Biomedical subjects

Murray Grossman

Publications and source records attributed to Murray Grossman.

At least 19 recordsLinked to original sources

PubMed2007

Reversal of the concreteness effect for verbs in patients with semantic dementia.

The authors assessed comprehension of carefully matched classes of words, manipulating grammatical subcategory (noun and verb) and semantic (concrete and abstract) characteristics for participants with semantic dementia (SD) or probable Alzheimer's disease (AD). Participants selected the best of four words that matched a verbal description. Participants with AD or SD were significantly impaired with verbs compared with nouns. Moreover, participants with SD showed significantly greater difficulty with motion verbs compared to cognition verbs. The authors argue that two factors contribute to the difficulty with motion verbs for patients with SD. First, the verb semantic network is very poorly organized relative to the noun semantic network, leaving verbs more vulnerable to a progressive neurodegenerative disease. Second, visual feature knowledge is degraded in patients with SD because of the anatomic distribution of the disease in visual association cortex, causing relatively greater difficulty for concrete verbs compared to abstract verbs.

Aged↗

PubMed2006

Deep brain stimulation in neurologic disorders.

Deep brain stimulation (DBS) is an effective surgical therapy for well-selected patients with medically intractable Parkinson's disease (PD) and essential tremor (ET). The purpose of this review is to describe the success of DBS in these two disorders and its promising application in dystonia, Tourette Syndrome (TS) and epilepsy. In the last 10 years, numerous short- and intermediate-term outcome studies have demonstrated significant relief to patients with PD and ET. A few long-term follow-up studies have also reported sustained benefits. When successful, DBS greatly reduces most of parkinsonian motor symptoms and drug-induced dyskinesia, and it frequently improves patients' ability to perform activities of daily living with less encumbrance from motor fluctuations. Quality of life is enhanced and many patients are able to significantly reduce the amount of antiparkinsonian medications required to still get good pharmacological benefit. Overall, adverse effects associated with DBS tend to be transient, although device-related and other postoperative complications do occur. DBS should be considered the surgical procedure of choice for patients who meet strict criteria with medically intractable PD, ET and selected cases of dystonia.

Clinical Trials as Topic↗

PubMed2006

How necessary are the stripes of a tiger? Diagnostic and characteristic features in an fMRI study of word meaning.

This study contrasted two approaches to word meaning: the statistically determined role of high-contribution features like striped in the meaning of complex nouns like "tiger" typically used in studies of semantic memory, and the contribution of diagnostic features like parent's brother that play a critical role in the meaning of nominal kinds like "uncle." fMRI monitored regional brain activity while participants read complex noun descriptions consisting of statistically high-contribution and low-contribution features; and nominal kind descriptions consisting of diagnostic and characteristic features. We found different patterns of activation depending on the type of noun and the type of feature contributing to the noun. Complex nouns recruited significantly greater bilateral superior temporal and left prefrontal activation compared to nominal kind nouns, while nominal kind nouns activated bilateral medial parietal and right inferior parietal regions more than complex nouns. Moreover, features making a statistically high contribution to complex noun meaning activated right inferior frontal cortex relative to low-contribution features, while diagnostic features of nominal kinds activated left dorsolateral prefrontal and right parietal regions more than characteristic features. These findings are consistent with the hypothesis that at least two different neural mechanisms appear to support word meaning: one driven by a statistically determined approach to feature knowledge, and the other sensitive to the qualitatively critical role that a specific diagnostic feature plays in word meaning.

Adult↗

PubMed2006

Biochemical and pathological characterization of frontotemporal dementia due to a Leu266Val mutation in microtubule-associated protein tau in an African American individual.

Frontotemporal dementia (FTD) is a clinically heterogeneous disorder characterized by alterations in language and/or behavior, often in association with Parkinsonism or motor neuron disease. A familial form of FTD is associated with mutations in the microtubule-associated protein tau (MAPT) gene. We report here on the clinical, neuroimaging, cerebral spinal fluid biomarker, genetic, biochemical and postmortem neuropathological analyses of a case of familial FTD with a Leu266Val MAPT mutation which results in a very early age of onset and a rapid course of disease. This is also the first reported case of any MAPT mutation in an individual of African American ethnicity.

Adult↗

PubMed2006

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

Amino Acid Sequence↗

PubMed2006

Oops! Resolving social dilemmas in frontotemporal dementia.

OBJECTIVES: Our social cognition model posits that social knowledge and executive resources guide interpersonal decision making. We investigated this model by examining the resolution of standardised social dilemmas in patients with a social and executive disorder (SOC/EXEC) caused by frontotemporal dementia (FTD). METHODS: Patients with SOC/EXEC (n = 12) and those with progressive aphasia (APH, n = 14) completed measures requiring resolution of social dilemmas (Guilford's Cartoon Predictions Test), social cognition (theory of mind false belief vignettes and a behavioural rating measure of empathy) and executive measures of cognitive flexibility (Visual Verbal Test). Regression analysis related judgments of social dilemmas to cortical volume using voxel based morphometry of high resolution structural MRI. RESULTS: Patients with SOC/EXEC were impaired in judgments of social dilemmas as well as theory of mind, self-awareness of empathy and cognitive flexibility. Patients with APH were much less impaired in the social and cognitive measures. There were strong correlations among social dilemma, theory of mind and mental flexibility measures in patients with SOC/EXEC, and stepwise regression showed that mental flexibility was most predictive of social dilemma judgments. Social dilemma impairments in the SOC/EXEC sample correlated with cortical atrophy in the orbital frontal, superior temporal, visual association and posterior cingulate regions of the right hemisphere. CONCLUSIONS: Deficits in patients with SOC/EXEC in resolving social dilemmas are related to depleted executive resources and social knowledge that appear to arise from disease that interrupts a right frontal-temporal neural network crucial for mediating social cognition.

Aged↗

PubMed2006

Quantifier comprehension in corticobasal degeneration.

In this study, we investigated patients with focal neurodegenerative diseases to examine a formal linguistic distinction between classes of generalized quantifiers, like "some X" and "less than half of X." Our model of quantifier comprehension proposes that number knowledge is required to understand both first-order and higher-order quantifiers. The present results demonstrate that corticobasal degeneration (CBD) patients, who have number knowledge impairments but little evidence for a deficit understanding other aspects of language, are impaired in their comprehension of quantifiers relative to healthy seniors, Alzheimer's disease (AD) and frontotemporal dementia (FTD) patients [F(3,77)=4.98; p<.005]. Moreover, our model attempts to honor a distinction in complexity between classes of quantifiers such that working memory is required to comprehend higher-order quantifiers. Our results support this distinction by demonstrating that FTD and AD patients, who have working memory limitations, have greater difficulty understanding higher-order quantifiers relative to first-order quantifiers [F(1,77)=124.29; p<.001]. An important implication of these findings is that the meaning of generalized quantifiers appears to involve two dissociable components, number knowledge and working memory, which are supported by distinct brain regions.

Aged↗

PubMed2006

Alterations in working memory as a function of leukoaraiosis in dementia.

Dementia research suggests executive dysfunction is best understood within the context of disease-specific neuropathology. Leukoaraiosis (LA) results in executive dysfunction yet little is known about its impact on specific aspects of working memory (WM). This study aimed to investigate the relationship between MRI LA severity and WM in dementia. A visual rating scale was used to assign patients with dementia into groups with minimal-mild LA (Low LA; n=34) and moderate-severe LA (High LA; n=32). A modified Digit Span Backward Task consisting of 3-, 4-, and 5-span trials measured specific components of WM. Short-term storage and rehearsal in WM were assessed by the total number of digits reported regardless of recall order (ANY-ORDER; e.g., 47981 recalled '18943', score=4). Mental manipulation in the form of disengagement and temporal re-ordering was assessed by the total number of digits recalled in correct position (SERIAL-ORDER; e.g., 47981 recalled '18943', score=3). There was no difference between LA groups on ANY-ORDER comparisons. The High LA group obtained lower SERIAL-ORDER scores than the Low LA group. Stepwise regression analyses were conducted that first entered MMSE scores then composite z-scores reflecting executive functioning, language and memory. ANY-ORDER performance variance was explained solely by dementia severity. SERIAL-ORDER performance variance was further explained by executive dysfunction. Results suggest that high degrees of LA do not interfere with immediate (digit) recall but do interfere with disengagement and temporal re-ordering. LA may disconnect the frontal lobes from subcortical and cortical structures that form the neuronal networks critical for these WM functions.

Aged↗

PubMed2006

Category-specific effects in semantic memory: category-task interactions suggested by fMRI.

Much work has investigated the neural representation of specific categories of knowledge, but relatively scant attention has been paid in the cognitive neuroscience literature to the semantic processes that contribute to semantic memory. In this study, we monitored regional cortical activity with fMRI while healthy young adults evaluated visually displayed NATURAL KIND, ARTIFACT, and ABSTRACT nouns with two standard tasks: Typicality judgments and Pleasantness judgments. We observed a significant interaction effect between the category of knowledge and the type of judgment used to evaluate members of these semantic categories. Typicality judgments recruited greater temporal-occipital activation relative to Pleasantness judgments of the same category, and this was seen for comparisons of all three semantic categories. However, when contrasted with Typicality judgments, Pleasantness judgments activated a different anatomic distribution for each semantic category. These findings are consistent with a dynamic approach to semantic memory that includes at least two components: semantic knowledge and semantic processes that interpret this knowledge in several ways depending on the particular semantic challenge.

Adult↗

PubMed2006

Frontotemporal dementia: clinicopathological correlations.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is characterized by impairments in social, behavioral, and/or language function, but postmortem studies indicate that multiple neuropathological entities lead to FTLD. This study assessed whether specific clinical features predict the underlying pathology. METHODS: A clinicopathological correlation was performed on 90 consecutive patients with a pathological diagnosis of frontotemporal dementia and was compared with an additional 24 cases accrued during the same time period with a clinical diagnosis of FTLD, but with pathology not typically associated with frontotemporal dementia. RESULTS: Postmortem examination showed multiple pathologies including tauopathies (46%), FTLD with ubiquitin-positive inclusions (29%), and Alzheimer's disease (17%). The pathological groups manifested some distinct demographic, clinical, and neuropsychological features, although these attributes showed only a statistical association with the underlying pathology. FTLD with ubiquitin-positive inclusions was more likely to present with both social and language dysfunction, and motor neuron disease was more likely to emerge in these patients. Tauopathies were more commonly associated with an extrapyramidal disorder. Alzheimer's disease was associated with relatively greater deficits in memory and executive function. INTERPRETATION: Clinical and neuropsychological features contribute to delineating the spectrum of pathology underlying a patient diagnosed with FTLD, but biomarkers are needed that, together with the clinical phenotype, can predict the underlying neuropathology.

Adult↗

PubMed2006

How does the brain support script comprehension? A study of executive processes and semantic knowledge in dementia.

The neuropsychological substrate of scripts, routines which guide much of human behavior, is unclear. We propose a model of script comprehension characterized by the interaction of semantic knowledge for script content, and executive resources that organize this knowledge into goal directed behavior. We examined these neuropsychological components by asking participants with Alzheimer's disease (AD) and frontotemporal dementia (behavioral disorder/dysexecutive syndrome (BDD) and semantic dementia (SD) subtypes), to judge the coherence of four-phrase scripts. The BDD group detected significantly fewer sequencing errors than semantic errors; the AD and SD groups detected these errors with equal frequency. Independent semantic measures predicted both semantic and sequencing script errors, while executive measures predicted sequencing errors only. Findings support a multi-component model of script comprehension.

Aged↗

PubMed2006

Alzheimer's "other dementia".

A short history of Alzheimer disease and vascular dementia is presented. The socio-medical events that led to the dominance of Alzheimer disease are discussed. Alzheimer's contributions to our current understanding of vascular dementia are reviewed.

Alzheimer Disease↗

PubMed2006

Language and the aging brain: patterns of neural compensation revealed by functional brain imaging.

Human aging brings with it declines in sensory function, both in vision and in hearing, as well as a general slowing in a variety of perceptual and cognitive operations. Yet in spite of these declines, language comprehension typically remains well preserved in normal aging. We review data from functional magnetic resonance imaging (fMRI) to describe a two-component model of sentence comprehension: a core sentence-processing area located in the perisylvian region of the left cerebral hemisphere and an associated network of brain regions that support the working memory and other resources needed for comprehension of long or syntactically complex sentences. We use this two-component model to describe the nature of compensatory recruitment of novel brain regions observed when healthy older adults show the same success at comprehending sentences as their younger adult counterparts. We suggest that this plasticity in neural recruitment contributes to the stability of language comprehension in the aging brain.

Aged↗

PubMed2006

Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies.

Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is a common neuropathological subtype of frontotemporal dementia. Although this subtype of frontotemporal dementia is defined by the presence of ubiquitin-positive but tau- and alpha-synuclein-negative inclusions, it is unclear whether all cases of FTLD-U have the same underlying pathogenesis. Examination of tissue sections from FTLD-U brains stained with anti-ubiquitin antibodies revealed heterogeneity in the morphological characteristics of pathological inclusions among subsets of cases. Three types of FTLD-U were delineated based on morphology and distribution of ubiquitin-positive inclusions. To address the hypothesis that FTLD-U is pathologically heterogeneous, novel monoclonal antibodies (mAbs) were generated by immunization of mice with high molecular mass (Mr > 250 kd) insoluble material prepared by biochemical fractionation of FTLD-U brains. Novel mAbs were identified that immunolabeled all of the ubiquitin-positive inclusions in one subset of FTLD-U cases, whereas other mAbs stained the ubiquitin-positive inclusions in a second subset of cases. These novel mAbs did not stain inclusions in other neurodegenerative disorders, including tauopathies and alpha-synucleinopathies. Therefore, ubiquitin immunohistochemistry and the immunostaining properties of the novel mAbs generated here suggest that FTLD-U is pathologically heterogeneous. Identification of the disease proteins recognized by these mAbs will further advance understanding of molecular substrates of FTLD-U neurodegenerative pathways.

Aged↗

PubMed2005

Can patients with Alzheimer's disease learn a category implicitly?

Can a person with a damaged medial-temporal lobe learn a category implicitly? To address this question, we compared the performance of participants with mild Alzheimer's disease (AD) to that of age-matched controls in a standard implicit learning task. In this task, participants were first presented a series of objects, then told the objects formed a category, and then had to categorize a long sequence of test items [Knowlton B. J., Squire L. R. (1993). The learning of categories: parallel brain systems for item memory and category knowledge. Science, 262, 1747-1749]. We tested the hypotheses that: (1) both Control and AD participants would show evidence for implicit learning after the unwanted contribution of learning during test is removed; (2) the degree of implicit learning is the same for AD and Control participants; (3) training with exemplars that are highly similar to an unseen prototype will lead to better implicit category learning than training with exemplars that are less similar to a prototype. With respect to the first hypothesis, we found that both AD and Control participants performed better on tests of implicit learning than could be attributed to just learning on test trials. We found no clear means for evaluating our second hypothesis, and argue that comparisons of the degree of implicit learning between patient and control groups in this paradigm are confounded by the contribution of other memory systems. In line with the third hypothesis, only training with similar exemplars resulted in significant implicit category learning for AD participants.

Aged↗

PubMed2005

Large-scale neural network for sentence processing.

Our model of sentence comprehension includes at least grammatical processes important for structure-building, and executive resources such as working memory that support these grammatical processes. We hypothesized that a core network of brain regions supports grammatical processes, and that additional brain regions are activated depending on the working memory demands associated with processing a particular grammatical feature. We used functional magnetic resonance imaging (fMRI) to test this hypothesis by comparing cortical activation patterns during coherence judgments of sentences with three different syntactic features. We found activation of the ventral portion of left inferior frontal cortex during judgments of violations of each grammatical feature. Increased recruitment of the dorsal portion of left inferior frontal cortex was seen during judgments of violations of specific grammatical features that appear to involve a more prominent working memory component. Left posterolateral temporal cortex and anterior cingulate were also implicated in judging some of the grammatical features. Our observations are consistent with a large-scale neural network for sentence processing that includes a core set of regions for detecting and repairing several different kinds of grammatical features, and additional regions that appear to participate depending on the working memory demands associated with processing a particular grammatical feature.

Adolescent↗

PubMed2005

Neural basis for generalized quantifier comprehension.

Generalized quantifiers like "all cars" are semantically well understood, yet we know little about their neural representation. Our model of quantifier processing includes a numerosity device, operations that combine number elements and working memory. Semantic theory posits two types of quantifiers: first-order quantifiers identify a number state (e.g. "at least 3") and higher-order quantifiers additionally require maintaining a number state actively in working memory for comparison with another state (e.g. "less than half"). We used BOLD fMRI to test the hypothesis that all quantifiers recruit inferior parietal cortex associated with numerosity, while only higher-order quantifiers recruit prefrontal cortex associated with executive resources like working memory. Our findings showed that first-order and higher-order quantifiers both recruit right inferior parietal cortex, suggesting that a numerosity component contributes to quantifier comprehension. Moreover, only probes of higher-order quantifiers recruited right dorsolateral prefrontal cortex, suggesting involvement of executive resources like working memory. We also observed activation of thalamus and anterior cingulate that may be associated with selective attention. Our findings are consistent with a large-scale neural network centered in frontal and parietal cortex that supports comprehension of generalized quantifiers.

Adult↗

PubMed2005

Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease.

We assessed cerebrospinal fluid (CSF) levels of tau and other biomarkers of neurodegenerative disease. CSF tau levels vary widely in reports of frontotemporal dementia (FTD). CSF samples were assayed for tau, amyloid beta1-42 (A1-42), and the isoprostane 8,12-iso-iPF2a-VI (iP) prospectively in 64 patients with FTD, retrospectively in 26 autopsied cases with FTD or Alzheimer's disease (AD), and in 13 healthy seniors. To validate our observations in vivo, we correlated CSF tau levels with cortical atrophy in 17 FTD patients using voxel-based morphometry analyses of high-resolution magnetic resonance imaging. CSF levels of tau, Abeta1-42, and iP differed significantly in FTD compared with AD. Individual patient analyses showed that 34% of FD patients had significantly low levels of CSF tau, although this was never seen in AD. A discriminant analysis based on CSF levels of tau, Abeta1-42, and iP was able to classify 88.5% of these patients in a manner that corresponds to their clinical or autopsy diagnosis. Magnetic resonance imaging studies showed that CSF tau levels correlate significantly with right frontal and left temporal cortical atrophy, brain regions known to be atrophic in patients with autopsy-proved FTD. We conclude that CSF tau levels are significantly reduced in many patients with FTD.

Age of Onset↗