William W Seeley

Publications (52)329.39 Total impact

• Article: Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS.

  Thomas A Ravenscroft, Matt C Baker, Nicola J Rutherford, Manuela Neumann, Ian R Mackenzie, Keith A Josephs, Bradley F Boeve, Ronald Petersen, Glenda M Halliday, Jillian Kril, John C van Swieten, William W Seeley, Dennis W Dickson, Rosa Rademakers
  [show abstract] [hide abstract]
  ABSTRACT: The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.
  Neurobiology of aging 04/2013; · 5.94 Impact Factor
• Article: Progranulin Mutations as Risk Factors for Alzheimer Disease.

  David C Perry, Manja Lehmann, Jennifer S Yokoyama, Anna Karydas, Jason Jiyong Lee, Giovanni Coppola, Lea T Grinberg, Dan Geschwind, William W Seeley, Bruce L Miller, Howard Rosen, Gil Rabinovici
  [show abstract] [hide abstract]
  ABSTRACT: IMPORTANCE Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review. OBSERVATIONS This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD. CONCLUSIONS AND RELEVANCE In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.
  JAMA neurology. 04/2013;
• Article: The salience network causally influences default mode network activity during moral reasoning.

  Winston Chiong, Stephen M Wilson, Mark D'Esposito, Andrew S Kayser, Scott N Grossman, Pardis Poorzand, William W Seeley, Bruce L Miller, Katherine P Rankin
  [show abstract] [hide abstract]
  ABSTRACT: Large-scale brain networks are integral to the coordination of human behaviour, and their anatomy provides insights into the clinical presentation and progression of neurodegenerative illnesses such as Alzheimer's disease, which targets the default mode network, and behavioural variant frontotemporal dementia, which targets a more anterior salience network. Although the default mode network is recruited when healthy subjects deliberate about 'personal' moral dilemmas, patients with Alzheimer's disease give normal responses to these dilemmas whereas patients with behavioural variant frontotemporal dementia give abnormal responses to these dilemmas. We hypothesized that this apparent discrepancy between activation- and patient-based studies of moral reasoning might reflect a modulatory role for the salience network in regulating default mode network activation. Using functional magnetic resonance imaging to characterize network activity of patients with behavioural variant frontotemporal dementia and healthy control subjects, we present four converging lines of evidence supporting a causal influence from the salience network to the default mode network during moral reasoning. First, as previously reported, the default mode network is recruited when healthy subjects deliberate about 'personal' moral dilemmas, but patients with behavioural variant frontotemporal dementia producing atrophy in the salience network give abnormally utilitarian responses to these dilemmas. Second, patients with behavioural variant frontotemporal dementia have reduced recruitment of the default mode network compared with healthy control subjects when deliberating about these dilemmas. Third, a Granger causality analysis of functional neuroimaging data from healthy control subjects demonstrates directed functional connectivity from nodes of the salience network to nodes of the default mode network during moral reasoning. Fourth, this Granger causal influence is diminished in patients with behavioural variant frontotemporal dementia. These findings are consistent with a broader model in which the salience network modulates the activity of other large-scale networks, and suggest a revision to a previously proposed 'dual-process' account of moral reasoning. These findings also characterize network interactions underlying abnormal moral reasoning in frontotemporal dementia, which may serve as a model for the aberrant judgement and interpersonal behaviour observed in this disease and in other disorders of social function. More broadly, these findings link recent work on the dynamic interrelationships between large-scale brain networks to observable impairments in dementia syndromes, which may shed light on how diseases that target one network also alter the function of interrelated networks.
  Brain 04/2013; · 9.46 Impact Factor
• Article: TDP-43 frontotemporal lobar degeneration and autoimmune disease.

  Zachary A Miller, Katherine P Rankin, Neill R Graff-Radford, Leonel T Takada, Virginia E Sturm, Clare M Cleveland, Lindsey A Criswell, Philipp A Jaeger, Trisha Stan, Kristin A Heggeli, [......], Maria Luisa Gorno-Tempini, Adam L Boxer, Howard J Rosen, Joel H Kramer, Giovanni Coppola, Daniel H Geschwind, Rosa Rademakers, William W Seeley, Tony Wyss-Coray, Bruce L Miller
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. OBJECTIVE: To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls. DESIGN: Case control. SETTING: Academic medical centres. PARTICIPANTS: 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels. OUTCOME MEASURES: χ(2) Comparison of autoimmune prevalence and follow-up logistic regression. RESULTS: There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC. CONCLUSIONS: svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.
  Journal of neurology, neurosurgery, and psychiatry 03/2013; · 4.87 Impact Factor
• Article: Neurodegenerative Disease Phenotypes in Carriers of MAPT p.A152T, A Risk Factor for Frontotemporal Dementia Spectrum Disorders and Alzheimer Disease.

  Suzee E Lee, Maria C Tartaglia, Görsev Yener, Sermin Genç, William W Seeley, Pascual Sanchez-Juan, Fermin Moreno, Mario F Mendez, Eric Klein, Rosa Rademakers, [......], Joel H Kramer, Robert O Kenet, Adam L Boxer, Michael D Geschwind, Maria-Luisa Gorno-Tempini, Anna M Karydas, Gil D Rabinovici, Giovanni Coppola, Daniel H Geschwind, Bruce L Miller
  [show abstract] [hide abstract]
  ABSTRACT: Recently, Coppola and colleagues demonstrated that a rare microtubule-associated protein tau (MAPT) sequence variant, c.454G>A (p.A152T) significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer disease (AD) in a screen of 15,369 subjects. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (n=2); 2 patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathologic correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
  Alzheimer disease and associated disorders 03/2013; · 2.88 Impact Factor
• Article: Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia.

  Elise G P Dopper, Serge A R B Rombouts, Lize C Jiskoot, Tom den Heijer, J Roos A de Graaf, Inge de Koning, Anke R Hammerschlag, Harro Seelaar, William W Seeley, Ilya M Veer, Mark A van Buchem, Patrizia Rizzu, John C van Swieten
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE: We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations. METHODS: In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex. RESULTS: Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found. CONCLUSIONS: This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.
  Neurology 02/2013; · 8.31 Impact Factor
• Article: Frontotemporal dementia in eight Chinese individuals.

  Steven Z Chao, Howard J Rosen, Virgina Azor, Hilary Ong, Marian M Tse, Ngan Betty Lai, Craig E Hou, William W Seeley, Bruce L Miller, Brandy R Matthews
  [show abstract] [hide abstract]
  ABSTRACT: Frontotemporal dementia (FTD) has rarely been reported in Chinese populations. There are many potential reasons for this, including possible hesitancy on the part of patients or families to bring FTD-related symptoms to medical attention. Here, we present data on eight Chinese individuals, all of whom met criteria for the behavioral variant of FTD or the semantic variant of primary progressive aphasia. These patients presented for neurological evaluation at a relatively advanced stage. The mean MMSE score at initial presentation was 15. Behavioral symptoms were common and usually elicited during the medical history only after direct questioning. Delay in presentation was attributed to a variety of issues, including family disagreements about whether the symptoms represented a disease and lack of medical insurance. These cases illustrate that the symptoms of FTD in Chinese-Americans are similar to those in Caucasians but various factors, some potentially culturally relevant, may influence the likelihood and timing of clinical presentation for FTD, as well as other dementias. Additional study of FTD in diverse ethnic groups needs to address barriers to clinical presentation, including factors that may be culturally specific.
  Neurocase 02/2013; 19(1):76-84. · 1.11 Impact Factor
• Article: Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation.

  Lea Tenenholz Grinberg, Xuehua Wang, Chao Wang, Peter Dongmin Sohn, Panos Theofilas, Manu Sidhu, John Benjamin Arevalo, Helmut Heinsen, Eric J Huang, Howard Rosen, Bruce L Miller, Li Gan, William W Seeley
  [show abstract] [hide abstract]
  ABSTRACT: Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau's ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.
  Acta Neuropathologica 01/2013; · 9.32 Impact Factor
• Article: Intrinsic connectivity network disruption in progressive supranuclear palsy.

  Raquel C Gardner, Adam L Boxer, Andrew Trujillo, Jacob B Mirsky, Christine C Guo, Efstathios D Gennatas, Hilary W Heuer, Eric Fine, Juan Zhou, Joel H Kramer, Bruce L Miller, William W Seeley
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE: Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP. METHODS: Using task-free functional magnetic resonance imaging, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region that shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity. RESULTS: Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletomotor, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within corticosubcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores. INTERPRETATION: This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes. Ann Neurol 2013;
  Annals of Neurology 01/2013; · 11.09 Impact Factor
• Article: Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer's disease.

  Manja Lehmann, Pia M Ghosh, Cindee Madison, Robert Laforce, Chiara Corbetta-Rastelli, Michael W Weiner, Michael D Greicius, William W Seeley, Maria L Gorno-Tempini, Howard J Rosen, Bruce L Miller, William J Jagust, Gil D Rabinovici
  [show abstract] [hide abstract]
  ABSTRACT: The factors driving clinical heterogeneity in Alzheimer's disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer's disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer's disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer's disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing-Alzheimer's Association criteria for probable Alzheimer's disease and showed evidence of amyloid deposition on (11)C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of (18)F-labelled fluorodeoxyglucose and (11)C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer's disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer's disease clinical groups showed syndrome-specific (18)F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer's disease variants showed diffuse patterns of (11)C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer's disease. The seed region of interest covariance analysis revealed distinct (18)F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer's disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, (11)C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, (18)F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer's disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer's disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer's disease and logopenic variant primary progressive aphasia), with a trend towards lower (18)F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in (11)C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer's disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer's disease.
  Brain 01/2013; · 9.46 Impact Factor
• Article: Neuropsychological, behavioral, and anatomical evolution in right temporal variant frontotemporal dementia: A longitudinal and post-mortem single case analysis.

  Maya L Henry, Stephen M Wilson, Jennifer M Ogar, Manu S Sidhu, Katherine P Rankin, Tatiana Cattaruzza, Bruce L Miller, Maria Luisa Gorno-Tempini, William W Seeley
  [show abstract] [hide abstract]
  ABSTRACT: We describe a patient with semantic variant of frontotemporal dementia who received longitudinal clinical evaluations and structural MRI scans and subsequently came to autopsy. She presented with early behavior changes and semantic loss for foods and people and ultimately developed a pervasive semantic impairment affecting social-emotional as well as linguistic domains. Imaging revealed predominant atrophy of the right temporal lobe, with later involvement of the left, and pathology confirmed bilateral temporal involvement. Findings support the view that left and right anterior temporal lobes serve as semantic hubs that may be affected differentially in semantic variant by early, relatively unilateral damage.
  Neurocase 11/2012; · 1.11 Impact Factor
• Article: Introduction to the special issue on connectivity.

  Michael D Greicius, William W Seeley
  NeuroImage 10/2012; 62(4):2181. · 5.89 Impact Factor
• Source

  Available from: Kathryn Volkening

  Article: Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype.

  Nicola J Rutherford, Michael G Heckman, Mariely Dejesus-Hernandez, Matt C Baker, Alexandra I Soto-Ortolaza, Sruti Rayaprolu, Heather Stewart, Elizabeth Finger, Kathryn Volkening, William W Seeley, [......], Michael J Strong, Bruce L Miller, Bradley F Boeve, Ryan J Uitti, Kevin B Boylan, Zbigniew K Wszolek, Neill R Graff-Radford, Dennis W Dickson, Owen A Ross, Rosa Rademakers
  [show abstract] [hide abstract]
  ABSTRACT: Expansions of the noncoding GGGGCC hexanucleotide repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study we aimed to determine whether the length of the normal-unexpanded-allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS, and 160 FTD-ALS patients, and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or nonmutation carriers.
  Neurobiology of aging 07/2012; 33(12):2950.e5-7. · 5.94 Impact Factor
• Article: Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels.

  Jessica S Damoiseaux, William W Seeley, Juan Zhou, William R Shirer, Giovanni Coppola, Anna Karydas, Howard J Rosen, Bruce L Miller, Joel H Kramer, Michael D Greicius
  [show abstract] [hide abstract]
  ABSTRACT: We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.
  Journal of Neuroscience 06/2012; 32(24):8254-62. · 7.11 Impact Factor
• Article: Behavioral Variant Frontotemporal Dementia with Corticobasal Degeneration Pathology: Phenotypic Comparison to bvFTD with Pick’s Disease

  Katherine P. Rankin, Mary Catherine Mayo, William W. Seeley, Suzee Lee, Gil Rabinovici, Maria Luisa Gorno-Tempini, Adam L. Boxer, Michael W. Weiner, John Q. Trojanowski, Stephen J. DeArmond, Bruce L. Miller
  [show abstract] [hide abstract]
  ABSTRACT: Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer’s-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed clinical characterization. All patients with CBD pathology and clinical assessment were reviewed (N = 17) and selected if they initially met criteria for bvFTD [bvFTD(CBD), N = 5]. Available bvFTD patients with Pick’s [bvFTD(Pick’s), N = 5] were selected as controls. Patients were also compared to healthy older controls [N = 53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick’s). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick’s) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal > ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick’s) patients. Despite a remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick’s disease neuropathology. KeywordsCorticobasal degeneration–Frontotemporal dementia–Behavior–Neuropsychiatry–Neuropsychology–Neuropathology
  Journal of Molecular Neuroscience 04/2012; 45(3):594-608. · 2.50 Impact Factor
• Article: Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick's disease pathology.

  Francesca Caso, Benno Gesierich, Maya Henry, Manu Sidhu, Amanda Lamarre, Miranda Babiak, Bruce L Miller, Gil D Rabinovici, Eric J Huang, William W Seeley, Maria Luisa Gorno-Tempini
  [show abstract] [hide abstract]
  ABSTRACT: The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick's disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer's disease (AD) (CERAD frequent/Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome.
  Behavioural neurology 04/2012; · 1.77 Impact Factor
• Article: ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease.

  Keith A Vossel, Nga Bien-Ly, Aubrey Bernardo, Katya Rascovsky, Anna Karydas, Gil D Rabinovici, Manu Sidhu, Eric J Huang, Bruce L Miller, Yadong Huang, William W Seeley
  [show abstract] [hide abstract]
  ABSTRACT: Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ε4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ε4 homozygote and an apoE ε3 homozygote. The apoE ε4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ε4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.
  Neurocase 04/2012; · 1.11 Impact Factor
• Article: Sporadic corticobasal syndrome due to FTLD-TDP

  Maria Carmela Tartaglia, Manu Sidhu, Victor Laluz, Caroline Racine, Gil D. Rabinovici, Kelly Creighton, Anna Karydas, Rosa Rademakers, Eric J. Huang, Bruce L. Miller, Stephen J. DeArmond, William W. Seeley
  [show abstract] [hide abstract]
  ABSTRACT: Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS. KeywordsCorticobasal degeneration-TDP-43-Frontotemporal lobar degeneration-Progranulin
  Acta Neuropathologica 04/2012; 119(3):365-374. · 9.32 Impact Factor
• Article: Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion.

  Baber K Khan, Jennifer S Yokoyama, Leonel T Takada, Sharon J Sha, Nicola J Rutherford, Jamie C Fong, Anna M Karydas, Teresa Wu, Robin S Ketelle, Matthew C Baker, [......], Giovanni Coppola, Daniel H Geschwind, Rosa Rademakers, Suzee E Lee, Howard J Rosen, Gil D Rabinovici, William W Seeley, Katherine P Rankin, Adam L Boxer, Bruce L Miller
  [show abstract] [hide abstract]
  ABSTRACT: Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD 'phenocopies' or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described. 384 patients with an FTD clinical spectrum and Alzheimer's disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls. Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable. C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.
  Journal of neurology, neurosurgery, and psychiatry 04/2012; 83(4):358-64. · 4.87 Impact Factor
• Article: Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease.

  Adam L Boxer, Siobhan Garbutt, William W Seeley, Aria Jafari, Hilary W Heuer, Jacob Mirsky, Joanna Hellmuth, John Q Trojanowski, Erik Huang, Steven DeArmond, John Neuhaus, Bruce L Miller
  [show abstract] [hide abstract]
  ABSTRACT: Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD). To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses. An infrared eye tracker was used to record visually guided saccades to 10° targets and antisaccades in subjects with autopsy-confirmed FTD and subjects with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal controls. Twelve subjects with FTD had an FTLD-TAR DNA-binding protein 43 pathology, 15 had an FTLD-tau pathology, and 1 subject showed an FTLD-fused in sarcoma protein pathology. Receiver operating curve statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry. Memory and Aging Center, Department of Neurology, University of California, San Francisco. A total of 28 subjects with autopsy-confirmed FTD, 10 subjects with autopsy-confirmed AD, and 27 age-matched normal controls. All subjects with FTD or AD were impaired relative to normal controls on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually guided saccade abnormalities. The AD cases displayed prominent increases in horizontal saccade latency that differentiated them from the FTD cases. Impairments in velocity and gain were most severe in individuals with progressive supranuclear palsy but were also present in other tauopathies. By using vertical and horizontal saccade velocity and gain as our measures, we were able to differentiate patients with progressive supranuclear palsy from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume. Decreased visually guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of progressive supranuclear palsy.
  Archives of neurology 04/2012; 69(4):509-17. · 6.31 Impact Factor