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Dive into the research topics where Adam L. Boxer is active.

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Featured researches published by Adam L. Boxer.


Neuron | 2011

Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

Mariely DeJesus-Hernandez; Ian R. Mackenzie; Bradley F. Boeve; Adam L. Boxer; Matt Baker; Nicola J. Rutherford; Alexandra M. Nicholson; NiCole Finch; Heather C. Flynn; Jennifer Adamson; Naomi Kouri; Aleksandra Wojtas; Pheth Sengdy; Ging-Yuek Robin Hsiung; Anna Karydas; William W. Seeley; Keith A. Josephs; Giovanni Coppola; Daniel H. Geschwind; Zbigniew K. Wszolek; Howard Feldman; David S. Knopman; Ronald C. Petersen; Bruce L. Miller; Dennis W. Dickson; Kevin B. Boylan; Neill R. Graff-Radford; Rosa Rademakers

Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.


Nature Medicine | 2007

Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins

Sandip Ray; Markus Britschgi; Charles Herbert; Yoshiko Takeda-Uchimura; Adam L. Boxer; Kaj Blennow; Leah Friedman; Douglas Galasko; Marek Jutel; Anna Karydas; Jeffrey Kaye; Jerzy Leszek; Bruce L. Miller; Lennart Minthon; Joseph F. Quinn; Gil D. Rabinovici; William H. Robinson; Marwan N. Sabbagh; Yuen T. So; D Larry Sparks; Massimo Tabaton; Jared R. Tinklenberg; Jerome A. Yesavage; Robert Tibshirani; Tony Wyss-Coray

A molecular test for Alzheimers disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimers and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimers disease 2–6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimers disease.


Neurology | 2013

Criteria for the diagnosis of corticobasal degeneration.

Melissa J. Armstrong; Irene Litvan; Anthony E. Lang; Thomas H. Bak; Kailash P. Bhatia; Barbara Borroni; Adam L. Boxer; Dennis W. Dickson; Murray Grossman; Mark Hallett; Keith A. Josephs; Andrew Kertesz; Suzee E. Lee; Bruce L. Miller; Stephen G. Reich; David E. Riley; Eduardo Tolosa; Alexander I. Tröster; Marie Vidailhet; William J. Weiner

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.


Acta Neuropathologica | 2013

Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons

Sandra Almeida; Eduardo Gascon; Helene Tran; Hsin Jung Chou; Tania F. Gendron; Steven R. DeGroot; Andrew R. Tapper; Chantal Sellier; Nicolas Charlet-Berguerand; Anna Karydas; William W. Seeley; Adam L. Boxer; Leonard Petrucelli; Bruce L. Miller; Fen-Biao Gao

The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had >1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.


Annals of Neurology | 2011

Clinicopathological correlations in corticobasal degeneration.

Suzee E. Lee; Gil D. Rabinovici; Mary Catherine Mayo; Stephen M. Wilson; William W. Seeley; Stephen J. DeArmond; Eric J. Huang; John Q. Trojanowski; Matthew E. Growdon; Jung Y. Jang; Manu Sidhu; Tricia See; Anna Karydas; Maria Luisa Gorno-Tempini; Adam L. Boxer; Michael W. Weiner; Michael D. Geschwind; Katherine P. Rankin; Bruce L. Miller

To characterize cognitive and behavioral features, physical findings, and brain atrophy patterns in pathology‐proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology.


Journal of Neurology, Neurosurgery, and Psychiatry | 2011

Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

Adam L. Boxer; Ian R. Mackenzie; Bradley F. Boeve; Matt Baker; William W. Seeley; Richard Crook; Howard Feldman; Ging Yuek R Hsiung; Nicola J. Rutherford; Victor Laluz; Jennifer L. Whitwell; Dean Foti; Eric McDade; Jennifer R. Molano; Anna Karydas; Aleksandra Wojtas; Jill S. Goldman; Jacob Mirsky; Pheth Sengdy; Stephen J. DeArmond; Bruce L. Miller; Rosa Rademakers

Background Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS. Methods The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20. Results Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS. Conclusions Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.


Neurology | 2005

Comparison of family histories in FTLD subtypes and related tauopathies

Jill Goldman; Jennifer M. Farmer; Elisabeth McCarty Wood; Julene K. Johnson; Adam L. Boxer; John Neuhaus; Catherine Lomen-Hoerth; Kirk C. Wilhelmsen; Virginia M.-Y. Lee; Murray Grossman; Bruce L. Miller

Pedigrees from 269 patients with frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), FTD with ALS (FTD/ALS), progressive nonfluent aphasia, semantic dementia (SD), corticobasal degeneration, and progressive supranuclear palsy were analyzed to determine the degree of heritability of these disorders. FTD/ALS was the most and SD the least heritable subtype. FTLD syndromes appear to have different etiologies and recurrence risks.


Alzheimers & Dementia | 2015

Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study

Massimo S. Fiandaca; Dimitrios Kapogiannis; Mark Mapstone; Adam L. Boxer; Erez Eitan; Janice B. Schwartz; Erin L. Abner; Ronald C. Petersen; Howard J. Federoff; Bruce L. Miller; Edward J. Goetzl

Proteins pathogenic in Alzheimers disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD.


Lancet Neurology | 2014

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial

Adam L. Boxer; Anthony E. Lang; Murray Grossman; David S. Knopman; Bruce L. Miller; Lon S. Schneider; Rachelle S. Doody; Andrew J. Lees; Lawrence I. Golbe; David R. Williams; Jean-Christophe Corvol; Albert C. Ludolph; David J. Burn; Stefan Lorenzl; Irene Litvan; Erik D. Roberson; Günter U. Höglinger; Mary Koestler; Clifford R. Jack; Viviana M. Van Deerlin; Christopher Randolph; Iryna Lobach; Hilary W. Heuer; Illana Gozes; Lesley Parker; Steve Whitaker; Joe Hirman; Alistair Stewart; Michael Gold; Bruce H. Morimoto

BACKGROUND In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. METHODS In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. FINDINGS 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). INTERPRETATION Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. FUNDING Allon Therapeutics.


Movement Disorders | 2017

Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria.

Günter U. Höglinger; Gesine Respondek; Maria Stamelou; Carolin Kurz; Keith A. Josephs; Anthony E. Lang; Brit Mollenhauer; Ulrich Müller; Christer Nilsson; Jennifer L. Whitwell; Thomas Arzberger; Elisabet Englund; Ellen Gelpi; Armin Giese; David J. Irwin; Wassilios G. Meissner; Alexander Pantelyat; Alex Rajput; John C. van Swieten; Claire Troakes; Angelo Antonini; Kailash P. Bhatia; Yaroslau Compta; Jean-Christophe Corvol; Carlo Colosimo; Dennis W. Dickson; Richard Dodel; Leslie W. Ferguson; Murray Grossman; Jan Kassubek

Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardsons syndrome.

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Joel H. Kramer

University of California

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Anna Karydas

University of California

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Murray Grossman

University of Pennsylvania

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