Publications by authors named "Murray Grossman"

402 Publications

Rates of longitudinal change in F-flortaucipir PET vary by brain region, cognitive impairment, and age in atypical Alzheimer's disease.

Alzheimers Dement 2021 Sep 13. Epub 2021 Sep 13.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD.

Methods: We assessed regional and interindividual variation in longitudinal change on F-flortaucipir PET imaging in 24 amyloid beta (Aβ)+ patients with atypical, early-onset amnestic or non-amnestic AD plus 62 Aβ- and 132 Aβ+ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants.

Results: In atypical AD, F-flortaucipir uptake slowed or declined over time in areas with high baseline signal and older, more impaired individuals. ADNI participants had reduced longitudinal change in early Braak stage regions relative to late-stage areas.

Discussion: Results suggested radioligand uptake plateaus or declines in advanced neurodegeneration. Further research should investigate whether results generalize to other radioligands and whether they relate to changes of the radioligand binding site structure or accessibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/alz.12456DOI Listing
September 2021

Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease.

Mov Disord 2021 Sep 4. Epub 2021 Sep 4.

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

Background: Neurofilament light chain protein (NfL) is a promising biomarker of neurodegeneration.

Objectives: To determine whether plasma and CSF NfL (1) associate with motor or cognitive status in Parkinson's disease (PD) and (2) predict future motor or cognitive decline in PD.

Methods: Six hundred and fifteen participants with neurodegenerative diseases, including 152 PD and 200 healthy control participants, provided a plasma and/or cerebrospinal fluid (CSF) NfL sample. Diagnostic groups were compared using the Kruskal-Wallis rank test. Within PD, cross-sectional associations between NfL and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and Mattis Dementia Rating Scale (DRS-2) scores were assessed by linear regression; longitudinal analyses were performed using linear mixed-effects models and Cox regression.

Results: Plasma and CSF NfL levels correlated substantially (Spearman r = 0.64, P < 0.001); NfL was highest in neurocognitive disorders. PD participants with high plasma NfL were more likely to develop incident cognitive impairment (HR 5.34, P = 0.005).

Conclusions: Plasma NfL is a useful prognostic biomarker for PD, predicting clinical conversion to mild cognitive impairment or dementia. © 2021 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28779DOI Listing
September 2021

Common genetic variation is associated with longitudinal decline and network features in behavioral variant frontotemporal degeneration.

Neurobiol Aging 2021 Aug 3;108:16-23. Epub 2021 Aug 3.

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

The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to compromised frontal networks. We studied 81 individuals clinically diagnosed with bvFTD who were genotyped for rs1768208 and coded using a dominant model reflecting the presence (i.e., MOBP +) or absence (MOBP -) of the T risk allele. Linear mixed-effects models assessed the association of genotype on neuropsychological performance over time. Regression analyses examined differences in network structure by MOBP genotype. We found a genotype by time interaction for declining cognitive performance, whereby MOBP + individuals demonstrated faster rates of decline in executive function. The presence of a MOBP risk allele was associated with degradation of white matter network features in the frontal lobe. These findings suggest that individual genetic variation may contribute to heterogeneity in clinical progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.07.018DOI Listing
August 2021

Automated Analysis of Digitized Letter Fluency Data.

Front Psychol 2021 29;12:654214. Epub 2021 Jul 29.

Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, United States.

The letter-guided naming fluency task is a measure of an individual's executive function and working memory. This study employed a novel, automated, quantifiable, and reproducible method to investigate how language characteristics of words produced during a fluency task are related to fluency performance, inter-word response time (RT), and over task duration using digitized F-letter-guided fluency recordings produced by 76 young healthy participants. Our automated algorithm counted the number of correct responses from the transcripts of the F-letter fluency data, and individual words were rated for concreteness, ambiguity, frequency, familiarity, and age of acquisition (AoA). Using a forced aligner, the transcripts were automatically aligned with the corresponding audio recordings. We measured inter-word RT, word duration, and word start time from the forced alignments. Articulation rate was also computed. Phonetic and semantic distances between two consecutive F-letter words were measured. We found that total F-letter score was significantly correlated with the mean values of word frequency, familiarity, AoA, word duration, phonetic similarity, and articulation rate; total score was also correlated with an individual's standard deviation of AoA, familiarity, and phonetic similarity. RT was negatively correlated with frequency and ambiguity of F-letter words and was positively correlated with AoA, number of phonemes, and phonetic and semantic distances. Lastly, the frequency, ambiguity, AoA, number of phonemes, and semantic distance of words produced significantly changed over time during the task. The method employed in this paper demonstrates the successful implementation of our automated language processing pipelines in a standardized neuropsychological task. This novel approach captures subtle and rich language characteristics during test performance that enhance informativeness and cannot be extracted manually without massive effort. This work will serve as the reference for letter-guided category fluency production similarly acquired in neurodegenerative patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyg.2021.654214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359864PMC
July 2021

Longitudinal naming and repetition relates to AD pathology and burden in autopsy-confirmed primary progressive aphasia.

Alzheimers Dement (N Y) 2021 2;7(1):e12188. Epub 2021 Aug 2.

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

Introduction: In primary progressive aphasia (PPA) patients with autopsy-confirmed Alzheimer's disease (AD) or frontotemporal lobar degeneration (FLTD), we tested how the core clinical features of logopenic PPA-naming and repetition-change over time and relate to pathologic burden.

Methods: In PPA with AD (n = 13) or FTLD (n = 16) pathology, Boston Naming Test and Forward Digit Span measured longitudinal naming and repetition; as reference, Mini-Mental State Examination (MMSE) measured global cognition. Pathologic burden in left peri-Sylvian regions was related to longitudinal cognitive decline.

Results: PPA with AD showed greater decline in naming (= 0.021) and repetition (= 0.020), compared to FTLD; there was no difference in MMSE decline (= 0.99). Across all PPA, declining naming (= 0.0084) and repetition (= 0.011) were associated with angular, superior-middle temporal (naming = 0.014; repetition = 0.011) and middle frontal (naming = 0.041; repetition = 0.030) pathologic burden.

Discussion: Unique longitudinal profiles of naming and repetition performance in PPA with AD are related to left peri-Sylvian pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/trc2.12188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327471PMC
August 2021

Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care.

Front Neurol 2021 1;12:694872. Epub 2021 Jul 1.

Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2021.694872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284317PMC
July 2021

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

Brain 2021 Jul 14. Epub 2021 Jul 14.

Human Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangle was measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden reveal significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we find similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu Ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab262DOI Listing
July 2021

Digital Speech Analysis in Progressive Supranuclear Palsy and Corticobasal Syndromes.

J Alzheimers Dis 2021 ;82(1):33-45

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

Background: Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood.

Objective: Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA.

Methods: Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n = 87), naPPA (n = 25), and healthy controls (HC, n = 41). We related these measures to grammatical performance and speech fluency, core features of naPPA, to neuropsychological measures of naming, executive, memory and visuoconstructional functioning, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) levels in patients with available biofluid analytes.

Results: Both naPPA and PSPS-CBS speech produced shorter speech segments, longer pauses, higher pause rates, reduced fundamental frequency (f0) pitch ranges, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, reduced verb production, and higher partial word production. In both groups, acoustic duration measures generally correlated with speech fluency, measured as words per minute, and grammatical performance. Speech measures did not correlate with standard neuropsychological measures. CSF pTau levels correlated with f0 range in PSPS-CBS and naPPA.

Conclusion: Lexical and acoustic speech features of PSPS-CBS overlaps those of naPPA and are related to CSF pTau levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-201132DOI Listing
September 2021

TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy.

Acta Neuropathol 2021 10 21;142(4):629-642. Epub 2021 Jun 21.

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

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)-allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. To elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02330-2DOI Listing
October 2021

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

Acta Neuropathol 2021 08 5;142(2):243-257. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02318-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270872PMC
August 2021

CSF sTREM2 is elevated in a subset in GRN-related frontotemporal dementia.

Neurobiol Aging 2021 07 4;103:158.e1-158.e5. Epub 2021 Mar 4.

Alzheimer Center Rotterdam and Dept. of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address:

Excessive microglial activation might be a central pathological process in GRN-related frontotemporal dementia (FTD-GRN). We measured soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is shed from disease-associated microglia following cleavage of TREM2, in cerebrospinal fluid of 34 presymptomatic and 35 symptomatic GRN mutation carriers, 6 presymptomatic and 32 symptomatic C9orf72 mutation carriers and 67 healthy noncarriers by ELISA. Although no group differences in sTREM2 levels were observed (GRN: symptomatic (median 5.2 ng/mL, interquartile range [3.9-9.2]) vs. presymptomatic (4.3 ng/mL [2.6-6.1]) vs. noncarriers (4.2 ng/mL [2.6-5.5]): p = 0.059; C9orf72: symptomatic (4.3 [2.9-7.0]) vs. presymptomatic (3.2 [2.2-4.2]) vs. noncarriers: p = 0.294), high levels were seen in a subset of GRN, but not C9orf72, mutation carriers, which might reflect differential TREM2-related microglial activation. Interestingly, 2 presymptomatic carriers with low sTREM2 levels developed symptoms after 1 year, whereas 2 with high levels became symptomatic after >5 years. While sTREM2 is not a promising diagnostic biomarker for FTD-GRN or FTD-C9orf72, further research might elucidate its potential to monitor microglial activity and predict disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.024DOI Listing
July 2021

Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Cortex 2021 06 19;139:99-115. Epub 2021 Mar 19.

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119343PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 05 7;96(18):e2296-e2312. Epub 2021 Apr 7.

From the University of California, San Francisco (J.C.R., P.W., A.M.S., Y.C., A.W., S.-Y.M.G., P.A.L., H.W.H., J.C.F., J.B.T., A.M.K., L.L.M., J.K., J.H.K., B.L.M., H.J.S., A.L.B.); UK Dementia Research Centre (C.H., D.M.C., R.S.C., M.B., M.F., C.V.G., G.P., L.R., I.S., E.T., J.D.R.), UCL Institute of Neurology, Queen Square, London; Quanterix Corp (E.V., L.S., A.J., D.H.), Lexington; Novartis Institutes for Biomedical Research Inc (L.Y., A. Khinikar, R.S.), Cambridge, MA; Novartis Pharma AG (A. Kieloch, M.-A.V.), Basel, Switzerland; Bluefield Project to Cure Frontotemporal Dementia (L.L.M., R.P.), San Francisco, CA; Mayo Clinic (K.K., D.S.K., B.F.B.), Rochester, MN; Mayo Clinic (N.G.-R., L.P., R.R.), Jacksonville, FL; University of Pennsylvania (D.J.I., M.G.), Philadelphia; University of California, Los Angeles (E.M.R., G.C., M.F.M., Y.B.); Harvard University/Massachusetts General Hospital (B.D.C.), Boston, MA; Washington University (N.G.), St. Louis, MO; Columbia University (E.D.H.), New York, NY; University of British Columbia (I.R.M., G.-Y.R.H.), Vancouver, Canada; Case Western Reserve University (B.S.A.), Cleveland, OH; University of Washington (K.D.-R.), Seattle; Laboratory of Neuroimaging (A.W.T.), University of Southern California, Los Angeles; Northwestern University (S.W.), Chicago, IL; University of North Carolina (D.I.K.), Chapel Hill; Texas Health Presbyterian Hospital Dallas (D.K.); University of California, San Diego (I.L.); Johns Hopkins Hospital (C.U.O., A.P.), Baltimore, MD; University of Alabama at Birmingham (E.D.R.); University of Toronto (M.C.T., M.M.), Ontario, Canada; Indiana University School of Medicine (T.F.), Indianapolis; Biogen Inc (W.C., J.C., D.L.G.), Cambridge, MA; Erasmus Medical Centre (J.C.v.S.), Rotterdam, the Netherlands; University of Brescia (B.B.), Italy; University of Barcelona (R.S.-V.); Donostia University Hospital (F.M.), San Sebastian, Gipuzkoa, Spain; Clinique Interdisciplinaire de Mémoire (R.L.), Département des Sciences Neurologiques, CHU de Québec; Faculté de Médecine (R.L.), Université Laval, Quebec, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; University of Tübingen (M.S.); Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Fondazione IRCCS Ospedale Policlinico (D.G.); University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospital (J.B.R.), University of Cambridge, UK; University of Western Ontario (E.F.), London, Canada; KU Leuven (R.V.), Belgium; Neurology Service (R.V.), University Hospitals Leuven, Belgium; University of Lisbon (A.d.M.), Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University of Coimbra (I.S.), Portugal; McGill University (S.D.), Montreal, Québec, Canada; University of Oxford (C.R.B.); Wolfson Molecular Imaging Centre (A.G.), University of Manchester, UK; University of Duisburg-Essen (A.G.), Duisberg; Ludwig-Maximilians-Universität München (J.L., A.D.); German Center for Neurodegenerative Diseases (J.L.), Munich Cluster for Systems Neurology (SyNergy); University of Ulm (M.O.), Germany; and Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence, and IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

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 single-molecule array in original (n = 277) and validation (n = 297) cohorts. , , and mutation carriers and noncarriers 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 nonprogressors (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 those with 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.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166434PMC
May 2021

Automated analysis of lexical features in frontotemporal degeneration.

Cortex 2021 04 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-021-01129-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901087PMC
February 2021

Lessons learned from a progressive supranuclear palsy trial.

Authors:
Murray Grossman

Lancet Neurol 2021 03;20(3):162-163

Penn Frontotemporal Degeneration Center and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(21)00035-1DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105963PMC
April 2021

Association of Mitochondrial DNA Genomic Variation With Risk of Pick Disease.

Neurology 2021 03 10;96(13):e1755-e1760. Epub 2021 Feb 10.

From the Department of Neuroscience (R.R.V., M.C.B., A.I.S.-B., R.L.W., S.K., S.F.R., R.R., D.W.D., O.A.R.), Division of Biomedical Statistics and Informatics (M.G.H., P.W.J.), Department of Neurology (R.J.U., Z.K.W.), and Department of Clinical Genomics (O.A.R.), Mayo Clinic, Jacksonville, FL; Perelman School of Medicine (E.S., J.Q.T., V.M.V.D.) and Department of Neurology (M.G.), University of Pennsylvania, Philadelphia; and VIB-UAntwerp Center for Molecular Neurology (R.R.), University of Antwerp, Belgium.

Objective: To determine whether stable polymorphisms that define mitochondrial haplogroups in mitochondrial DNA (mtDNA) are associated with Pick disease risk, we genotyped 52 pathologically confirmed cases of Pick disease and 910 neurologically healthy controls and performed case-control association analysis.

Methods: Fifty-two pathologically confirmed cases of Pick disease from Mayo Clinic Florida (n = 38) and the University of Pennsylvania (n = 14) and 910 neurologically healthy controls collected from Mayo Clinic Florida were genotyped for unique mtDNA haplogroup-defining variants. Mitochondrial haplogroups were determined, and in a case-control analysis, associations of mtDNA haplogroups with risk of Pick disease were evaluated with logistic regression models that were adjusted for age and sex.

Results: No individual mtDNA haplogroups or superhaplogroups were significantly associated with risk of Pick disease after adjustment for multiple testing ( < 0.0021, considered significant). However, nominally significant ( < 0.05) associations toward an increased risk of Pick disease were observed for mtDNA haplogroup W (5.8% cases vs 1.6% controls, odds ratio [OR] 4.78, = 0.020) and subhaplogroup H4 (5.8% cases vs 1.2% controls, OR 4.82, = 0.021).

Conclusion: Our findings indicate that mtDNA variation is not a disease driver but may influence disease susceptibility. Ongoing genetic assessments in larger cohorts of Pick disease are currently underway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055308PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 Aug 15;47(5):707-708. Epub 2021 Feb 15.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nan.12698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298266PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 2021 05 23;17(5):822-830. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/alz.12233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119305PMC
May 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.09.10.20192054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654918PMC
November 2020

Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants.

JAMA Netw Open 2020 10 1;3(10):e2022847. Epub 2020 Oct 1.

Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco.

Importance: Several clinical trials are planned for familial forms of frontotemporal lobar degeneration (f-FTLD). Precise modeling of brain atrophy in f-FTLD could improve the power to detect a treatment effect.

Objective: To characterize regions and rates of atrophy in the 3 primary f-FTLD genetic groups (MAPT, GRN, and C9orf72) across all disease stages from asymptomatic to dementia.

Design, Setting, And Participants: This investigation was a case-control study of participants enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration or Longitudinal Evaluation of Familial Frontotemporal Dementia studies. The study took place at 18 North American academic medical centers between January 2009 and September 2018. Participants with f-FTLD (n = 100) with a known pathogenic variant (MAPT [n = 28], GRN [n = 33], or C9orf72 [n = 39]) were grouped according to disease stage (ie, Clinical Dementia Rating [CDR] plus National Alzheimer's Coordinating Center [NACC] FTLD module). Included were participants with at least 2 structural magnetic resonance images at presymptomatic (CDR + NACC FTLD = 0 [n = 57]), mild or questionable (CDR + NACC FTLD = 0.5 [n = 15]), or symptomatic (CDR + NACC FTLD = ≥1 [n = 28]) disease stages. The control group included family members of known pathogenic variant carriers who did not carry the pathogenic variant (n = 60).

Main Outcomes And Measures: This study fitted bayesian linear mixed-effects models in each voxel of the brain to quantify the rate of atrophy in each of the 3 genes, at each of the 3 disease stages, compared with controls. The study also analyzed rates of clinical decline in each of these groups, as measured by the CDR + NACC FTLD box score.

Results: The sample included 100 participants with f-FTLD with a known pathogenic variant (mean [SD] age, 50.48 [13.78] years; 53 [53%] female) and 60 family members of known pathogenic variant carriers who did not carry the pathogenic variant (mean [SD] age, 47.51 [12.43] years; 36 [60%] female). MAPT and GRN pathogenic variants were associated with increased rates of volume loss compared with controls at all stages of disease. In MAPT pathogenic variant carriers, statistically significant regions of accelerated volume loss compared with controls were identified in temporal regions bilaterally in the presymptomatic stage, with global spread in the symptomatic stage. For example, mean [SD] rates of atrophy in the left temporal were -231 [47] mm3 per year during the presymptomatic stage, -381 [208] mm3 per year during the mild stage, and -1485 [1025] mm3 per year during the symptomatic stage (P < .05). GRN pathogenic variant carriers generally had minimal increases in atrophy rates between the presymptomatic and mild stages, with rapid increases in atrophy rates in the symptomatic stages. For example, in the right frontal lobes, annualized volume loss was -267 [81] mm3 per year in the presymptomatic stage and -182 [90] mm3 per year in the mild stage, but -1169 [555] mm3 per year in the symptomatic stage. Compared with the other groups, C9orf72 expansion carriers showed minimal increases in rate of volume loss with disease progression. For example, the mean (SD) annualized rates of atrophy in the right frontal lobe in C9orf72 expansion carriers was -272 (118) mm3 per year in presymptomatic stages, -310 (189) mm3 per year in mildly symptomatic stages, and -251 (145) mm3 per year in symptomatic stages.

Conclusions And Relevance: These findings are relevant to clinical trial planning and suggest that the mechanism by which C9orf72 pathogenic variants lead to symptoms may be fundamentally different from the mechanisms associated with other pathogenic variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.22847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593814PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732256PMC
December 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aay8826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818661PMC
November 2020
-->