John Q Trojanowski

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (992)6736.97 Total impact

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    ABSTRACT: A series of derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonists, 3-(6-((4-chlorophenyl)sulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid and 3-(3-(2-((4-chlorophenyl)sulfonamido)ethyl)phenyl) propanoic acid, were synthesized in which the carboxylic acid functional group was replaced with substituted cyclopentane-1,3-dione (CPD) bioisosteres. Characterization of these molecules led to the discovery of remarkably potent new analogues, some of which were considerably more active than the corresponding parent carboxylic acid compounds. Depending on the choice of the C2 substituent of the CPD unit, these new derivatives can produce either a reversible or an apparent irreversible inhibition of the human TP receptor. Given the potency and the long-lasting inhibition of TP receptor signaling, these novel antagonists may comprise promising leads for the development of antithromboxane therapies.
    ACS Medicinal Chemistry Letters 09/2014; 5(9):1015-20. · 3.31 Impact Factor
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    ABSTRACT: Neurofibrillary tangles composed of hyperphosphorylated fibrillized tau are found in numerous tauopathies including Alzheimer's Disease. Increasing evidence suggests that tau pathology can be transmitted from cell-to-cell, however the mechanisms involved in the initiation of tau fibrillization and spreading of disease linked to progression of tau pathology are poorly understood. We show here that intracerebral injections of preformed synthetic tau fibrils into the hippocampus or frontal cortex of young tau transgenic mice expressing mutant human P301L tau induces tau hyperphosphorylation and aggregation around the site of injection, as well as a time-dependent propagation of tau pathology to interconnected brain areas distant from the injection site. Furthermore, we show that the tau pathology as a consequence of injection of tau preformed fibrils into the hippocampus induces selective loss of CA1 neurons. Together, our data confirm previous studies on the seeded induction and the spreading of tau pathology in a different tau transgenic mouse model and reveals neuronal loss associated with seeded tau pathology in tau transgenic mouse brain. These results further validate the utility of the tau seeding model in studying disease transmission, and provide a more complete in vivo tauopathy model with associated neurodegeneration which can be used to investigate the mechanisms involved in tau aggregation and spreading, as well as aid in the search for disease modifying treatments for Alzheimer's Disease and related tauopathies.
    Neurobiology of Disease 09/2014; · 5.62 Impact Factor
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    ABSTRACT: Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.
    JAMA Neurology 09/2014; · 7.58 Impact Factor
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    ABSTRACT: Neuronal insulin signaling abnormalities have been associated with Alzheimer's disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS(616), IRS1-pS(312) and downstream target Akt-pS(473) measures were most elevated in AD but were also significantly increased in the tauopathies: Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS(616) with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS(616) expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS(616) frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-β.
    Acta neuropathologica. 08/2014;
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    ABSTRACT: The goal of this study was to identify factors contributing to hippocampal atrophy rate (HAR) in clinically normal older adults (NC) and participants with mild cognitive impairment (MCI). Longitudinal HAR was measured on T1-weighted magnetic resonance imaging, and the contribution of age, gender, apolipoprotein E (ApoE) ε4 status, intracranial volume, white matter lesions, and β-amyloid (Aβ) levels to HAR was determined using linear regression. Age-related effects of HAR were compared in Aβ positive (Aβ+) and Aβ negative (Aβ-) participants. Age and Aβ levels had independent effects on HAR in NC, whereas gender, ApoE ε4 status, and Aβ levels were associated with HAR in MCI. In multivariable models, Aβ levels were associated with HAR in NC; ApoE ε4 and Aβ levels were associated with HAR in MCI. In MCI, age was a stronger predictor of HAR in Aβ- versus Aβ+ participants. HAR was higher in Aβ+ participants, but most of the HAR was because of factors other than Aβ status. Age-related effects on HAR did not differ between NC versus MCI participants with the same Aβ status. Therefore, we conclude that even when accounting for other covariates, Aβ status, and not age, is a significant predictor of HAR; and that most of the HAR is not accounted for by Aβ status in either NC or MCI.
    Neurobiology of aging. 08/2014;
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    ABSTRACT: Cycloalkylpolyones hold promise in drug design as carboxylic acid bio-isosteres. To investigate cyclopentane-1,2-diones as potential surrogates of the carboxylic acid functional group, the acidity, tautomerism, and geometry of hydrogen bonding of representative compounds were evaluated. Prototypic derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonist, 3-(3-(2-((4-chlorophenyl)sulfonamido)-ethyl)phenyl)propanoic acid, in which the carboxylic acid moiety is replaced by the cyclopentane-1,2-dione unit, were synthesized and evaluated as TP receptor antagonists. Cyclopentane-1,2-dione derivative 9 was found to be a potent TP receptor antagonist with an IC50 value comparable to that of the parent carboxylic acid. These results indicate that the cyclopentane-1,2-dione may be a potentially useful carboxylic acid bio-isostere.
    Bioorganic & medicinal chemistry letters. 07/2014;
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    ABSTRACT: Alzheimer's disease, which is defined pathologically by abundant amyloid plaques and neurofibrillary tangles concurrent with synaptic and neuronal loss, is the most common underlying cause of dementia in the elderly. Among the oldest-old, those aged 90 and older, other ageing-related brain pathologies are prevalent in addition to Alzheimer's disease, including cerebrovascular disease and hippocampal sclerosis. Although definite Alzheimer's disease pathology can distinguish dementia from normal individuals, the pathologies underlying cognitive impairment, especially in the oldest-old, remain poorly understood. We therefore conducted studies to determine the relative contributions of Alzheimer's disease pathology, cerebrovascular disease, hippocampal sclerosis and the altered expression of three synaptic proteins to cognitive status and global cognitive function. Relative immunohistochemistry intensity measures were obtained for synaptophysin, Synaptic vesicle transporter Sv2 (now known as SV2A) and Vesicular glutamate transporter 1 in the outer molecular layer of the hippocampal dentate gyrus on the first 157 participants of 'The 90+ Study' who came to autopsy, including participants with dementia (n = 84), those with cognitive impairment but no dementia (n = 37) and those with normal cognition (n = 36). Thal phase, Braak stage, cerebrovascular disease, hippocampal sclerosis and Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) were also analysed. All measures were obtained blind to cognitive diagnosis. Global cognition was tested by the Mini-Mental State Examinaton. Logistic regression analysis explored the association between the pathological measures and the odds of being in the different cognitive groups whereas multiple regression analyses explored the association between pathological measures and global cognition scores. No measure clearly distinguished the control and cognitive impairment groups. Comparing the cognitive impairment and dementia groups, synaptophysin and SV2 were reduced, whereas Braak stage, TDP-43 and hippocampal sclerosis frequency increased. Thal phase and VGLUT1 did not distinguish the cognitive impairment and dementia groups. All measures distinguished the dementia and control groups and all markers associated with the cognitive test scores. When all markers were analysed simultaneously, a reduction in synaptophysin, a high Braak stage and the presence of TDP-43 and hippocampal sclerosis associated with global cognitive function. These findings suggest that tangle pathology, hippocampal sclerosis, TDP-43 and perforant pathway synaptic loss are the major contributors to dementia in the oldest-old. Although an increase in plaque pathology and glutamatergic synaptic loss may be early events associated with cognitive impairment, we conclude that those with cognitive impairment, but no dementia, are indistinguishable from cognitively normal subjects based on the measures reported here.
    Brain : a journal of neurology. 07/2014;
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    ABSTRACT: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD).METHODS: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37).RESULTS: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p = 0.04) but not with TDP-43 proteinopathies (p > 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p < 0.01). MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p < 0.01).CONCLUSIONS: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings.
    Neurology 07/2014; · 8.25 Impact Factor
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    ABSTRACT: Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies.
    Journal of medicinal chemistry. 07/2014;
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    ABSTRACT: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD
    The Lancet Neurology 07/2014; 3(7):686-99. · 23.92 Impact Factor
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    ABSTRACT: Background Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance.Methods We examined healthy controls (CN, N = 169) versus AD dementia patients (N = 118), and stable (sMCI; no dementia, followed up for at least 2 years, N = 165) versus progressive MCI (pMCI; conversion to AD dementia, N = 59). All subjects had florbetapir PET (global and regional; temporal, frontal, parietal, and cingulate) and CSF Aβ42 measurements at baseline. We compared area under the curve (AUC), sensitivity, and specificity (testing a priori and optimized cutoffs). Clinical diagnosis was the reference standard.ResultsCSF Aβ42 and (global or regional) PET florbetapir did not differ in AUC (CN vs. AD, CSF 84.4%; global PET 86.9%; difference [95% confidence interval] −6.7 to 1.5). CSF Aβ42 and global PET florbetapir did not differ in sensitivity, but PET had greater specificity than CSF in most comparisons. Sixteen CN progressed to MCI and AD (six Aβ negative, seven Aβ positive, and three PET positive but CSF negative).InterpretationThe overall diagnostic accuracies of CSF Aβ42 and PET florbetapir were similar, but PET had greater specificity. This was because some CN and sMCI subjects appear pathological using CSF but not using PET, suggesting that low CSF Aβ42 not always translates to cognitive decline or brain Aβ accumulation. Other factors, including costs and side effects, may also be considered when determining the optimal modality for different applications.
    Annals of Clinical and Translational Neurology. 07/2014;
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    ABSTRACT: Cognitive impairment, including dementia, is common in Parkinson's disease (PD). The Mini-Mental State Examination (MMSE) has been recommended as a screening tool for Parkinson's disease dementia (PDD), with values below 26 indicative of possible dementia. Using a detailed neuropsychological battery, we examined the range of cognitive impairment in PD patients with an MMSE score of 26 or higher. In this multicenter, cross-sectional, observational study, we performed neuropsychological testing in a sample of 788 PD patients with MMSE scores of 26 or higher. Evaluation included tests of global cognition, executive function, language, memory, and visuospatial skills. A consensus panel reviewed results for 342 subjects and assigned a diagnosis of no cognitive impairment, mild cognitive impairment, or dementia. Sixty-seven percent of the 788 subjects performed 1.5 standard deviations below the normative mean on at least one test. On eight of the 15 tests, more than 20% of subjects scored 1.5 standard deviations or more below the normative mean. Greatest impairments were found on Hopkins Verbal Learning and Digit Symbol Coding tests. The sensitivity of the MMSE to detect dementia was 45% in a subset of participants who underwent clinical diagnostic procedures. A remarkably wide range of cognitive impairment can be found in PD patients with a relatively high score on the MMSE, including a level of cognitive impairment consistent with dementia. Given these findings, clinicians must be aware of the limitations of the MMSE in detecting cognitive impairment, including dementia, in PD. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 07/2014; · 5.63 Impact Factor
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    ABSTRACT: We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf's nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke's column in 30.6 % of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS.
    Acta neuropathologica. 06/2014;
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    ABSTRACT: Current neuropathological Alzheimer's disease (AD) criteria from the National Institute on Aging-Alzheimer's Association (NIA-AA) incorporate two staging systems for Aβ pathology, namely the Thal Aβ phase (TAP) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) methods. The goal of this study was to compare and contrast results obtained with these two different staging systems for Aβ pathology since this is critical for future correlations of Aβ amyloid imaging data with Aβ neuropathology data based on immunohistochemical detection of Aβ deposits. A total of 123 cases, divided into 82 training and 41 validation cases, with a diagnosis of either unremarkable adult brain (normal) or AD and CERAD scores ranging from none to frequent were included. There was no clear and consistent relationship between CERAD and the TAP Aβ scores with the exception of scores for the highest plaque burdens (i.e., CERAD C3 and TAP A3) in the cases studied here. However, we developed an algorithm that relates CERAD scores to TAP scores with high agreement (94 % in training and 98 % in the validation set). In addition, TAP scores were a better predictor of dementia (sensitivity of 94 % specificity 87.7 %) than CERAD scores (sensitivity of 57 % specificity 100 %). Yet, further research is needed to define strategies to relate CERAD and TAP Aβ plaque scores to compare their utility and for determining the clinical associations of these different amyloid staging systems with aging and AD.
    Acta neuropathologica. 06/2014;
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    ABSTRACT: Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.
    Cell reports. 06/2014;
  • Amyotrophic lateral sclerosis & frontotemporal degeneration. 05/2014;
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    ABSTRACT: Alexander disease (AxD) is a rare neurodegenerative disorder characterized pathologically by the presence of eosinophilic inclusions known as Rosenthal fibers (RFs) within astrocytes, and is caused by dominant mutations in the coding region of the gene encoding glial fibrillary acidic protein (GFAP). GFAP is the major astrocytic intermediate filament, and in AxD patient brain tissue GFAP is a major component of RFs. TAR DNA binding protein of 43 kDa (TDP-43) is the major pathological protein in almost all cases of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and ∼50% of frontotemporal lobar degeneration (FTLD), designated as FTLD-TDP. In ALS and FTLD-TDP, TDP-43 becomes insoluble, ubiquitinated, and pathologically phosphorylated and accumulates in cytoplasmic inclusions in both neurons and glia of affected brain and spinal cord regions. Previously, TDP-43 was detected in RFs of human pilocytic astrocytomas; however, involvement of TDP-43 in AxD has not been determined. Here we show that TDP-43 is present in RFs in AxD patient brains, and that insoluble phosphorylated full-length and high molecular weight TDP-43 accumulates in white matter of such brains. Phosphorylated TDP-43 also accumulates in the detergent-insoluble fraction from affected brain regions of Gfap(R236H/+) knock-in mice, which harbor a GFAP mutation homologous to one that causes AxD in humans, and TDP-43 colocalizes with astrocytic RF pathology in Gfap(R236H/+) mice and transgenic mice overexpressing human wild-type GFAP. These findings suggest common pathogenic mechanisms in ALS, FTLD, and AxD, and this is the first report of TDP-43 involvement in a neurological disorder primarily affecting astrocytes.
    Journal of Neuroscience 05/2014; 34(19):6448-58. · 6.91 Impact Factor
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    ABSTRACT: IMPORTANCE The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. OBJECTIVE To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. DESIGN, SETTING, AND PARTICIPANTS Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive. MAIN OUTCOMES AND MEASURES Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models. RESULTS Baseline gray matter volumes were similar among the CN Aβ groups, but atrophy rates were increased in frontoparietal regions in the declining Aβ-negative and Aβ-positive groups and in amygdala and temporal regions in the Aβ-positive group. Aβ-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions. CONCLUSIONS AND RELEVANCE Emerging Aβ pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage Aβ pathology may have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD.
    JAMA neurology. 04/2014;
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    ABSTRACT: PET imaging of amyloid-beta (Abeta) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Abeta pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Abeta pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Abeta (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies. Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result. Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.
    Acta neuropathologica communications. 04/2014; 2(1):46.
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    ABSTRACT: Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.
    Journal of neuropathology and experimental neurology. 04/2014;

Publication Stats

59k Citations
6,736.97 Total Impact Points

Institutions

  • 1990–2014
    • University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Radiology
      • • Department of Neurosurgery
      • • Department of Psychiatry
      • • Department of Pathology
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 1983–2014
    • Hospital of the University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Neurology
      • • Department of Neurosurgery
      Philadelphia, Pennsylvania, United States
  • 2013
    • Regis University
      • School of Pharmacy
      Denver, Colorado, United States
    • Mayo Clinic - Rochester
      • Department of Neurology
      Rochester, Minnesota, United States
    • Inha University Hospital
      Sinhyeon, South Gyeongsang, South Korea
    • Lawrence Berkeley National Laboratory
      Berkeley, California, United States
    • St. Jude Children's Research Hospital
      Memphis, Tennessee, United States
    • Duke University
      Durham, North Carolina, United States
    • Universität Ulm
      • Division of Neurophysiology
      Ulm, Baden-Württemberg, Germany
  • 2011–2013
    • Emory University
      • Department of Neurology
      Atlanta, Georgia, United States
    • Mayo Foundation for Medical Education and Research
      • Division of Biomedical Statistics and Informatics
      Scottsdale, AZ, United States
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
    • University of California, Berkeley
      • Division of Epidemiology
      Berkeley, MO, United States
    • Overton Brooks VA Medical Center
      Shreveport, Louisiana, United States
  • 2012
    • IRCCS Centro San Giovanni di Dio, Fatebenefratelli, Brescia
      Brescia, Lombardy, Italy
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Stanford University
      • Department of Genetics
      Stanford, CA, United States
    • Stanford Medicine
      Stanford, California, United States
    • Chiba-East National Hospital
      Tiba, Chiba, Japan
  • 2005–2012
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, CA, United States
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2009–2011
    • University of Gothenburg
      • Department of Psychiatry and Neurochemistry
      Göteborg, Vaestra Goetaland, Sweden
    • University of Zurich
      • Institut für Neuropathologie
      Zürich, ZH, Switzerland
    • Monell Chemical Senses Center
      Philadelphia, Pennsylvania, United States
    • Trinity College
      Hartford, Connecticut, United States
  • 2007–2011
    • University of British Columbia - Vancouver
      • Department of Pathology and Laboratory Medicine
      Vancouver, British Columbia, Canada
  • 1996–2011
    • The University of Tokyo
      • • Faculty & Graduate School of Medicine
      • • Department of Pharmaceutical Sciences
      Tokyo, Tokyo-to, Japan
  • 2010
    • University of California, San Diego
      • Department of Neurosciences
      San Diego, CA, United States
    • University of Washington Seattle
      • International Clinical Research Center (ICRC)
      Seattle, WA, United States
    • United States Department of Veterans Affairs
      Bedford, Massachusetts, United States
  • 2009–2010
    • University of California, Los Angeles
      • • Department of Neurology
      • • Laboratory of Neuro Imaging
      Los Angeles, CA, United States
  • 2007–2010
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States
  • 2004–2009
    • Drexel University College of Medicine
      • Department of Neurology
      Philadelphia, PA, United States
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • Erasmus MC
      • Department of Clinical Genetics
      Rotterdam, South Holland, Netherlands
  • 2008
    • Vancouver General Hospital
      • Department of Pathology and Laboratory Medicine (UBC)
      Vancouver, British Columbia, Canada
  • 2007–2008
    • Ludwig-Maximilian-University of Munich
      • Center for Neuropathology and Prion Research
      München, Bavaria, Germany
  • 2000–2007
    • Carl von Ossietzky Universität Oldenburg
      Oldenburg, Lower Saxony, Germany
  • 2006
    • Elan Pharmaceuticals
      Dublin, Leinster, Ireland
    • Avid Radiopharmaceuticals
      Philadelphia, Pennsylvania, United States
  • 2004–2006
    • National Institute on Aging
      Baltimore, Maryland, United States
  • 1985–2006
    • The Children's Hospital of Philadelphia
      • • Department of Pathology and Laboratory Medicine
      • • Department of Neurology
      Philadelphia, PA, United States
  • 1997–2004
    • Washington University in St. Louis
      • • Knight Alzheimer's Disease Research Center (ADRC)
      • • Department of Neurology
      San Luis, Missouri, United States
    • State University of New York Downstate Medical Center
      • Department of Pathology
      Brooklyn, NY, United States
  • 2003
    • University of Oklahoma Health Sciences Center
      Oklahoma City, Oklahoma, United States
    • University of Kentucky
      Lexington, Kentucky, United States
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2002
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • Goethe-Universität Frankfurt am Main
      Frankfurt, Hesse, Germany
  • 2001
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      • Neurorianimazione
      Milano, Lombardy, Italy
    • Johns Hopkins University
      • Department of Neurology
      Baltimore, MD, United States
    • Drexel University
      • Department of Neurology
      Philadelphia, Pennsylvania, United States
  • 1998–2000
    • American University of Health Sciences
      United States
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
  • 1999
    • Banner Sun Health Research Institute
      Sun City, Arizona, United States
  • 1995–1998
    • McGill University
      • Centre for Research in Neuroscience
      Montréal, Quebec, Canada
    • Tohoku University
      • Division of Physiological Sciences
      Sendai-shi, Miyagi-ken, Japan
    • The University of Calgary
      Calgary, Alberta, Canada
  • 1989–1998
    • Wistar Institute
      Philadelphia, Pennsylvania, United States
  • 1994–1997
    • National Hospital Organization Kurihama Medical and Addiction Center
      Йокосука, Kanagawa, Japan
    • University of Groningen
      Groningen, Groningen, Netherlands
    • Albert Einstein College of Medicine
      • Department of Pathology
      New York City, NY, United States
  • 1994–1996
    • National Institute on Alcohol Abuse and Alcoholism
      Maryland, United States
  • 1993
    • Georgia Health Sciences University
      • Department of Cellular Biology & Anatomy
      Augusta, GA, United States
  • 1991
    • Duke University Medical Center
      • Department of Pathology
      Durham, NC, United States