Sandra Weintraub

Northwestern University, Evanston, Illinois, United States

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Publications (194)1336.91 Total impact

  • Neurology 07/2015; DOI:10.1212/WNL.0000000000001851 · 8.30 Impact Factor
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    ABSTRACT: Wernicke's aphasia is characterized by severe word and sentence comprehension impairments. The location of the underlying lesion site, known as Wernicke's area, remains controversial. Questions related to this controversy were addressed in 72 patients with primary progressive aphasia who collectively displayed a wide spectrum of cortical atrophy sites and language impairment patterns. Clinico-anatomical correlations were explored at the individual and group levels. These analyses showed that neuronal loss in temporoparietal areas, traditionally included within Wernicke's area, leave single word comprehension intact and cause inconsistent impairments of sentence comprehension. The most severe sentence comprehension impairments were associated with a heterogeneous set of cortical atrophy sites variably encompassing temporoparietal components of Wernicke's area, Broca's area, and dorsal premotor cortex. Severe comprehension impairments for single words, on the other hand, were invariably associated with peak atrophy sites in the left temporal pole and adjacent anterior temporal cortex, a pattern of atrophy that left sentence comprehension intact. These results show that the neural substrates of word and sentence comprehension are dissociable and that a circumscribed cortical area equally critical for word and sentence comprehension is unlikely to exist anywhere in the cerebral cortex. Reports of combined word and sentence comprehension impairments in Wernicke's aphasia come almost exclusively from patients with cerebrovascular accidents where brain damage extends into subcortical white matter. The syndrome of Wernicke's aphasia is thus likely to reflect damage not only to the cerebral cortex but also to underlying axonal pathways, leading to strategic cortico-cortical disconnections within the language network. The results of this investigation further reinforce the conclusion that the left anterior temporal lobe, a region ignored by classic aphasiology, needs to be inserted into the language network with a critical role in the multisynaptic hierarchy underlying word comprehension and object naming. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 06/2015; DOI:10.1093/brain/awv154 · 10.23 Impact Factor
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    ABSTRACT: We examined the intriguing but controversial idea that disrupted sleep-dependent consolidation contributes to age-related memory decline. Slow-wave activity during sleep may help strengthen neural connections and provide memories with long-term stability, in which case decreased slow-wave activity in older adults could contribute to their weaker memories. One prediction from this account is that age-related memory deficits should be reduced by artificially enhancing slow-wave activity. In young adults, applying transcranial current oscillating at a slow frequency (0.75 Hz) during sleep improves memory. Here, we tested whether this procedure can improve memory in older adults. In 2 sessions separated by 1 week, we applied either slow-oscillatory stimulation or sham stimulation during an afternoon nap in a double-blind, crossover design. Memory tests were administered before and after sleep. A larger improvement in word-pair recall and higher slow-wave activity was observed with slow-oscillatory stimulation than with sham stimulation. This is the first demonstration that this procedure can improve memory in older adults, suggesting that declarative memory performance in older adults is partly dependent on slow-wave activity during sleep. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 06/2015; DOI:10.1016/j.neurobiolaging.2015.05.014 · 4.85 Impact Factor
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    ABSTRACT: The goal of the Care Pathway Model for Dementia (CARE-D) is to improve quality of life and daily functioning both for individuals diagnosed with dementia and for their families or other caregivers. This is accomplished by developing individualized recommendations focused on a person's strengths and weaknesses as determined by formal neurocognitive and psychosocial evaluations. Careful attention is given to the stage of illness and an individual's stage in life, to connecting families with services that target an individual's cognitive and behavioral symptoms, and to providing education and emotional support specific to symptoms, clinical diagnosis, and prognosis. Copyright © 2015 Elsevier Inc. All rights reserved.
    The Psychiatric clinics of North America 06/2015; 38(2):333-352. DOI:10.1016/j.psc.2015.01.005 · 1.87 Impact Factor
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    ABSTRACT: Eye movement trajectories during a verbally cued object search task were used as probes of lexico-semantic associations in an anomic patient with primary progressive aphasia. Visual search was normal on trials where the target object could be named but became lengthy and inefficient on trials where the object failed to be named. The abnormality was most profound if the noun denoting the object could not be recognized. Even trials where the name of the target object was recognized but not retrieved triggered abnormal eye movements, demonstrating that retrieval failures can have underlying associative components despite intact comprehension of the corresponding noun.
    Neurocase 05/2015; DOI:10.1080/13554794.2015.1045523 · 1.38 Impact Factor
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    ABSTRACT: Alzheimer neuropathology (AD) is found in almost half of patients with non-semantic primary progressive aphasia (PPA). This study examined hippocampal abnormalities in PPA to determine similarities to those described in amnestic AD. In 37 PPA patients and 32 healthy controls, we generated hippocampal subfield surface maps from structural MRIs and administered a face memory test. We analyzed group and hemisphere differences for surface shape measures and their relationship with test scores and ApoE genotype. The hippocampus in PPA showed inward deformity (CA1 and subiculum subfields) and outward deformity (CA2-4+DG subfield) and smaller left than right volumes. Memory performance was related to hippocampal shape abnormalities in PPA patients, but not controls, even in the absence of memory impairments. Hippocampal deformity in PPA is related to memory test scores. This may reflect a combination of intrinsic degenerative phenomena with transsynaptic or Wallerian effects of neocortical neuronal loss.
    03/2015; 1(1):14-23. DOI:10.1016/j.dadm.2014.11.013
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    ABSTRACT: The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer's disease, are not fully understood. Because age is the primary risk factor for Alzheimer's disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-β accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer's disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-β1-42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer's disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-β42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer's disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-β accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer's disease. Selective intraneuronal amyloid-β accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer's disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 03/2015; 138(6). DOI:10.1093/brain/awv024 · 10.23 Impact Factor
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    ABSTRACT: This human study is based on an established cohort of "SuperAgers," 80+-year-old individuals with episodic memory function at a level equal to, or better than, individuals 20-30 years younger. A preliminary investigation using structural brain imaging revealed a region of anterior cingulate cortex that was thicker in SuperAgers compared with healthy 50- to 65-year-olds. Here, we investigated the in vivo structural features of cingulate cortex in a larger sample of SuperAgers and conducted a histologic analysis of this region in postmortem specimens. A region-of-interest MRI structural analysis found cingulate cortex to be thinner in cognitively average 80+ year olds (n = 21) than in the healthy middle-aged group (n = 18). A region of the anterior cingulate cortex in the right hemisphere displayed greater thickness in SuperAgers (n = 31) compared with cognitively average 80+ year olds and also to the much younger healthy 50-60 year olds (p < 0.01). Postmortem investigations were conducted in the cingulate cortex in five SuperAgers, five cognitively average elderly individuals, and five individuals with amnestic mild cognitive impairment. Compared with other subject groups, SuperAgers showed a lower frequency of Alzheimer-type neurofibrillary tangles (p < 0.05). There were no differences in total neuronal size or count between subject groups. Interestingly, relative to total neuronal packing density, there was a higher density of von Economo neurons (p < 0.05), particularly in anterior cingulate regions of SuperAgers. These findings suggest that reduced vulnerability to the age-related emergence of Alzheimer pathology and higher von Economo neuron density in anterior cingulate cortex may represent biological correlates of high memory capacity in advanced old age. Copyright © 2015 the authors 0270-6474/15/351781-11$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2015; 35(4):1781-91. DOI:10.1523/JNEUROSCI.2998-14.2015 · 6.75 Impact Factor
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    ABSTRACT: Combined pathologies are common, particularly in the very elderly with AD as the primary pathologic diagnosis. In such patients, AD plus vascular disease (VaD) or Lewy body disease (LBD), or both, with or without limbic TDP-43 inclusions, are the most frequent combined pathologies. In contrast, combined pathologies are rare in cases with a primary diagnosis of frontotemporal lobar degeneration (FTLD). Autopsy remains the gold standard for specific pathologic / molecular diagnoses. We present the case of an 80 year old woman with an 11 year history of a mixed behavioral and aphasic phenotype who subsequently displayed gait abnormality, tremor, and falls. Evaluation of microscopic H & E sections and histochemical and immunohistochemical stains revealed three major pathologic diagnoses: AD, FTLD-TDP, and FTLD-tau-PSP. The FTLD-TDP pathology (type A) was prominent in frontal and temporal cortex; the AD tangle density was greatest in the parietal lobe; and the PSP pathology was predominantly in basal ganglia and brainstem. We felt that the FTLD-TDP and AD pathologies were most likely to have contributed to the language and behavior abnormalities while the PSP pathology was most likely to have contributed to the movement disorder. This patient shows that in old age, cognitive impairments are likely to reflect complex interactions of multiple etiologic factors, each of which may have a differential contribution to the overall clinical picture. The results emphasize the importance of following recommended guidelines for evaluating all pathologies present in brains from those with dementia of any type, and for careful clinicopathologic correlation.
    American Association of Neuropathologists, 2015., Denver, Colorado; 01/2015
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    ABSTRACT: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.
    JAMA Neurology 12/2014; DOI:10.1001/jamaneurol.2014.2157 · 7.01 Impact Factor
  • JAMA Neurology 12/2014; 71(12):1576-1577. DOI:10.1001/jamaneurol.2014.2805 · 7.01 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. DOI:10.1186/1750-1326-9-38 · 5.29 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; 10(10). DOI:10.1038/nrneurol.2014.159 · 14.10 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; 83(13). DOI:10.1212/WNL.0000000000000824 · 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; 30(3). DOI:10.1177/1533317514545377 · 1.43 Impact Factor
  • Journal of the American Geriatrics Society 08/2014; 62(8). DOI:10.1111/jgs.12967 · 4.22 Impact Factor
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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 06/2014; DOI:10.1017/S1355617714000411 · 3.01 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 06/2014; 20(6):1-12. DOI:10.1017/S1355617714000320 · 3.01 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 06/2014; 20(6):1-9. DOI:10.1017/S1355617714000460 · 3.01 Impact Factor
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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; 20(6):1-11. DOI:10.1017/S1355617714000241 · 3.01 Impact Factor

Publication Stats

9k Citations
1,336.91 Total Impact Points

Institutions

  • 2000–2015
    • Northwestern University
      • • Department of Psychiatry and Behavioral Sciences
      • • Division of Hospital Medicine
      • • Division of Gastroenterology and Hepatology
      • • Cognitive Neurology and Alzheimer's Disease Center
      Evanston, Illinois, United States
  • 2013
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • King's College London
      • Department of Forensic and Neurodevelopmental Science
      Londinium, England, United Kingdom
  • 2009
    • University of California, San Diego
      San Diego, California, United States
  • 2008
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 1996
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 1989–1996
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1994
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1991
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, Massachusetts, United States