Sandra Weintraub

Northwestern University, Evanston, Illinois, United States

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Publications (185)1159 Total impact

  • JAMA Neurology 12/2014; 71(12):1576-1577. · 7.58 Impact Factor
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    ABSTRACT: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
    Molecular Neurodegeneration 09/2014; 9(1):38. · 4.01 Impact Factor
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    ABSTRACT: Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.
    Nature Reviews Neurology 09/2014; · 15.52 Impact Factor
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    ABSTRACT: The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials.
    Neurology 08/2014; · 8.30 Impact Factor
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    ABSTRACT: New strategies are needed to help people cope with the repercussions of neurodegenerative disorders such as Alzheimer's disease. Patients and caregivers face different challenges, but here we investigated an intervention tailored for this combined population. The program focused on training skills such as attending to the present moment nonjudgmentally, which may help reduce maladaptive emotional responses. Patients participated together with caregivers in weekly group sessions over 8 weeks. An assessment battery was individually administered before and after the program. Pre-post analyses revealed several benefits, including increased quality-of-life ratings, fewer depressive symptoms, and better subjective sleep quality. In addition, participants indicated that they were grateful for the opportunity to learn to apply mindfulness skills and that they would recommend the program to others. In conclusion, mindfulness training can be beneficial for patients and their caregivers, it can be delivered at low cost to combined groups, and it is worthy of further investigation.
    American journal of Alzheimer's disease and other dementias. 08/2014;
  • Journal of the American Geriatrics Society 08/2014; 62(8). · 4.22 Impact Factor
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    ABSTRACT: This study introduces a special series on validity studies of the Cognition Battery (CB) from the U.S. National Institutes of Health Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) (Gershon, Wagster et al., 2013) in an adult sample. This first study in the series describes the sample, each of the seven instruments in the NIHTB-CB briefly, and the general approach to data analysis. Data are provided on test-retest reliability and practice effects, and raw scores (mean, standard deviation, range) are presented for each instrument and the gold standard instruments used to measure construct validity. Accompanying papers provide details on each instrument, including information about instrument development, psychometric properties, age and education effects on performance, and convergent and discriminant construct validity. One study in the series is devoted to a factor analysis of the NIHTB-CB in adults and another describes the psychometric properties of three composite scores derived from the individual measures representing fluid and crystallized abilities and their combination. The NIHTB-CB is designed to provide a brief, comprehensive, common set of measures to allow comparisons among disparate studies and to improve scientific communication. (JINS, 2014, 20, 1-12).
    Journal of the International Neuropsychological Society : JINS. 06/2014;
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    ABSTRACT: Language facilitates communication and efficient encoding of thought and experience. Because of its essential role in early childhood development, in educational achievement and in subsequent life adaptation, language was included as one of the subdomains in the NIH Toolbox for the Assessment of Neurological and Behavioral Function Cognition Battery (NIHTB-CB). There are many different components of language functioning, including syntactic processing (i.e., morphology and grammar) and lexical semantics. For purposes of the NIHTB-CB, two tests of language-a picture vocabulary test and a reading recognition test-were selected by consensus based on literature reviews, iterative expert input, and a desire to assess in English and Spanish. NIHTB-CB's picture vocabulary and reading recognition tests are administered using computer adaptive testing and scored using item response theory. Data are presented from the validation of the English versions in a sample of adults ages 20-85 years (Spanish results will be presented in a future publication). Both tests demonstrated high test-retest reliability and good construct validity compared to corresponding gold-standard measures. Scores on the NIH Toolbox measures were consistent with age-related expectations, namely, growth in language during early development, with relative stabilization into late adulthood. (JINS, 2014, 20, 1-10).
    Journal of the International Neuropsychological Society : JINS. 06/2014;
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    ABSTRACT: This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) Composite Scores in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20-85 years), gender, education, and ethnicity. The NIHTB-CB contains seven computer-based instruments assessing five cognitive sub-domains: Language, Executive Function, Episodic Memory, Processing Speed, and Working Memory. Participants completed the NIHTB-CB, corresponding gold standard validation measures selected to tap the same cognitive abilities, and sociodemographic questionnaires. Three Composite Scores were derived for both the NIHTB-CB and gold standard batteries: "Crystallized Cognition Composite," "Fluid Cognition Composite," and "Total Cognition Composite" scores. NIHTB Composite Scores showed acceptable internal consistency (Cronbach's alphas=0.84 Crystallized, 0.83 Fluid, 0.77 Total), excellent test-retest reliability (r: 0.86-0.92), strong convergent (r: 0.78-0.90) and discriminant (r: 0.19-0.39) validities versus gold standard composites, and expected age effects (r=0.18 crystallized, r=-0.68 fluid, r=-0.26 total). Significant relationships with self-reported prior school difficulties and current health status, employment, and presence of a disability provided evidence of external validity. The NIH Toolbox Cognition Battery Composite Scores have excellent reliability and validity, suggesting they can be used effectively in epidemiologic and clinical studies. (JINS, 2014, 20, 1-11).
    Journal of the International Neuropsychological Society 06/2014; · 2.70 Impact Factor
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    ABSTRACT: This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) executive function measures in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20-85 years), gender, education and ethnicity. The NIHTB-CB contains two computer-based instruments assessing executive function: the Dimensional Change Card Sort (a measure of cognitive flexibility) and a flanker task (a measure of inhibitory control and selective attention). Participants completed the NIHTB-CB, corresponding gold standard convergent and discriminant measures, and sociodemographic questionnaires. A subset of participants (N=89) was retested 7 to 21 days later. Results reveal excellent sensitivity to age-related changes during adulthood, excellent test-retest reliability, and adequate to good convergent and discriminant validity. The NIH Toolbox EF measures can be used effectively in epidemiologic and clinical studies. (JINS, 2014, 20, 1-10).
    Journal of the International Neuropsychological Society : JINS. 06/2014;
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    ABSTRACT: The NIH Toolbox (NIHTB) Pattern Comparison Processing Speed Test was developed to assess processing speed within the NIHTB for the Assessment of Neurological Behavior and Function Cognition Battery (NIHTB-CB). This study highlights validation data collected in adults ages 18-85 on this measure and reports descriptive data, test-retest reliability, construct validity, and preliminary work creating a composite index of processing speed. Results indicated good test-retest reliability. There was also evidence for both convergent and discriminant validity; the Pattern Comparison Processing Speed Test demonstrated moderate significant correlations with other processing speed tests (i.e., WAIS-IV Coding, Symbol Search and Processing Speed Index), small significant correlations with measures of working memory (i.e., WAIS-IV Letter-Number Sequencing and PASAT), and non-significant correlations with a test of vocabulary comprehension (i.e., PPVT-IV). Finally, analyses comparing and combining scores on the NIHTB Pattern Comparison Processing Speed Test with other measures of simple reaction time from the NIHTB-CB indicated that a Processing Speed Composite score performed better than any test examined in isolation. The NIHTB Pattern Comparison Processing Speed Test exhibits several strengths: it is appropriate for use across the lifespan (ages, 3-85 years), it is short and easy to administer, and it has high construct validity. (JINS, 2014, 20, 1-12).
    Journal of the International Neuropsychological Society 06/2014; · 2.70 Impact Factor
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    ABSTRACT: Episodic memory is one of the most important cognitive domains that involves acquiring, storing and recalling new information. In this article, we describe a new measure developed for the NIH Toolbox, called the Picture Sequence Memory Test (PSMT) that is the first to examine episodic memory across the age range from 3 to 85. We describe the development of the measure and present validation data for ages 20 to 85. The PSMT involves presentation of sequences of pictured objects and activities in a fixed order on a computer screen and simultaneously verbally described, that the participant must remember and then reproduce over three learning trials. The results indicate good test-retest reliability and construct validity. Performance is strongly related to well-established "gold standard" measures of episodic memory and, as expected, much less well correlated with those of a measure of vocabulary. It shows clear decline with aging in parallel with a gold standard summary measure and relates to several other demographic factors and to self-reported general health status. The PSMT appears to be a reliable and valid test of episodic memory for adults, a finding similar to those found for the same measure with children. (JINS, 2014, 20, 1-9).
    Journal of the International Neuropsychological Society : JINS. 06/2014;
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    ABSTRACT: Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated 4 genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1), and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 control subjects, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1, or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% vs. 0% in control subjects, p = 0.013), whereas the frequency in probands with FTD was identical to control subjects. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.
    Neurobiology of aging. 05/2014;
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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;
  • Neuropathology and Applied Neurobiology 04/2014; · 4.84 Impact Factor
  • M-Marsel Mesulam, Sandra Weintraub
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    ABSTRACT: Hair-splitting details of syndromic classification can hardly be expected to attract much attention. As in all areas of science, however, sound nosology and uniform nomenclature are important for progress in neurology. This is particularly true for the neurodegenerative syndromes, including primary progressive aphasia (PPA), where heterogeneity of phenotype and cellular pathology has defied attempts to coherent clinicopathologic correlations.
    Neurology 03/2014; · 8.30 Impact Factor
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    ABSTRACT: Fifty-eight autopsies of patients with primary progressive aphasia are reported. Twenty-three of these were previously described (Mesulam et al., 2008) but had their neuropathological diagnoses updated to fit current criteria. Thirty-five of the cases are new. Their clinical classification was guided as closely as possible by the 2011 consensus guidelines (Gorno-Tempini et al., 2011). Tissue diagnoses included Alzheimer's disease in 45% and frontotemporal lobar degeneration (FTLD) in the others, with an approximately equal split between TAR DNA binding protein 43 proteinopathies and tauopathies. The most common and distinctive feature for all pathologies associated with primary progressive aphasia was the asymmetric prominence of atrophy, neuronal loss, and disease-specific proteinopathy in the language-dominant (mostly left) hemisphere. The Alzheimer's disease pathology in primary progressive aphasia displayed multiple atypical features. Males tended to predominate, the neurofibrillary pathology was more intense in the language-dominant hemisphere, the Braak pattern of hippocampo-entorhinal prominence was tilted in favour of the neocortex, and the APOE e4 allele was not a risk factor. Mean onset age was under 65 in the FTLD as well as Alzheimer's disease groups. The FTLD-TAR DNA binding protein 43 group had the youngest onset and fastest progression whereas the Alzheimer's disease and FTLD-tau groups did not differ from each other in either onset age or progression rate. Each cellular pathology type had a preferred but not invariant clinical presentation. The most common aphasic manifestation was of the logopenic type for Alzheimer pathology and of the agrammatic type for FTLD-tau. The progressive supranuclear palsy subtype of FTLD-tau consistently caused prominent speech abnormality together with agrammatism whereas FTLD-TAR DNA binding protein 43 of type C consistently led to semantic primary progressive aphasia. The presence of agrammatism made Alzheimer's disease pathology very unlikely whereas the presence of a logopenic aphasia or word comprehension impairment made FTLD-tau unlikely. The association of logopenic primary progressive aphasia with Alzheimer's disease pathology was much more modest than has been implied by results of in vivo amyloid imaging studies. Individual features of the aphasia, such as agrammatism and comprehension impairment, were as informative of underlying pathology as more laborious subtype diagnoses. At the single patient level, no clinical pattern was pathognomonic of a specific neuropathology type, highlighting the critical role of biomarkers for diagnosing the underlying disease. During clinical subtyping, some patients were unclassifiable by the 2011 guidelines whereas others simultaneously fit two subtypes. Revisions of criteria for logopenic primary progressive aphasia are proposed to address these challenges.
    Brain 02/2014; · 10.23 Impact Factor
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    ABSTRACT: Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
    Acta Neuropathologica 01/2014; · 9.73 Impact Factor
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    ABSTRACT: The molecular basis of selective neuronal vulnerability in Alzheimer's disease (AD) remains poorly understood. Using basal forebrain cholinergic neurons (BFCNs) as a model and immunohistochemistry, we have demonstrated significant age-related loss of the calcium-binding protein calbindin-D28K (CB) from BFCN, which was associated with tangle formation and degeneration in AD. Here, we determined alterations in RNA and protein for CB and the Ca(2+)-responsive proteins Ca(2+)/calmodulin-dependent protein kinase I (CaMKI), growth-associated protein-43 (GAP43), and calpain in the BF. We observed progressive downregulation of CB and CaMKI RNA in laser-captured BFCN in the normal-aged-AD continuum. We also detected progressive loss of CB, CaMKIδ, and GAP43 proteins in BF homogenates in aging and AD. Activated μ-calpain, a calcium-sensitive protease that degrades CaMKI and GAP43, was significantly increased in the normal aged BF and was 10 times higher in AD BF. Overactivation of μ-calpain was confirmed using proteolytic fragments of its substrate spectrin. Substantial age- and AD-related alterations in Ca(2+)-sensing proteins most likely contribute to selective vulnerability of BFCN to degeneration in AD.
    Neurobiology of aging 12/2013; · 5.94 Impact Factor
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    ABSTRACT: Age-related changes in circadian rhythms may contribute to the sleep disruption observed in older adults. A reduction of the responsiveness to photic stimuli in the circadian timing system has been hypothesized as a possible reason for the advanced circadian phase in older adults. This project compared the phase shifting response to 2hours of broad spectrum white light at moderate and high intensity in young and older adults. The subjects included 29 healthy young (25.1 ± 4.1 years, M:F=8:21) and 16 healthy older subjects (66.5 ± 6.0 years, M:F=5:11) who participated in two 4-night / 3-day laboratory stays, separated by at least 3 weeks. Subjects were randomly assigned to one of three different time points 8hr before (-8), 3hr before (-3), or 3hr after (+3) the core body temperature minimum (CBTmin) measured on the baseline night. For each condition subjects were exposed in a randomized order to 2h light pulses of 2 intensities (2,000 and 8,000lux) during the 2 different laboratory stays. The phase shifts were analyzed by the time of melatonin midpoint on the nights before and after the light exposure. Older subjects in this study showed an earlier baseline phase and lower amplitude of the melatonin rhythm compared to young subjects, but there was no evidence of age-related changes in the magnitude or the direction of phase shifts of melatonin midpoint in response to 2hr of light at either 2,000 or 8,000 lux. These results indicate that the acute phase-shifting response to moderate or high intensity light is not significantly affected by age.
    The Journal of Physiology 10/2013; · 4.38 Impact Factor

Publication Stats

6k Citations
1,159.00 Total Impact Points

Institutions

  • 1995–2014
    • Northwestern University
      • • Cognitive Neurology and Alzheimer's Disease Center
      • • Division of Hospital Medicine
      • • Interdepartmental Neuroscience Center
      • • Department of Psychiatry and Behavioral Sciences
      • • Department of Psychology
      • • Department of Neurobiology
      Evanston, Illinois, United States
  • 2013
    • Texas State University
      • Department of Psychology
      San Marcos, TX, United States
    • King's College London
      • Department of Forensic and Neurodevelopmental Science
      London, ENG, United Kingdom
  • 2011
    • Lifespan
      Providence, Rhode Island, United States
    • University of Illinois at Chicago
      • Department of Pharmacy Administration
      Chicago, IL, United States
  • 2008–2011
    • Rush University Medical Center
      • Department of Neurological Sciences
      Chicago, Illinois, United States
    • Montreal Heart Institute
      Montréal, Quebec, Canada
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 2009
    • McGill University
      • Department of Neurology and Neurosurgery
      Montréal, Quebec, Canada
  • 2006
    • Mayo Foundation for Medical Education and Research
      • Department of Neuroscience
      Scottsdale, AZ, United States
  • 2000
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 1994–1996
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1986–1994
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1992
    • Brigham and Women's Hospital
      • Department of Neurology
      Boston, MA, United States
  • 1990
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States