Hope Center Member publications

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CSF Tau phosphorylation at Thr205 is associated with loss of white matter integrity in autosomal dominant Alzheimer disease(2022) Neurobiology of Disease, 168, art. no. 105714

Strain, J.F.a , Barthelemy, N.a , Horie, K.a , Gordon, B.A.a c d , Kilgore, C.a , Aschenbrenner, A.a , Cruchaga, C.a , Xiong, C.c h , Joseph-Mathurin, N.b c , Hassenstab, J.a c h , Fagan, A.M.a c , Li, Y.a , Karch, C.M.b , Perrin, R.J.a , Berman, S.B.e , Chhatwal, J.P.f , Graff-Radford, N.R.g , Mori, H.h , Levin, J.i , Noble, J.M.m , Allegri, R.j , Schofield, P.R.k l , Marcus, D.S.c , Holtzman, D.M.a c , Morris, J.C.a c , Benzinger, T.L.S.b c , McDade, E.M.a , Bateman, R.J.a c , Ances, B.M.a b c

AbstractBackground: Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer’s disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s). Methods: In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD. Results: The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss. Conclusions: We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline. © 2022

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Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach(2022) Frontiers in Neurology, 13, art. no. 828525

Mayhew, A.G.a , James, M.K.a , Moore, U.a , Sutherland, H.a , Jacobs, M.b c , Feng, J.b , Lowes, L.P.d , Alfano, L.N.d , Muni Lofra, R.a , Rufibach, L.E.e , Rose, K.f , Duong, T.g h , Bello, L.i , Pedrosa-Hernández, I.j , Holsten, S.k , Sakamoto, C.l , Canal, A.m , Sánchez-Aguilera Práxedes, N.n , Thiele, S.o , Siener, C.p , Vandevelde, B.q , DeWolf, B.g , Maron, E.r , Gordish-Dressman, H.b c , Hilsden, H.a , Guglieri, M.a , Hogrel, J.-Y.m , Blamire, A.M.s , Carlier, P.G.t , Spuler, S.u , Day, J.W.v , Jones, K.J.f , Bharucha-Goebel, D.X.w x , Salort-Campana, E.q , Pestronk, A.p , Walter, M.C.o , Paradas, C.y , Stojkovic, T.m , Mori-Yoshimura, M.z , Bravver, E.k , Díaz-Manera, J.aa ab , Pegoraro, E.i , Mendell, J.R.d , Jain COS Consortiumd , Straub, V.a

AbstractDysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation’s Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R2 0.18). EK scores were strongly associated with PUL (Pseudo R2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy. Copyright © 2022 Mayhew, James, Moore, Sutherland, Jacobs, Feng, Lowes, Alfano, Muni Lofra, Rufibach, Rose, Duong, Bello, Pedrosa-Hernández, Holsten, Sakamoto, Canal, Sánchez-Aguilera Práxedes, Thiele, Siener, Vandevelde, DeWolf, Maron, Gordish-Dressman, Hilsden, Guglieri, Hogrel, Blamire, Carlier, Spuler, Day, Jones, Bharucha-Goebel, Salort-Campana, Pestronk, Walter, Paradas, Stojkovic, Mori-Yoshimura, Bravver, Díaz-Manera, Pegoraro, Mendell and Straub.

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Wolframin is a novel regulator of tau pathology and neurodegeneration(2022) Acta Neuropathologica

Chen, S.a b , Acosta, D.a , Li, L.a , Liang, J.a , Chang, Y.b c , Wang, C.c , Fitzgerald, J.a , Morrison, C.a , Goulbourne, C.N.d , Nakano, Y.e , Villegas, N.C.H.e f , Venkataraman, L.a g , Brown, C.h , Serrano, G.E.i , Bell, E.j , Wemlinger, T.k , Wu, M.a , Kokiko-Cochran, O.N.a , Popovich, P.a , Flowers, X.E.l , Honig, L.S.l , Vonsattel, J.P.l , Scharre, D.W.j , Beach, T.G.i , Ma, Q.c , Kuret, J.m , Kõks, S.n o , Urano, F.h , Duff, K.E.e p , Fu, H.a q

AbstractSelective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer’s disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

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Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus(2022) Nature Neuroscience

Duy, P.Q.a b c , Weise, S.C.d , Marini, C.e , Li, X.-J.f g , Liang, D.a , Dahl, P.J.h i , Ma, S.a , Spajic, A.a , Dong, W.j , Juusola, J.k , Kiziltug, E.b , Kundishora, A.J.b , Koundal, S.l , Pedram, M.Z.l , Torres-Fernández, L.A.d , Händler, K.m n o , De Domenico, E.m n o , Becker, M.m n o , Ulas, T.m n o , Juranek, S.A.p , Cuevas, E.q , Hao, L.T.b , Jux, B.d , Sousa, A.M.M.a , Liu, F.a , Kim, S.-K.a , Li, M.a , Yang, Y.r , Takeo, Y.b , Duque, A.a , Nelson-Williams, C.s , Ha, Y.t , Selvaganesan, K.t , Robert, S.M.b , Singh, A.K.b , Allington, G.b , Furey, C.G.b , Timberlake, A.T.s , Reeves, B.C.b , Smith, H.b , Dunbar, A.b , DeSpenza, T., Jr.b , Goto, J.u , Marlier, A.b , Moreno-De-Luca, A.v , Yu, X.w , Butler, W.E.w , Carter, B.S.w , Lake, E.M.R.t , Constable, R.T.t , Rakic, P.a , Lin, H.r , Deniz, E.x , Benveniste, H.l , Malvankar, N.S.h i , Estrada-Veras, J.I.y z aa , Walsh, C.A.ab ac ad , Alper, S.L.ad ae , Schultze, J.L.m n o , Paeschke, K.p , Doetzlhofer, A.f g , Wulczyn, F.G.e , Jin, S.C.af , Lifton, R.P.j , Sestan, N.a , Kolanus, W.d , Kahle, K.T.w ab ad ag

AbstractHydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain–CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Biomarker clustering in autosomal dominant Alzheimer’s disease(2022) Alzheimer’s and Dementia

Luckett, P.H.w , Chen, C.w , Gordon, B.A.w , Wisch, J.w , Berman, S.B.a , Chhatwal, J.P.b , Cruchaga, C.w , Fagan, A.M.w , Farlow, M.R.c , Fox, N.C.d , Jucker, M.e f , Levin, J.g h i , Masters, C.L.j , Mori, H.k , Noble, J.M.l , Salloway, S.m , Schofield, P.R.n o , Brickman, A.M.p q , Brooks, W.S.n o , Cash, D.M.d , Fulham, M.J.p q , Ghetti, B.c , Jack, C.R., Jr.r , Vöglein, J.g , Klunk, W.E.a , Koeppe, R.s , Su, Y.t , Weiner, M.u v , Wang, Q.w , Marcus, D.w , Koudelis, D.w , Joseph-Mathurin, N.w , Cash, L.w , Hornbeck, R.w , Xiong, C.w , Perrin, R.J.w , Karch, C.M.w , Hassenstab, J.w , McDade, E.w , Morris, J.C.w , Benzinger, T.L.S.w , Bateman, R.J.w , Ances, B.M.w , for the Dominantly Inherited Alzheimer Network (DIAN)w

AbstractINTRODUCTION: As the number of biomarkers used to study Alzheimer’s disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression. © 2022 the Alzheimer’s Association.

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Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy characterized by long-read sequencing(2022) American Journal of Medical Genetics, Part A

Mehinovic, E.a , Gray, T.b , Campbell, M.b , Ekholm, J.c , Wenger, A.c , Rowell, W.c , Grudo, A.c , Grimwood, J.d , Korlach, J.c , Gurnett, C.e , Constantino, J.N.b , Turner, T.N.a

AbstractCurrently, protein-coding de novo variants and large copy number variants have been identified as important for ~30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long-read sequencing was applied to a family with autism, epileptic encephalopathy, cognitive impairment, and mild dysmorphic features (two affected female siblings, unaffected parents, and one unaffected male sibling) with no known clinical variant. From our long-read sequencing data, a de novo missense variant in the KCNC2 gene (encodes Kv3.2) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment revealed the variant was not in controls, highly conserved, and predicted damaging. This specific missense variant (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long-lasting open state. Seven additional missense variants have been identified in other individuals with neurodevelopmental disorders (p = 1.03 × 10−5). KCNC2 is most highly expressed in the brain; in particular, in the thalamus and is enriched in GABAergic neurons. Long-read sequencing was useful in discovering the relevant variant in this family with autism that had remained a mystery for several years and will potentially have great benefits in the clinic once it is widely available. © 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.

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APOE Antibody Inhibits Aβ-Associated Tau Seeding and Spreading in a Mouse Model(2022) Annals of Neurology

Gratuze, M., Jiang, H., Wang, C., Xiong, M., Bao, X., Holtzman, D.M.

AbstractAPOE is the strongest genetic factor for late-onset Alzheimer’s disease (AD). A specific conformation of the ApoE protein is present in amyloid-β (Aβ) containing plaques. Immunotherapy targeting ApoE in plaques reduces brain Aβ deposits in mice. Here, we evaluated the effects of the anti-human APOE antibody HAE-4 on amyloid plaques, Aβ-mediated tau seeding and spreading, and neuritic dystrophy in the 5XFAD amyloid mice expressing human ApoE4. HAE-4 reduced Aβ plaques as well as Aβ-driven tau seeding/spreading and neuritic dystrophy. These results demonstrate that HAE-4 may provide therapeutic effects on amyloid removal and Aβ driven downstream consequences such as tauopathy. ANN NEUROL 2022. © 2022 American Neurological Association.

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Deep learning resting state functional magnetic resonance imaging lateralization of temporal lobe epilepsy(2022) Epilepsia

Luckett, P.H.a , Maccotta, L.b , Lee, J.J.c , Park, K.Y.a , U. F. Dosenbach, N.b , Ances, B.M.b , Hogan, R.E.b , Shimony, J.S.c , Leuthardt, E.C.a

AbstractObjective: Localization of focal epilepsy is critical for surgical treatment of refractory seizures. There remains a great need for noninvasive techniques to localize seizures for surgical decision-making. We investigate the use of deep learning using resting state functional magnetic resonance imaging (RS-fMRI) to identify the hemisphere of seizure onset in temporal lobe epilepsy (TLE) patients. Methods: A total of 2132 healthy controls and 32 preoperative TLE patients were studied. All participants underwent structural MRI and RS-fMRI. Healthy control data were used to generate training samples for a three-dimensional convolutional neural network (3DCNN). RS-fMRI was synthetically altered in randomly lateralized regions in the healthy control participants. The model was then trained to classify the hemisphere containing synthetic noise. Finally, the model was tested on TLE patients to assess its performance for detecting biological seizure onset zones, and gradient-weighted class activation mapping (Grad-CAM) identified the strongest predictive regions. Results: The 3DCNN classified healthy control hemispheres known to contain synthetic noise with 96% accuracy, and TLE hemispheres clinically identified to be seizure onset zones with 90.6% accuracy. Grad-CAM identified a range of temporal, frontal, parietal, and subcortical regions that were strong anatomical predictors of the seizure onset zone, and the resting state networks that colocalized with Grad-CAM results included default mode, medial temporal, and dorsal attention networks. Lastly, in an analysis of a subset of patients with postsurgical outcomes, the 3DCNN leveraged a more focal set of regions to achieve classification in patients with Engel Class >I compared to Engel Class I. Significance: Noninvasive techniques capable of localizing the seizure onset zone could improve presurgical planning in patients with intractable epilepsy. We have demonstrated the ability of deep learning to identify the correct hemisphere of the seizure onset zone in TLE patients using RS-fMRI with high accuracy. This approach represents a novel technique of seizure lateralization that could improve preoperative surgical planning. © 2022 International League Against Epilepsy.

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Posted on April 18, 2022
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