCE that account for only half of the total myoclonus-dystonia patients. As such, this case required intensive genetic analyses rather than screening only for a small subset of well-characterized mutations. Results Childhood onset myoclonus and worsening dystonia with age were identified in a young woman. She underwent screening for common causes of twitching movements, followed by whole-exome sequencing which identified a de novo novel variant in the SGCE gene, resulting in a diagnosis of SGCE myoclonus-dystonia. Discussion Myoclonus-dystonia should be considered in patients with symptoms of head and upper extremity myoclonus early in life, especially with co-occurring dystonia, even in the absence of a family history of similar symptoms. Diagnosis of this condition should take place using sequencing, as new mutations continue to be discovered. Copyright © 2024 The Author(s).
Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSK23NS125107
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
A 39UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP
(2024) Neurology: Genetics, 10 (1), art. no. e200124, .
Chemparathy, A.a , Le Guen, Y.a b , Zeng, Y.c , Gorzynski, J.c d , Jensen, T.D.c , Yang, C.e , Kasireddy, N.a , Talozzi, L.a , Belloy, M.a , Stewart, I.a , Gitler, A.D.c , Wagner, A.D.f g , Mormino, E.f g , Henderson, V.W.a h , Wyss-Coray, T.a , Ashley, E.c d , Cruchaga, C.e , Greicius, M.D.a
a The Department of Neurology and Neurological Sciences, Stanford University School of MedicineCA, United States
b Quantitative Sciences Unit, Department of Medicine, Stanford University School of MedicineCA, United States
c Department of Genetics, Stanford University School of MedicineCA, United States
d Division of Cardiology, Department of Medicine, Stanford University School of MedicineCA, United States
e Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
f Wu Tsai Neurosciences Institute, Stanford UniversityCA, United States
g Department of Psychology, Stanford UniversityCA, United States
h Department of Epidemiology and Population Health, Stanford UniversityCA, United States
Abstract
Background and Objectives Single-nucleotide variants near TMEM106B associate with the risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but the causal variant at this locus remains unclear. Here, we asked whether a novel structural variant on TMEM106B is the causal variant. Methods An exploratory analysis identified structural variants on neurodegeneration-related genes. Subsequent analyses focused on an Alu element insertion on the 39UTR of TMEM106B. This study included data from longitudinal aging and neurogenerative disease cohorts at Stanford University, case-control cohorts in the Alzheimer Disease Sequencing Project (ADSP), and expression and proteomics data from Washington University in St. Louis (WUSTL). Four hundred thirty-two individuals from 2 Stanford aging cohorts were whole-genome long-read and short-read sequenced. A total of 16,906 samples from ADSP were short-read sequenced. Genotypes, transcriptomics, and proteomics data were available in 1,979 participants from an aging and dementia cohort at WUSTL. Selection criteria were specific to each cohort. In primary analyses, the linkage disequilibrium between the TMEM106B locus variants in the FTLD-TDP GWAS and the 39UTR insertion was estimated. We then estimated linkage by ancestry in the ADSP and evaluated the effect of the TMEM106B lead variant on mRNA and protein levels. Results The primary analysis included 432 participants (52.5% female, age range 45–92 years). We identified a 316 bp Alu insertion overlapping the TMEM106B 39UTR tightly linked with top GWAS variants rs3173615(C) and rs1990622(A). In ADSP European ancestry participants, this insertion is in equivalent linkage with rs1990622(A) (R2 = 0.962, D’ = 0.998) and rs3173615(C) (R2 = 0.960, D’ = 0.996). In African ancestry participants, the insertion is in stronger linkage with rs1990622(A) (R2 = 0.992, D’ = 0.998) than with rs3173615(C) (R2 = 0.811, D’ = 0.994). In public data sets, rs1990622 was consistently associated with TMEM106B protein levels but not with mRNA expression. In the WUSTL data set, rs1990622 is associated with TMEM106B protein levels in plasma and CSF, but not with TMEM106B mRNA expression. Discussion We identified a novel Alu element insertion in the 39UTR of TMEM106B in tight linkage with the lead FTLD-TDP risk variant. The lead variant is associated with TMEM106B protein levels, but not expression. The 39UTR insertion is a lead candidate for the causal variant at this complex locus, pending confirmation with functional studies. Copyright © 2024 The Author(s).
Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAP01AG003991, RF1AG053303, RF1AG074007, RF1AG058501, U01AG058922, R01AG044546, AARF-20-683984
Alzheimer’s AssociationAA
National Institutes of HealthNIHK99AG075238, R01AG048076, RO1AG060747, R01AG074339, P30AG066515, R35AG072290
National Institutes of HealthNIH
P30AG066444, P01AG03991, P01AG026276
U.S. Department of DefenseDODW81XWH2010849, ZEN-22-848604
U.S. Department of DefenseDOD
Document Type: Article
Publication Stage: Final
Source: Scopus
Dementia risk scores, apolipoprotein E, and risk of Alzheimer’s disease: One size does not fit all
(2024) Alzheimer’s and Dementia, .
Andrews, S.J.a , Boeriu, A.I.a , Belloy, M.E.b c d , Renton, A.E.e , Fulton-Howard, B.e , Brenowitz, W.D.f g , Yaffe, K.a g h , for the Alzheimer’s Disease Neuroimaging Initiativei
a Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, United States
b Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
c NeuroGenomics and Informatics Center, Washington University School of Medicine, St.Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St.Louis, MO, United States
e Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
f Kaiser Permanente Center for Health Research, Portland, OR, United States
g Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States
h Department of Neurology, University of California San Francisco, San Francisco, CA, United States
Abstract
INTRODUCTION: Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities. METHODS: We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in National Alzheimer’s Coordinating Center (NACC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI), and assessed their interaction with apolipoprotein E (APOE). RESULTS: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the apolipoprotein E*ε4 (APOE*ε4) risk effect and attenuated the APOE*ε2 protective effect. DISCUSSION: Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health. Highlights: Dementia risk scores demonstrate race/ethnic-specific effects on dementia risk. Unfavorable modifiable risk profiles moderate the effect of APOE on dementia risk. Dementia risk scores need to be validated in diverse populations. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
APOE; dementia; dementia risk scores; race/ethnicity
Funding details
Alzheimer’s AssociationAA
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNI
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDF
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
BiogenR35AG071916, ABA‐22‐969581, 5U24AG072122, U19AG069701, K01AG062722
National Institutes of HealthNIHU24 AG072122, U01 AG024904
Document Type: Article
Publication Stage: Article in Press
Source: Scopus