Publications by authors named "David J Irwin"

150 Publications

Tau immunotherapy is associated with glial responses in FTLD-tau.

Acta Neuropathol 2021 May 5. Epub 2021 May 5.

Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, 613A Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA, 19104, USA.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.
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http://dx.doi.org/10.1007/s00401-021-02318-yDOI Listing
May 2021

Neurofilament Light Chain Related to Longitudinal Decline in Frontotemporal Lobar Degeneration.

Neurol Clin Pract 2021 Apr;11(2):105-116

Penn Frontotemporal Degeneration Center (JVZ, DJI, KR, L. Massimo, CTM, MG) and Department of Neurology (DJI, KR, L. Massimo, CTM, AC-P, LE, L. McCluskey, D. Wolk, MG), Department of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research (EBL, LMS, VM-YL, JBT, JQT), Department of Psychiatry (D. Weintraub), University of Pennsylvania, Philadelphia; Institute of Neuroscience and Physiology (KB, HZ), Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory (KB, HZ), Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL (HZ); and Department of Neurodegenerative Disease (HZ), UCL Institute of Neurology, UK.

Objective: Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology.

Methods: This case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes.

Results: In FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures.

Conclusion: CSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.
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http://dx.doi.org/10.1212/CPJ.0000000000000959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032415PMC
April 2021

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

Neurology 2021 Apr 7. Epub 2021 Apr 7.

Julio C. Rojas, University of California, San Francisco, San Francisco, CA, USA Ping Wang, University of California, San Francisco, San Francisco, CA, USA Adam M. Staffaroni, University of California, San Francisco, San Francisco, CA, USA Carolin Heller, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Yann Cobigo University of California, San Francisco, San Francisco, CA, USA Amy Wolf, University of California, San Francisco, San Francisco, CA, USA Sheng-Yang M. Goh, University of California, San Francisco, San Francisco, CA, USA Peter A. Ljubenkov, University of California, San Francisco, San Francisco, CA, USA Hilary W. Heuer, University of California, San Francisco, San Francisco, CA, USA Jamie C. Fong, University of California, San Francisco, San Francisco, CA, USA Joanne B. Taylor, University of California, San Francisco, San Francisco, CA, USA Eliseo Veras, Quanterix Corporation, Lexington, MA, USA Linan Song, Quanterix Corporation, Lexington, MA, USA Andreas Jeromin, Quanterix Corporation, Lexington, MA, USA David Hanlon, Quanterix Corporation, Lexington, MA, USA Lili Yu, Novartis Institutes for Biomedical Research Inc, Cambridge, MA, USA Arvind Kinhikar, Novartis Institutes for Biomedical Research Inc, Cambridge, MA, USA Rajeev Sivasankaran, Novartis Institutes for Biomedical Research Inc, Cambridge, MA, USAAgnieszka Kieloch, Novartis Pharma AG, Basel, Switzerland Marie-Anne Valentin, Novartis Pharma AG, Basel, Switzerland Anna M. Karydas, University of California, San Francisco, San Francisco, CA, USA Laura L. Mitic, University of California, San Francisco, San Francisco, CA, USA and Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA, USA Rodney Pearlman, Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA, USA John Kornak, University of California, San Francisco, San Francisco, CA, USA Joel H. Kramer, University of California, San Francisco, San Francisco, CA, USA Bruce L. Miller, University of California, San Francisco, San Francisco, CA, USA Kejal Kantarci, Mayo Clinic, Rochester, MN, USA David S. Knopman, Mayo Clinic, Rochester, MN, USA Neill Graff-Radford, Mayo Clinic, Jacksonville, FL, USA Leonard Petrucelli, Mayo Clinic, Jacksonville, FL, USA Rosa Rademakers, Mayo Clinic, Jacksonville, FL, USA David J. Irwin, University of Pennsylvania, Philadelphia, PA, USA Murray Grossman, University of Pennsylvania, Philadelphia, PA, USA Eliana Marisa Ramos, University of California, Los Angeles, Los Angeles, CA, USA Giovanni Coppola, University of California, Los Angeles, Los Angeles, CA, USA Mario F. Mendez, University of California, Los Angeles, Los Angeles, CA, USA Yvette Bordelon, University of California, Los Angeles, Los Angeles, CA, USA Bradford C. Dickerson, Harvard University/Massachusetts General Hospital, Boston, MA, USA Nupur Ghoshal, Washington University, St. Louis, MO, US Edward D. Huey, Columbia University, New York, NY, USA Ian R. Mackenzie, University of British Columbia, Vancouver, British Columbia, Canada Brian S. Appleby, Case Western Reserve University, Cleveland, OH, USA Kimiko Domoto-Reilly, University of Washington, Seattle, WA, USA Ging-Yuek R. Hsiung, University of British Columbia, Vancouver, British Columbia, Canada Arthur W. Toga, Laboratory of Neuroimaging, University of Southern California, Los Angeles, CA, USA Sandra Weintraub, Northwestern University, Chicago, IL, USA Daniel I. Kaufer, University of North Carolina, Chapel Hill, NC, USA Diana Kerwin, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA Irene Litvan, University of California, San Diego, San Diego, CA, USA Chiadikaobi U. Onyike, Johns Hopkins Hospital, Baltimore, MD, USA Alexander Pantelyat, Johns Hopkins Hospital, Baltimore, MD, USA Erik D. Roberson, University of Alabama, Birmingham, AL, USA Maria C. Tartaglia, University of Toronto, ON, Canada Tatiana Foroud, Indiana University School of Medicine, Indianapolis, IN, USA Weiping Chen, Biogen Inc., Cambridge, MA, USA Julie Czerkowicz, Biogen Inc., Cambridge, MA, USA Danielle L. Graham, Biogen Inc., Cambridge, MA, USA John C. van Swieten, Erasmus Medical Centre, Rotterdam, Netherlands Barbara Borroni, University of Brescia, Brescia, Italy Raquel Sanchez-Valle, University of Barcelona, Barcelona, Spain Fermin Moreno, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain Robert Laforce, Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, QC, Canada Caroline Graff, Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden and Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden Matthis Synofzik, University of Tübingen, Tübingen, Germany and Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany Daniela Galimberti, Fondazione IRCCS Ospedale Policlinico, Milan, Italy and University of Milan, Centro Dino Ferrari, Milan, Italy James B. Rowe, Department of Clinical Neurosciences and Cambridge University Hospital, University of Cambridge, Cambridge, UK Mario Masellis, University of Toronto, ON, Canada Elizabeth Finger, University of Western Ontario, London, ON, Canada Rik Vandenberghe, KU Leuven, Leuven, Belgium and Neurology Service, University Hospitals Leuven, BelgiumAlexandre de Mendonça, University of Lisbon, Lisbon, Portugal Fabrizio Tagliavini, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyIsabel Santana, University of Coimbra, Coimbra, Portugal Simon Ducharme, McGill University, Montreal, Québec, Canada Chris R. Butler, University of Oxford, Oxford, UK Alexander Gerhard, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK and University of Duisburg-Essen, Germany Johannes Levin, Ludwig-Maximilians-Universität München, Munich, Germany and German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Adrian Danek, Ludwig-Maximilians-Universität München, Munich, Germany Markus Otto, University of Ulm, Ulm, Germany Sandro Sorbi, University of Florence, Florence, Italy David M. Cash, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Rhian S. Convery, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Martina Bocchetta, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Martha Foiani, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Caroline V. Greaves, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Georgia Peakman, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Lucy Russell, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Imogen Swift, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Emily Todd, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Jonathan D. Rohrer, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Bradley F. Boeve, Mayo Clinic, Rochester, MN, USA Howard J. Rosen, University of California, San Francisco, San Francisco, CA, USA Adam L. Boxer, MD, University of California, San Francisco, San Francisco, CA, USA.

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with Simoa in original (n = 277) and validation (n = 297) cohorts. , and mutation carriers and non-carriers from the same families were classified by disease severity [asymptomatic, prodromal and full phenotype] using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to non-progressors (original: 11.4 ± 7 pg/mL vs. 6.7 ± 5 pg/mL, = 0.002; validation: 14.1 ± 12 pg/mL vs. 8.7 ± 6 pg/mL, = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression, and is a potential tool to select participants for prevention clinical trials.

Classification Of Evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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http://dx.doi.org/10.1212/WNL.0000000000011848DOI Listing
April 2021

Dimethyl Fumarate, an Approved Multiple Sclerosis Treatment, Reduces Brain Oxidative Stress in SIV-Infected Rhesus Macaques: Potential Therapeutic Repurposing for HIV Neuroprotection.

Antioxidants (Basel) 2021 Mar 9;10(3). Epub 2021 Mar 9.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Dimethyl fumarate (DMF), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, induces antioxidant enzymes, in part through transcriptional upregulation. We hypothesized that DMF administration to simian immunodeficiency virus (SIV)-infected rhesus macaques would induce antioxidant enzyme expression and reduce oxidative injury and inflammation throughout the brain. Nine SIV-infected, CD8-T-lymphocyte-depleted rhesus macaques were studied. Five received oral DMF prior to the SIV infection and through to the necropsy day. Protein expression was analyzed in 11 brain regions, as well as the thymus, liver, and spleen, using Western blot and immunohistochemistry for antioxidant, inflammatory, and neuronal proteins. Additionally, oxidative stress was determined in brain sections using immunohistochemistry (8-OHdG, 3NT) and optical redox imaging of oxidized flavoproteins containing flavin adenine dinucleotide (Fp) and reduced nicotinamide adenine dinucleotide (NADH). The DMF treatment was associated with no changes in virus replication; higher expressions of the antioxidant enzymes NQO1, GPX1, and HO-1 in the brain and PRDX1 and HO-2 in the spleen; lower levels of 8-OHdG and 3NT; a lower optical redox ratio. The DMF treatment was also associated with increased expressions of cell-adhesion molecules (VCAM-1, ICAM-1) and no changes in HLA-DR, CD68, GFAP, NFL, or synaptic proteins. The concordantly increased brain antioxidant enzyme expressions and reduced oxidative stress in DMF-treated SIV-infected macaques suggest that DMF could limit oxidative stress throughout the brain through effective induction of the endogenous antioxidant response. We propose that DMF could potentially induce neuroprotective brain responses in persons living with HIV.
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http://dx.doi.org/10.3390/antiox10030416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998206PMC
March 2021

Automated analysis of lexical features in frontotemporal degeneration.

Cortex 2021 Apr 6;137:215-231. Epub 2021 Feb 6.

Linguistic Data Consortium, University of Pennsylvania, Philadelphia, PA, USA.

We implemented an automated analysis of lexical aspects of semi-structured speech produced by healthy elderly controls (n = 37) and three patient groups with frontotemporal degeneration (FTD): behavioral variant FTD (n = 74), semantic variant primary progressive aphasia (svPPA, n = 42), and nonfluent/agrammatic PPA (naPPA, n = 22). Based on previous findings, we hypothesized that the three patient groups and controls would differ in the counts of part-of-speech (POS) categories and several lexical measures. With a natural language processing program, we automatically tagged POS categories of all words produced during a picture description task. We further counted the number of wh-words, and we rated nouns for abstractness, ambiguity, frequency, familiarity, and age of acquisition. We also computed the cross-entropy estimation, where low cross-entropy indicates high predictability, and lexical diversity for each description. We validated a subset of the POS data that were automatically tagged with the Google Universal POS scheme using gold-standard POS data tagged by a linguist, and we found that the POS categories from our automated methods were more than 90% accurate. For svPPA patients, we found fewer unique nouns than in naPPA and more pronouns and wh-words than in the other groups. We also found high abstractness, ambiguity, frequency, and familiarity for nouns and the lowest cross-entropy estimation among all groups. These measures were associated with cortical thinning in the left temporal lobe. In naPPA patients, we found increased speech errors and partial words compared to controls, and these impairments were associated with cortical thinning in the left middle frontal gyrus. bvFTD patients' adjective production was decreased compared to controls and was correlated with their apathy scores. Their adjective production was associated with cortical thinning in the dorsolateral frontal and orbitofrontal gyri. Our results demonstrate distinct language profiles in subgroups of FTD patients and validate our automated method of analyzing FTD patients' speech.
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http://dx.doi.org/10.1016/j.cortex.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044033PMC
April 2021

Frontotemporal lobar degeneration proteinopathies have disparate microscopic patterns of white and grey matter pathology.

Acta Neuropathol Commun 2021 02 23;9(1):30. Epub 2021 Feb 23.

Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been understudied. We performed a neuropathological study of subcortical WM and adjacent GM in a large autopsy cohort (n = 92; FTLD-Tau = 37, FTLD-TDP = 55) using a validated digital image approach. The antemortem clinical phenotype was behavioral-variant frontotemporal dementia (bvFTD) in 23 patients with FTLD-Tau and 42 with FTLD-TDP, and primary progressive aphasia (PPA) in 14 patients with FTLD-Tau and 13 with FTLD-TDP. We used linear mixed-effects models to: (1) compare WM pathology burden between proteinopathies; (2) investigate the relationship between WM pathology burden and WM degeneration using luxol fast blue (LFB) myelin staining; (3) study regional patterns of pathology burden in clinico-pathological groups. WM pathology burden was greater in FTLD-Tau compared to FTLD-TDP across regions (beta = 4.21, SE = 0.34, p < 0.001), and correlated with the degree of WM degeneration in both FTLD-Tau (beta = 0.32, SE = 0.10, p = 0.002) and FTLD-TDP (beta = 0.40, SE = 0.08, p < 0.001). WM degeneration was greater in FTLD-Tau than FTLD-TDP particularly in middle-frontal and anterior cingulate regions (p < 0.05). Distinct regional patterns of WM and GM inclusions characterized FTLD-Tau and FTLD-TDP proteinopathies, and associated in part with clinical phenotype. In FTLD-Tau, WM pathology was particularly severe in the dorsolateral frontal cortex in nonfluent-variant PPA, and GM pathology in dorsolateral and paralimbic frontal regions with some variation across tauopathies. Differently, FTLD-TDP had little WM regional variability, but showed severe GM pathology burden in ventromedial prefrontal regions in both bvFTD and PPA. To conclude, FTLD-Tau and FTLD-TDP proteinopathies have distinct severity and regional distribution of WM and GM pathology, which may impact their clinical presentation, with overall greater severity of WM pathology as a distinguishing feature of tauopathies.
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http://dx.doi.org/10.1186/s40478-021-01129-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901087PMC
February 2021

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

Neurology 2021 04 16;96(14):e1855-e1864. Epub 2021 Feb 16.

From the Department of Neurology (E.H., D.J.I., K.R., N.N., S.S., T.F.T., M.S., A.D., A.C.-P., A.S., N.D., D.W., S.N.V., D.A.W., D.M.-H., J.F.M., J.E.D., M.G., K.A.Q.C.), Frontotemporal Degeneration Center (E.H., D.J.I., K.R., N.N., S.S., M.G., K.A.Q.C.), Parkinson's Disease and Movement Disorders Center (T.F.T., M.S., A.D., A.C.-P., A.S., N.D., D.W.), Digital Neuropathology Laboratory (D.J.I.), Alzheimer's Disease Center (J.Q.T., S.N.V., D.A.W., D.M.-H.), Center for Neurodegenerative Disease Research (L.M.S., J.Q.T.), and Department of Pathology and Laboratory Medicine (L.M.S., J.Q.T., D.A.W.), Perelman School of Medicine at the University of Pennsylvania; and Michael J. Crescenz VA Medical Center (D.W., J.F.M., J.E.D.), Parkinson's Disease Research, Education, and Clinical Center, Philadelphia, PA.

Objective: To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology.

Methods: We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.

Results: Patients with LBD + AD performed worse on BNT than patients with LBD - AD ( = 4.80, = 0.03); both groups performed similarly on LF, RDS, and MMSE (all > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28, < 0.05) and p-tau (ρ = -0.26, = 0.05) but not Aβ ( > 0.1).

Conclusion: Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.
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http://dx.doi.org/10.1212/WNL.0000000000011699DOI Listing
April 2021

More Than Words: Extra-Sylvian Neuroanatomic Networks Support Indirect Speech Act Comprehension and Discourse in Behavioral Variant Frontotemporal Dementia.

Front Hum Neurosci 2020 14;14:598131. Epub 2021 Jan 14.

Penn Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.

Indirect speech acts-responding "I forgot to wear my watch today" to someone who asked for the time-are ubiquitous in daily conversation, but are understudied in current neurobiological models of language. To comprehend an indirect speech act like this one, listeners must not only decode the lexical-semantic content of the utterance, but also make a pragmatic, bridging inference. This inference allows listeners to derive the speaker's true, intended meaning-in the above dialog, for example, that the speaker cannot provide the time. In the present work, we address this major gap by asking non-aphasic patients with behavioral variant frontotemporal dementia (bvFTD, = 21) and brain-damaged controls with amnestic mild cognitive impairment (MCI, = 17) to judge simple question-answer dialogs of the form: "Do you want some cake for dessert?" "I'm on a very strict diet right now," and relate the results to structural and diffusion MRI. Accuracy and reaction time results demonstrate that subjects with bvFTD, but not MCI, are selectively impaired in indirect relative to direct speech act comprehension, due in part to their social and executive limitations, and performance is related to caregivers' judgment of communication efficacy. MRI imaging associates the observed impairment in bvFTD to cortical thinning not only in traditional language-associated regions, but also in fronto-parietal regions implicated in social and executive cerebral networks. Finally, diffusion tensor imaging analyses implicate white matter tracts in both dorsal and ventral projection streams, including superior longitudinal fasciculus, frontal aslant, and uncinate fasciculus. These results have strong implications for updated neurobiological models of language, and emphasize a core, language-mediated social disorder in patients with bvFTD.
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http://dx.doi.org/10.3389/fnhum.2020.598131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842266PMC
January 2021

Hippocampal subfield pathologic Burden in Lewy body diseases versus Alzheimer's disease.

Neuropathol Appl Neurobiol 2021 Jan 25. Epub 2021 Jan 25.

Penn Digital Neuropathology Laboratory at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/nan.12698DOI Listing
January 2021

Lexical and Acoustic Characteristics of Young and Older Healthy Adults.

J Speech Lang Hear Res 2021 02 13;64(2):302-314. Epub 2021 Jan 13.

Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia.

Purpose This study examines the effect of age on language use with an automated analysis of digitized speech obtained from semistructured, narrative speech samples. Method We examined the Cookie Theft picture descriptions produced by 37 older and 76 young healthy participants. Using modern natural language processing and automatic speech recognition tools, we automatically annotated part-of-speech categories of all tokens, calculated the number of tense-inflected verbs, mean length of clause, and vocabulary diversity, and we rated nouns and verbs for five lexical features: word frequency, familiarity, concreteness, age of acquisition, and semantic ambiguity. We also segmented the speech signals into speech and silence and calculated acoustic features, such as total speech time, mean speech and pause segment durations, and pitch values. Results Older speakers produced significantly more fillers, pronouns, and verbs and fewer conjunctions, determiners, nouns, and prepositions than young participants. Older speakers' nouns and verbs were more familiar, more frequent (verbs only), and less ambiguous compared to those of young speakers. Older speakers produced shorter clauses with a lower vocabulary diversity than young participants. They also produced shorter speech segments and longer pauses with increased total speech time and total number of words. Lastly, we observed an interaction of age and sex in pitch ranges. Conclusions Our results suggest that older speakers' lexical content is less diverse, and these speakers produce shorter clauses than young participants in monologic, narrative speech. Our findings show that lexical and acoustic characteristics of semistructured speech samples can be examined with automated methods.
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http://dx.doi.org/10.1044/2020_JSLHR-19-00384DOI Listing
February 2021

Cross-sectional and longitudinal medial temporal lobe subregional atrophy patterns in semantic variant primary progressive aphasia.

Neurobiol Aging 2021 02 23;98:231-241. Epub 2020 Nov 23.

Department of Neurology, Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, USA.

T1-magnetic resonance imaging (MRI) studies report early atrophy in the left anterior temporal lobe, especially the perirhinal cortex, in semantic variant primary progressive aphasia (svPPA). Improved segmentation protocols using high-resolution T2-MRI have enabled fine-grained medial temporal lobe (MTL) subregional measurements, which may provide novel information on the atrophy pattern and disease progression in svPPA. We aimed to investigate the MTL subregional atrophy pattern cross-sectionally and longitudinally in patients with svPPA as compared with controls and patients with Alzheimer's disease (AD). MTL subregional volumes were obtained using the Automated Segmentation for Hippocampal Subfields software from high-resolution T2-MRIs in 15 svPPA, 37 AD, and 23 healthy controls. All MTL volumes were corrected for intracranial volume and parahippocampal cortices for slice number. Longitudinal atrophy rates of all subregions were obtained using an unbiased deformation-based morphometry pipeline in 6 svPPA patients, 9 controls, and 12 AD patients. Cross-sectionally, significant volume loss was observed in svPPA compared with controls in the left MTL, right cornu ammonis 1 (CA1), Brodmann area (BA)35, and BA36 (subdivisions of the perirhinal cortex). Compared with AD patients, svPPA patients had significantly smaller left CA1, BA35, and left and right BA36 volumes. Longitudinally, svPPA patients had significantly greater atrophy rates of left and right BA36 than controls but not relative to AD patients. Fine-grained analysis of MTL atrophy patterns provides information about the evolution of atrophy in svPPA. These results indicate that MTL subregional measures might be useful markers to track disease progression or for clinical trials in svPPA.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018475PMC
February 2021

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

EMBO Mol Med 2021 Jan 3;13(1):e12595. Epub 2020 Dec 3.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.
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http://dx.doi.org/10.15252/emmm.202012595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799365PMC
January 2021

Brain volumetric deficits in MAPT mutation carriers: a multisite study.

Ann Clin Transl Neurol 2021 01 28;8(1):95-110. Epub 2020 Nov 28.

Mayo Clinic, Jacksonville, Florida, USA.

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.

Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.

Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.

Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.
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http://dx.doi.org/10.1002/acn3.51249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818091PMC
January 2021

ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration.

Alzheimers Dement 2020 Nov 23. Epub 2020 Nov 23.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATN ) using CSF total tau (t-tau) to a modified strategy (ATN ) using CSF neurofilament light chain (NfL) in an autopsy cohort.

Methods: ATN and ATN were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27).

Results: ATN more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATN (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATN misclassified fewer AD and FTLD as "Normal" (2%) than ATN (14%).

Discussion: ATN is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.
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http://dx.doi.org/10.1002/alz.12233DOI Listing
November 2020

Automated analysis of lexical features in Frontotemporal Degeneration.

medRxiv 2020 Nov 4. Epub 2020 Nov 4.

Linguistic Data Consortium, University of Pennsylvania, Philadelphia, PA, USA.

We implemented an automated analysis of lexical aspects of semi-structured speech produced by healthy elderly controls (n=37) and three patient groups with frontotemporal degeneration (FTD): behavioral variant FTD (n=74), semantic variant primary progressive aphasia (svPPA, n=42), and nonfluent/agrammatic PPA (naPPA, n=22). Based on previous findings, we hypothesized that the three patient groups and controls would differ in the counts of part-of-speech (POS) categories and several lexical measures. With a natural language processing program, we automatically tagged POS categories of all words produced during a picture description task. We further counted the number of -words, and we rated nouns for abstractness, ambiguity, frequency, familiarity, and age of acquisition. We also computed the cross-entropy estimation, which is a measure of word predictability, and lexical diversity for each description. We validated a subset of the POS data that were automatically tagged with the Google Universal POS scheme using gold-standard POS data tagged by a linguist, and we found that the POS categories from our automated methods were more than 90% accurate. For svPPA patients, we found fewer unique nouns than in naPPA and more pronouns and -words than in the other groups. We also found high abstractness, ambiguity, frequency, and familiarity for nouns and the lowest cross-entropy estimation among all groups. These measures were associated with cortical thinning in the left temporal lobe. In naPPA patients, we found increased speech errors and partial words compared to controls, and these impairments were associated with cortical thinning in the left middle frontal gyrus. bvFTD patients' adjective production was decreased compared to controls and was correlated with their apathy scores. Their adjective production was associated with cortical thinning in the dorsolateral frontal and orbitofrontal gyri. Our results demonstrate distinct language profiles in subgroups of FTD patients and validate our automated method of analyzing FTD patients' speech.
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http://dx.doi.org/10.1101/2020.09.10.20192054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654918PMC
November 2020

An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline.

Nat Commun 2020 11 2;11(1):5522. Epub 2020 Nov 2.

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599-7260, USA.

Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.
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http://dx.doi.org/10.1038/s41467-020-19317-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606452PMC
November 2020

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials.

Alzheimers Res Ther 2020 10 29;12(1):137. Epub 2020 Oct 29.

Lewy Body Dementia Association, S.W., Lilburn, GA, USA.

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.
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http://dx.doi.org/10.1186/s13195-020-00703-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597002PMC
October 2020

Tau pathology associates with in vivo cortical thinning in Lewy body disorders.

Ann Clin Transl Neurol 2020 12 27;7(12):2342-2355. Epub 2020 Oct 27.

Penn Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).

Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ  > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBD-AD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions.

Results: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBD-AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Aβ or alpha-synuclein pathology.

Interpretation: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.
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http://dx.doi.org/10.1002/acn3.51183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732256PMC
December 2020

Biomarker Use for Dementia With Lewy Body Diagnosis: Survey of US Experts.

Alzheimer Dis Assoc Disord 2021 Jan-Mar 01;35(1):55-61

Department of Neurology, Comprehensive Center for Brain Health, University of Miami Miller School of Medicine, Miami, FL.

Background: Dementia with Lewy body (DLB) diagnostic criteria define "indicative" and "supportive" biomarkers, but clinical practice patterns are unknown.

Methods: An anonymous survey querying clinical use of diagnostic tests/biomarkers was sent to 38 center of excellence investigators. The survey included "indicative" biomarkers (dopamine transporter scan, myocardial scintigraphy, polysomnography), "supportive" biomarkers [magnetic resonance imaging (MRI)], positron emission tomography, or single-photon emission computed tomography perfusion/metabolism scans, quantitative electroencephalography), and other diagnostic tests (neuropsychological testing, cerebrospinal fluid analysis, genetics). Responses were analyzed descriptively.

Results: Of the 22 respondents (58%), all reported the capability to perform neuropsychological testing, MRI, polysomnography, dopamine transporter scans, positron emission tomography/single-photon emission computed tomography scans, and cerebrospinal fluid analysis; 96% could order genetic testing. Neuropsychological testing and MRI were the most commonly ordered tests. Diagnostic testing beyond MRI and neuropsychological testing was most helpful in the context of "possible" DLB and mild cognitive impairment and to assist with differential diagnosis. Myocardial scintigraphy and electroencephalograpy use were rare.

Conclusions And Relevance: Neuropsychological testing and MRI remain the most widely used diagnostic tests by DLB specialists. Other tests-particularly indicative biomarkers-are used only selectively. Research is needed to validate existing potential DLB biomarkers, develop new biomarkers, and investigate mechanisms to improve DLB diagnosis.
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http://dx.doi.org/10.1097/WAD.0000000000000414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904569PMC
June 2020

Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.

Science 2020 11 1;370(6519). Epub 2020 Oct 1.

Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, PA, USA.

Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.
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http://dx.doi.org/10.1126/science.aay8826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818661PMC
November 2020

Multimodal in vivo and postmortem assessments of tau in Lewy body disorders.

Neurobiol Aging 2020 12 21;96:137-147. Epub 2020 Aug 21.

Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

We compared regional retention of F-flortaucipir between 20 patients with Lewy body disorders (LBD), 12 Alzheimer's disease patients with positive amyloid positron emission tomography (PET) scans (AD+Aβ) and 15 healthy controls with negative amyloid PET scans (HC-Aβ). In LBD subjects, we compared the relationship between F-flortaucipir retention and cerebrospinal fluid (CSF) tau, cognitive performance, and neuropathological tau at autopsy. The LBD cohort was stratified using an Aβ42 cut-off of 192 pg/mL to enrich for groups likely harboring tau pathology (LBD+Aβ = 11, LBD-Aβ = 9). F-flortaucipir retention was higher in LBD+AB than HC-Aβ in five, largely temporal-parietal regions with sparing of medial temporal regions. Higher retention was associated with higher CSF total-tau levels (p = 0.04), poorer domain-specific cognitive performance (p = 0.02-0.04), and greater severity of neuropathological tau in corresponding regions. While F-flortaucipir retention in LBD is intermediate between healthy controls and AD, retention relates to cognitive impairment, CSF total-tau, and neuropathological tau. Future work in larger autopsy-validated cohorts is needed to define LBD-specific tau biomarker profiles.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819484PMC
December 2020

Clinical Conditions "Suggestive of Progressive Supranuclear Palsy"-Diagnostic Performance.

Mov Disord 2020 12 11;35(12):2301-2313. Epub 2020 Sep 11.

Department of Neurology, Technische Universität München, Munich, Germany.

Background: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level "suggestive of progressive supranuclear palsy" for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves.

Objective: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort.

Methods: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases.

Results: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years.

Conclusions: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953080PMC
December 2020

Degeneration of the locus coeruleus is a common feature of tauopathies and distinct from TDP-43 proteinopathies in the frontotemporal lobar degeneration spectrum.

Acta Neuropathol 2020 11 17;140(5):675-693. Epub 2020 Aug 17.

Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Neurodegeneration of the locus coeruleus (LC) in age-related neurodegenerative diseases such as Alzheimer's disease (AD) is well documented. However, detailed studies of LC neurodegeneration in the full spectrum of frontotemporal lobar degeneration (FTLD) proteinopathies comparing tauopathies (FTLD-tau) to TDP-43 proteinopathies (FTLD-TDP) are lacking. Here, we tested the hypothesis that there is greater LC neuropathology and neurodegeneration in FTLD-tau compared to FTLD-TDP. We examined 280 patients including FTLD-tau (n = 94), FTLD-TDP (n = 135), and two reference groups: clinical/pathological AD (n = 32) and healthy controls (HC, n = 19). Adjacent sections of pons tissue containing the LC were immunostained for phosphorylated TDP-43 (1D3-p409/410), hyperphosphorylated tau (PHF-1), and tyrosine hydroxylase (TH) to examine neuromelanin-containing noradrenergic neurons. Blinded to clinical and pathologic diagnoses, we semi-quantitatively scored inclusions of tau and TDP-43 both inside LC neuronal somas and in surrounding neuropil. We also digitally measured the percent area occupied of neuromelanin inside of TH-positive LC neurons and in surrounding neuropil to calculate a ratio of extracellular-to-intracellular neuromelanin as an objective composite measure of neurodegeneration. We found that LC tau burden in FTLD-tau was greater than LC TDP-43 burden in FTLD-TDP (z = - 11.38, p < 0.0001). Digital measures of LC neurodegeneration in FTLD-tau were comparable to AD (z = - 1.84, p > 0.05) but greater than FTLD-TDP (z = - 3.85, p < 0.0001) and HC (z = - 4.12, p < 0.0001). Both tau burden and neurodegeneration were consistently elevated in the LC across pathologic and clinical subgroups of FTLD-tau compared to FTLD-TDP subgroups. Moreover, LC tau burden positively correlated with neurodegeneration in the total FTLD group (rho = 0.24, p = 0.001), while TDP-43 burden did not correlate with LC neurodegeneration in FTLD-TDP (rho = - 0.01, p = 0.90). These findings suggest that patterns of disease propagation across all tauopathies include prominent LC tau and neurodegeneration that are relatively distinct from the minimal degenerative changes to the LC in FTLD-TDP and HC. Antemortem detection of LC neurodegeneration and/or function could potentially improve antemortem differentiation of underlying FTLD tauopathies from clinically similar FTLD-TDP proteinopathies.
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http://dx.doi.org/10.1007/s00401-020-02210-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554264PMC
November 2020

Defining and predicting transdiagnostic categories of neurodegenerative disease.

Nat Biomed Eng 2020 08 3;4(8):787-800. Epub 2020 Aug 3.

Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.

The prevalence of concomitant proteinopathies and heterogeneous clinical symptoms in neurodegenerative diseases hinders the identification of individuals who might be candidates for a particular intervention. Here, by applying an unsupervised clustering algorithm to post-mortem histopathological data from 895 patients with degeneration in the central nervous system, we show that six non-overlapping disease clusters can simultaneously account for tau neurofibrillary tangles, α-synuclein inclusions, neuritic plaques, inclusions of the transcriptional repressor TDP-43, angiopathy, neuron loss and gliosis. We also show that membership to the six transdiagnostic disease clusters, which explains more variance in cognitive phenotypes than can be explained by individual diagnoses, can be accurately predicted from scores of the Mini-Mental Status Exam, protein levels in cerebrospinal fluid, and genotype at the APOE and MAPT loci, via cross-validated multiple logistic regression. This combination of unsupervised and supervised data-driven tools provides a framework that could be used to identify latent disease subtypes in other areas of medicine.
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http://dx.doi.org/10.1038/s41551-020-0593-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946378PMC
August 2020

Automated analysis of natural speech in amyotrophic lateral sclerosis spectrum disorders.

Neurology 2020 09 16;95(12):e1629-e1639. Epub 2020 Jul 16.

From the Penn Frontotemporal Degeneration Center (N.N., S.A., C.M., D.J.I., M.G.), Department of Neurology (N.N., S.A., C.M., L.E., L.M., D.J.I., M.G.), and Linguistic Data Consortium (S.C., M.L.), Department of Linguistics, University of Pennsylvania, Philadelphia.

Objective: We implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS).

Methods: We recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS and frontotemporal degeneration [FTD]), 33 healthy controls, and neurodegenerative reference groups with behavioral variant FTD (n = 90) and nonfluent/agrammatic primary progressive aphasia (n = 23). Digitized, semistructured speech samples obtained from picture descriptions were automatically segmented with a Speech Activity Detector; continuous speech segments were pitch-tracked; and duration measures for speech and silent pause segments were extracted. Acoustic measures were calculated, including fundamental frequency (f0) range, mean speech and pause segment durations, total speech duration, and pause rate (pause count per minute of speech). Group comparisons related performance on acoustic measures to clinical scales of cognitive and motor impairments and explored MRI cortical thinning in ALS and ALS-FTD.

Results: The f0 range was significantly impaired in ALS spectrum disorders and was related to bulbar motor disease, and regression analyses related this to cortical thickness in primary motor cortex and perisylvian regions. Impaired speech and pause duration measures were related to the degree of cognitive impairment in ALS spectrum disorders, and regressions related duration measures to bilateral frontal opercula and left anterior insula.

Conclusion: Automated analyses of acoustic speech properties dissociate motor and cognitive components of speech deficits in ALS spectrum disorders.
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http://dx.doi.org/10.1212/WNL.0000000000010366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713725PMC
September 2020

Regional Brain Recovery from Acute Synaptic Injury in Simian Immunodeficiency Virus-Infected Rhesus Macaques Associates with Heme Oxygenase Isoform Expression.

J Virol 2020 09 15;94(19). Epub 2020 Sep 15.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Brain injury occurs within days in simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) infection, and some recovery may occur within weeks. Inflammation and oxidative stress associate with such injury, but what drives recovery is unknown. Chronic HIV infection associates with reduced brain frontal cortex expression of the antioxidant/anti-inflammatory enzyme heme oxygenase-1 (HO-1) and increased neuroinflammation in individuals with cognitive impairment. We hypothesized that acute regional brain injury and recovery associate with differences in regional brain HO-1 expression. Using SIV-infected rhesus macaques, we analyzed multiple brain regions through acute and chronic infection (90 days postinfection [dpi]) and quantified viral (SIV RNA), synaptic (PSD-95; synaptophysin), axonal (neurofilament/neurofilament light chain [NFL]), inflammatory, and antioxidant (enzymes, including heme oxygenase isoforms [HO-1, HO-2]) markers. PSD-95 was reduced in the brainstem, basal ganglia, neocortex, and cerebellum within 13 dpi, indicating acute synaptic injury throughout the brain. All areas except the brainstem recovered. Unchanged NFL was consistent with no acute axonal injury. SIV RNA expression was highest in the brainstem throughout infection, and it associated with neuroinflammation. Surprisingly, during the synaptic injury and recovery phases, HO-2, and not HO-1, progressively decreased in the brainstem. Thus, acute SIV synaptic injury occurs throughout the brain, with spontaneous recovery in regions other than the brainstem. Within the brainstem, the high SIV load and inflammation, along with reduction of HO-2, may impair recovery. In other brain regions, stable HO-2 expression, with or without increasing HO-1, may promote recovery. Our data support roles for heme oxygenase isoforms in modulating recovery from synaptic injury in SIV infection and suggest their therapeutic targeting for promoting neuronal recovery. Brain injury induced by acute simian (or human) immunodeficiency virus infection may persist or spontaneously resolve in different brain regions. Identifying the host factor(s) that promotes spontaneous recovery from such injury may reveal targets for therapeutic drug strategies for promoting recovery from acute neuronal injury. The gradual recovery from such injury observed in many, but not all, brain regions in the rhesus macaque model is consistent with the possible existence of a therapeutic window of opportunity for intervening to promote recovery, even in those regions not showing spontaneous recovery. In persons living with human immunodeficiency virus infection, such neuroprotective treatments could ultimately be considered as adjuncts to the initiation of antiretroviral drug therapy.
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http://dx.doi.org/10.1128/JVI.01102-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495379PMC
September 2020

ATN status in amnestic and non-amnestic Alzheimer's disease and frontotemporal lobar degeneration.

Brain 2020 07;143(7):2295-2311

Department of Neurology, University of Pennsylvania, Philadelphia, USA.

Under the ATN framework, CSF analytes provide evidence of the presence or absence of Alzheimer's disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer's disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in CSF concentrations of amyloid-β1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-β1-42. Results show that non-amnestic Alzheimer's disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cut-offs for positivity. Amyloid-β1-42 did not differ between amnestic and non-amnestic Alzheimer's disease, and receiver operating characteristic curve analyses indicated that amyloid-β1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-β1-42 were significantly lower in non-amnestic compared to amnestic Alzheimer's disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer's disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer's disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer's disease pathology. We conclude that amyloid-β1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer's disease than either the ATN framework or the phosphorylated-tau/amyloid-β1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer's disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer's disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364757PMC
July 2020

The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging.

iScience 2020 Jul 10;23(7):101255. Epub 2020 Jun 10.

Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

The microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.
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http://dx.doi.org/10.1016/j.isci.2020.101255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322077PMC
July 2020

Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease.

Ann Neurol 2020 09 2;88(3):574-587. Epub 2020 Jul 2.

Department of Pathology and Laboratory Medicine, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Objective: We analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.

Methods: Amyloid-β 1 to 42 (Aβ ), total tau (t-tau) and phosphorylated tau (p-tau) at the threonine 181 position were measured using the high-precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear-mixed effects models.

Results: We found patients with PD had lower CSF t-tau (median = 157.7 pg/mL; range = 80.9-467.0); p-tau (median = 13.4 pg/mL; range = 8.0-40.1), and Aβ (median = 846.2 pg/mL; range = 238.8-3,707.0) than HCs at baseline (CSF t-tau median = 173.5 pg/mL; range = 82.0-580.8; p-tau median = 15.4 pg/mL; range = 8.1-73.6; and Aβ median = 926.5 pg/mL; range = 239.1-3,297.0; p < 0.05-0.001) and a moderate-to-strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50-0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ at baseline and these patients with PD had lower p-tau levels (median = 10.8 pg/mL; range = 8.0-32.8) compared with 27.7% of HCs with pathologically low CSF Aβ (CSF p-tau median = 12.8 pg/mL; range 8.2-73.6; p < 0.03) In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ (mean difference = -41.83 pg/mL; p = 0.03) and CSF p-tau (mean difference = -0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD.

Interpretation: Our data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3-year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574-587.
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http://dx.doi.org/10.1002/ana.25811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497251PMC
September 2020

Tau immunophenotypes in chronic traumatic encephalopathy recapitulate those of ageing and Alzheimer's disease.

Brain 2020 05;143(5):1572-1587

Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer's disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer's disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer's disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer's disease and ageing may rest solely on the pattern and distribution of pathology.
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http://dx.doi.org/10.1093/brain/awaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241956PMC
May 2020