Alzheimer Disease: Grossman M

McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ, Anonymous00019. · Department of Neurology, Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University School of Medicine, 338 Krieger Hall, 3400 N Charles St, Baltimore, MD 21218-2685, USA. · Arch Neurol. · Pubmed #11708987 links to  free full text

Abstract: An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.

Grossman M, Koenig P, DeVita C, Glosser G, Moore P, Gee J, Detre J, Alsop D. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Neuropsychology. · Pubmed #14599278 No free full text.

Abstract: Patients with probable Alzheimer's disease (AD) have difficulty understanding verbs. To investigate the neural basis for this deficit, the authors used functional magnetic resonance imaging to examine patterns of neural activation during verb processing in 11 AD patients compared with 16 healthy seniors. Subjects judged the pleasantness of verbs, including MOTION verbs and COGNITION verbs. Healthy seniors and AD patients both activated posterolateral temporal and inferior frontal regions during judgments of verbs. These activations were relatively reduced and somewhat changed in their anatomic distribution in AD patients compared with healthy seniors, particularly for the subcategory of MOTION verbs, but AD patients showed minimal activation in association with COGNITION verbs. These findings imply that poor performance with verbs in AD is due in part to altered activation of the large-scale neural network that supports verb processing.

Glosser G, Gallo JL, Clark CM, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. · Neuropsychology. · Pubmed #11949711 No free full text.

Abstract: Memory encoding and retrieval strategies were assessed in patients with behavior-executive variant frontotemporal dementia (FTD), language variant FTD, and Alzheimer's disease (AD) using verbal and visuospatial supraspan learning tests. FTD patients obtained higher free recall, cued recall, and recognition scores than AD patients. Comparison of free recall scores with cued recall and recognition scores was similar in the 3 dementia groups. Groups did not differ in semantic clustering strategies during learning, but serial-order recall was more common in FTD patients. These data do not support the idea that FTD patients' poor memory is due to a selective retrieval disorder, though FTD patients may fail to implement sophisticated organizational strategies during learning. FTD patients' retained capacity for encoding new information into long-term declarative memory is likely due to relatively spared medial temporal lobe involvement.

Libon DJ, Xie SX, Wang X, Massimo L, Moore P, Vesely L, Khan A, Chatterjee A, Coslett HB, Hurtig HI, Liang TW, Grossman M. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19129, USA. · Neuropsychology. · Pubmed #19413447 No free full text.

Abstract: Few studies have assessed whether the patterns of neuropsychological impairment in patients with different frontotemporal lobar degeneration (FTLD) subtypes remain distinct over the duration of their illness or devolve into a common, undifferentiated neuropsychological state. A longitudinal neuropsychological analysis was obtained over 100 months assessing executive control, language/naming, and visuoconstruction in 441 patients diagnosed with Alzheimer's disease (AD) and four FTLD subtypes, i.e., a social comportment/dysexecutive (SOC/EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal degeneration (CBD). Initial group differences on each measure were maintained over the duration of illness, including several double dissociations. For example, AD patients exhibited a decline in 'animal' fluency; PNFA patients had difficulty on tests of executive control, SemD maintained their impairment on tests of naming, and CBD had presented with performance on visuoconstructional tests. None of the group by neuropsychological task interactions evaluating longitudinal decline was significant, suggesting that performance does not converge onto a common subtype over time. These data indicate that distinct patterns of neuropsychological impairment are maintained longitudinally, reflecting the unique anatomic distribution of relative disease burden in AD and FTLD.

Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM, Trojanowski JQ, Neumann M. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine,University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · J Neuropathol Exp Neurol. · Pubmed #18520774 No free full text.

Abstract: Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.

Bian H, Van Swieten JC, Leight S, Massimo L, Wood E, Forman M, Moore P, de Koning I, Clark CM, Rosso S, Trojanowski J, Lee VM, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Neurology. · Pubmed #18458217 links to  free full text

Abstract: OBJECTIVE: To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). BACKGROUND: It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations. METHODS: Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (A beta(42)). Patients also were assessed with a brief neuropsychological battery. RESULTS: CSF total tau level and the ratio of CSF total tau to A beta(42) (tau/A beta(42)) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/A beta(42) ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD. CONCLUSIONS: The ratio of CSF tau/A beta(42) is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.

Grossman M, Xie SX, Libon DJ, Wang X, Massimo L, Moore P, Vesely L, Berkowitz R, Chatterjee A, Coslett HB, Hurtig HI, Forman MS, Lee VM, Trojanowski JQ. · Department of Neurology, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104-4283, USA. · Neurology. · Pubmed #18420483 No free full text.

Abstract: BACKGROUND: The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively. METHODS: We examine longitudinal decline in cognitive functioning in an autopsy-proven cohort of patients with the clinical diagnosis of a FTLD spectrum disorder or FTLD pathology using a panel of neuropsychological measures. Patients are categorized according to findings at autopsy into tau-positive FTLD, tau-negative FTLD, and frontal variant-Alzheimer disease (fvAD) subgroups. RESULTS: Patients decline significantly over time on all neuropsychological measures. Moreover, several measures differentiate between histopathologically distinct subgroups throughout the course of the disease process. This includes a significant double dissociation involving relative difficulty on a visual constructional measure in tau-positive patients compared to relatively impaired visual confrontation naming in tau-negative patients. Longitudinal measures of FAS naming fluency and animal naming fluency also distinguish tau-positive patients and tau-negative patients with FTLD from patients with fvAD. Other measures show significant decline but do not distinguish between histopathologic groups longitudinally. CONCLUSION: Our findings suggest different longitudinal patterns of cognitive decline in pathologically defined subgroups of patients. Measures consistently distinguishing between patient subgroups can be used to bolster diagnostic accuracy throughout the course of these diseases, while measures demonstrating undifferentiated longitudinal decline may serve as useful endpoints in treatment trials.

Koenig P, Smith EE, Troiani V, Anderson C, Moore P, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Cereb Cortex. · Pubmed #18400793 No free full text.

Abstract: We used a prototype extraction task to assess implicit learning of a meaningful novel visual category. Cortical activation was monitored in young adults with functional magnetic resonance imaging. We observed occipital deactivation at test consistent with perceptually based implicit learning, and lateral temporal cortex deactivation reflecting implicit acquisition of the category's semantic nature. Medial temporal lobe (MTL) activation during exposure and test suggested involvement of explicit memory as well. Behavioral performance of Alzheimer's disease (AD) patients and healthy seniors was also assessed, and AD performance was correlated with gray matter volume using voxel-based morphometry. AD patients showed learning, consistent with preserved implicit memory, and confirming that AD patients' implicit memory is not limited to abstract patterns. However, patients were somewhat impaired relative to healthy seniors. Occipital and lateral temporal cortical volume correlated with successful AD patient performance, and thus overlapped with young adults' areas of deactivation. Patients' severe MTL atrophy precluded involvement of this region. AD patients thus appear to engage a cortically based implicit memory mechanism, whereas their relative deficit on this task may reflect their MTL disease. These findings suggest that implicit and explicit memory systems collaborate in neurologically intact individuals performing an ostensibly implicit memory task.

Cross K, Smith EE, Grossman M. · Department of Neurology--2 Gibson, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA. · Brain Lang. · Pubmed #18289659 links to  free full text

Abstract: We examined the semantic impairment for natural kinds in patients with probable Alzheimer's disease (AD) and semantic dementia (SD) using an inductive reasoning paradigm. To learn about the relationships between natural kind exemplars and how these are distinguished from manufactured artifacts, subjects judged the strength of arguments such as "Humans have a chemical called sebum. Therefore, frogs have a chemical called sebum." These judgments depend on subjects' perception of the similarity between the familiar objects named in the premise and the conclusion. Controls rated arguments generalizing from a natural kind to an artifact as significantly weaker than arguments generalizing from one natural kind to another natural kind. SD patients demonstrated a graded profile of generalization without evidence of a categorical distinction between natural kinds and artifacts. AD patients' judgments also suggested more difficulty than controls at distinguishing between natural kinds and artifacts. Both SD patients and AD patients resembled controls in their judgments of arguments where both objects are from the natural kinds category. Semantic knowledge thus appears to be sufficiently preserved in both AD and SD to support within-category similarity judgments. We suggest that SD patients may be impaired in part at identifying the features critical to diagnosing membership in a semantic category, while AD patients' performance is consistent with their semantic categorization deficit.

Grossman M, Libon DJ, Forman MS, Massimo L, Wood E, Moore P, Anderson C, Farmer J, Chatterjee A, Clark CM, Coslett HB, Hurtig HI, Lee VM, Trojanowski JQ. · Department of Neurology, 2 Gibson, University of Pennsylvania School of Medicine, 3400 Spruce St, Philadelphia, PA 19104-4283, USA. · Arch Neurol. · Pubmed #17998442 links to  free full text

Abstract: BACKGROUND: Clinical-pathologic studies are crucial to understanding brain-behavior relations and improving diagnostic accuracy in neurodegenerative diseases. OBJECTIVE: To establish clinical, neuropsychological, and imaging features of clinically diagnosed patients with frontotemporal dementia (FTD) that help discriminate between pathologically determined tau-positive FTD, tau-negative FTD, and frontal-variant Alzheimer disease. DESIGN: Retrospective clinical-pathologic survey. SETTING: Academic medical center. Patients Sixty-one participants with the clinical diagnosis of a frontotemporal spectrum disorder who underwent a neuropsychological evaluation and had an autopsy-confirmed disease. MAIN OUTCOME MEASURES: Neuropsychological performance and high-resolution structural magnetic resonance imaging (MRI). RESULTS: Distinguishing features of patients with tau-positive FTD include visual perceptual-spatial difficulty and an extrapyramidal disorder significantly more often than other patients, significant cortical atrophy in the frontal and parietal regions as evidenced on MRI, and the burden of pathology is greatest in the frontal and parietal regions. Patients with tau-negative FTD are distinguished by their greater difficulties with social, language, and verbally mediated executive functions, significant cortical atrophy in the frontal and temporal regions as evidenced on MRI, and significant frontal and temporal pathology. Patients with Alzheimer disease at autopsy have significantly impaired delayed recall during episodic memory testing; atrophy that involves temporal areas, including the hippocampus, as evidenced on MRI; and widely distributed pathology including the medial temporal structures. A discriminant function analysis grouped patients on the basis of clinical and neuropsychological features with 87.5% accuracy. CONCLUSION: Clinical, neuropsychological, and imaging profiles can contribute to accurate antemortem diagnosis in FTD.

Libon DJ, Massimo L, Moore P, Coslett HB, Chatterjee A, Aguirre GK, Rice A, Vesely L, Grossman M. · New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, NJ 08084, USA. · Dement Geriatr Cogn Disord. · Pubmed #17971665 No free full text.

Abstract: BACKGROUND: A neuropsychological screening instrument sensitive to neuropsychological deficits associated with Alzheimer's disease (AD) and patients with frontotemporal dementia (FTD) would be valuable for diagnostic evaluation. METHODS: The Philadelphia Brief Assessment of Cognition (PBAC) assesses working memory/executive control, language, visuospatial operations, verbal/visual episodic memory, and behavior/social comportment and can be administered and scored in 15-20 min. Participants included 149 patients with AD and four groups of FTD patients - i.e., patients with a decline in social comportment, personality, and executive functioning (SOC/EXEC), semantic dementia (SemD), progressive nonfluent aphasia (PNFA), and corticobasal syndrome (CBS). RESULTS: The total PBAC score correlated with the Mini-Mental State Examination. Between-group analysis of PBAC subscales and the results of logistic regression analyses produced substantial between-group differences, emphasizing the sensitivity of the test to differentiate dementia subtypes. AD patients were impaired on tests of episodic memory, SOC/EXEC patients were impaired on a measure of social comportment/behavioral disturbance, PNFA patients obtained low scores on tests of working memory/executive control, SemD patients obtained lower scores on language-mediated measures, and CBS patients were impaired on visuospatial/visual memory tests. CONCLUSION: These data support the usefulness of the PBAC as a relatively brief screening test of overall dementia severity across a wide range of dementia patients.

Xie SX, Forman MS, Farmer J, Moore P, Wang Y, Wang X, Clark CM, Coslett HB, Chatterjee A, Arnold SE, Rosen H, Karlawish JH, Van Deerlin VM, Lee VM, Trojanowski JQ, Grossman M. · Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine Philadelphia, PA, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #17615171 No free full text.

Abstract: OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

Grossman M, Murray R, Koenig P, Ash S, Cross K, Moore P, Troiani V. · Department of Neurology, University of Pennsylvania School of Medicine, USA. · Neuropsychologia. · Pubmed #17482652 links to  free full text

Abstract: We examined the implicit acquisition and mental representation of a novel verb in patients with probable Alzheimer's disease (AD). Patients were exposed to the new verb in a naturalistic manner as part of a simple picture story. We probed grammatical, semantic and thematic matrix knowledge of the verb soon after presentation and again 1 week later. We found partial verb acquisition that was retained over 1 week. AD patients did not differ from controls in their acquisition and retention of a new verb's major grammatical subcategory, although they acquired little of its semantic properties and displayed minimal acquisition of the new word's thematic matrix. Moreover, AD patients appeared to maintain their acquired grammatical knowledge over 1 week. We discuss the implications of these findings from several perspectives, including the modularity of the language processing system, the relationship between episodic memory and semantic memory, and the role of the preserved implicit memory system in AD patients' partially successful lexical acquisition.

Koenig P, Smith EE, Moore P, Glosser G, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Neuropsychology. · Pubmed #17402819 No free full text.

Abstract: We taught a novel animal category by rule-based and similarity-based processes to participants with Alzheimer's disease (AD), corticobasal degeneration (CBD), and healthy age-matched participants. Healthy participants successfully categorized by either process. AD patients' rule-based categorization was impaired, while their similarity-based categorization resembled that of healthy participants. Correlations of AD patients' performance with measures of executive functioning suggested a deficit in the cognitive resources necessary for engaging rule-based categorization. The contribution of limited executive resources to categorization difficulty in AD was further demonstrated in a second experiment in which features determining category membership were of lower salience. CBD patients were relatively impaired at similarity-based processing, suggesting that qualitatively distinct categorization processes can be selectively compromised in patients with focal neurodegenerative diseases. Moreover, AD patients' impaired categorization correlated with performance on a measure of semantic memory, implicating this categorization deficit in AD patients' semantic memory difficulty.

Libon DJ, Xie SX, Moore P, Farmer J, Antani S, McCawley G, Cross K, Grossman M. · New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine, Suite 1800, 42 East Laurel Rd., Stratford, NJ 08084, USA. · Neurology. · Pubmed #17261685 No free full text.

Abstract: OBJECTIVE: To differentiate frontotemporal dementia (FTD) subtypes from each other and from probable Alzheimer disease (AD) using neuropsychological tests. METHODS: Patients with FTD and AD (n = 109) were studied with a comprehensive neuropsychological protocol at first contact. Data were subjected to a principal components analysis (PCA) to extract core neuropsychological features. A five-factor solution accounted for 72.89% of the variance and yielded factors related to declarative memory, working memory/visuoconstruction, processing speed/mental flexibility, lexical retrieval, and semantic memory. RESULTS: Between- and within-group analyses revealed that patients with AD obtain their lowest scores on tests of declarative memory while semantic dementia (SemD) patients are particularly disadvantaged on tests of semantic memory. On tests of processing speed/mental flexibility time to completion was faster for social comportment/dysexecutive (SOC/EXEC) patients, but these patients made more errors on some tests. Patients with corticobasal degeneration (CBD) and progressive nonfluent aphasia (PNFA) were impaired on tests of working memory. Logistic regression analyses using factor scores successfully assigned FTD subgroups and AD patients into their respective diagnostic categories. CONCLUSION: Patients with differing frontotemporal dementia phenotypes can be distinguished from each other and from Alzheimer disease using neuropsychological tests.

Yi HA, Moore P, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Neuropsychology. · Pubmed #17201526 No free full text.

Abstract: 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.

McMillan CT, Clark R, Moore P, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Brain Cogn. · Pubmed #16949714 No free full text.

Abstract: 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.

Libon DJ, Price CC, Heilman KM, Grossman M. · New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, NJ 08084, USA. · Cogn Behav Neurol. · Pubmed #16783135 No free full text.

Abstract: 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.

Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, Lee VM, Miller BL, Trojanowski JQ, Grossman M. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Ann Neurol. · Pubmed #16718704 links to  free full text

Abstract: 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.

Bozoki A, Grossman M, Smith EE. · Michigan State University, MI, USA. · Neuropsychologia. · Pubmed #16229868 No free full text.

Abstract: 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.

Price CC, Grossman M. · Clinical and Health Psychology, University of Florida, Gainesville, FL, USA. · Brain Lang. · Pubmed #15896395 No free full text.

Abstract: An on-line "word detection" paradigm was used to assess the comprehension of thematic and transitive verb agreements during sentence processing in individuals diagnosed with probable Alzheimer's Disease (AD, n=15) and Frontotemporal Dementia (FTD, n=14). AD, FTD, and control participants (n=17) were asked to listen for a word in a sentence. Unbeknownst to the participants, the target word followed an agreement involving a verb's transitivity or thematic role component. Control participants took significantly longer to respond to a target word only when it immediately followed a violation of a thematic role agreement or a transitivity agreement, relative to target word detection immediately following the corresponding correct agreement. AD patients were selectively insensitive to thematic role agreement violations, although they demonstrated a normal processing pattern for transitivity agreements. This is consistent with previous observations showing selective difficulty with the thematic role component of a verb in AD. FTD patients were insensitive to violations of thematic role and transitivity agreements. FTD patients' impairment for both transitivity and thematic role agreements may reflect a broader degradation of verb knowledge that involves both grammatical and semantic representations, or difficulty processing sentence structure that also causes a thematic role deficit.

Grossman M, Farmer J, Leight S, Work M, Moore P, Van Deerlin V, Pratico D, Clark CM, Coslett HB, Chatterjee A, Gee J, Trojanowski JQ, Lee VM. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Ann Neurol. · Pubmed #15852395 No free full text.

Abstract: 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.

Grossman M, McMillan C, Moore P, Ding L, Glosser G, Work M, Gee J. · Department of Neurology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA. · Brain. · Pubmed #14761903 links to  free full text

Abstract: Confrontation naming is impaired in neurodegenerative conditions like Alzheimer's disease (AD), frontotemporal dementia (FTD) and corticobasal degeneration (CBD). Some behavioural observations suggest a common source of impaired naming across these patient groups, while others find partially unique patterns of naming difficulty. We hypothesized that a large-scale neural network underlies naming, and that patterns of impaired naming in AD, FTD and CBD reflect cortical atrophy that interrupts this network in a manner that is partially shared and partially unique across these patient groups. We tested this hypothesis by correlating naming impairments with voxel-based morphometric (VBM) analyses of cortical atrophy in structural MRIs of 50 patients. We found significant naming deficits in all patient groups. Naming also correlated with lexical retrieval in all patient groups, including subgroups of patients with FTD. VBM analyses showed significant cortical atrophy, which was shared across AD, FTD and CBD patients in the left lateral temporal cortex; this area correlated with naming accuracy in all groups. Left lateral temporal atrophy thus appears to interfere with a lexical retrieval component of naming in AD, FTD and CBD. Impaired naming also correlated with semantic memory and visual perceptual-spatial functioning in specific groups of patients and, correspondingly, naming correlated with cortical atrophy in partially distinct neuroanatomical distributions in AD, FTD, CBD and subgroups of patients with FTD. These partially unique correlation profiles appear to reflect selective interruption of other components of the naming process, including semantic and visual perceptual-spatial functioning. These findings are consistent with the hypothesis that a large-scale neural network supports naming, and that this network is interrupted in several distinct ways in patients with neurodegenerative diseases.

Gee J, Ding L, Xie Z, Lin M, DeVita C, Grossman M. · Department of Radiology, University of Pennsylvania, 3600 Market Street, Suite 370, Philadelphia, PA 19104-2644, USA. · Acad Radiol. · Pubmed #14697007 No free full text.

Abstract: RATIONALE AND OBJECTIVES: The purpose of this study was to test the hypothesis that distinct patterns of gray matter atrophy are responsible for unique interruptions of the naming process in Alzheimer's disease (AD) and frontotemporal dementia (FTD). MATERIALS AND METHODS: Voxel-based morphometry (VBM) was performed to characterize at the voxel level the neuroanatomic changes that occur in AD and FTD based on high-resolution T1-weighted three-dimensional (3D) spoiled-gradient echo images of patients (AD, n = 12; FTD, n = 29) and healthy control subjects (n = 12). The cortical atrophy measurements were correlated with performance on behavioral measures of naming and related processes to identify brain regions that may contribute to this language function. RESULTS: Both AD and FTD have significant naming difficulty, and this difficulty in naming correlates with a measure of lexical retrieval in both patient groups as well. However, only FTD patients showed a correlation with semantic memory. Areas of cortical atrophy common to AD and FTD were found in the anterior temporal, posterolateral temporal, and dorsolateral prefrontal regions of the left hemisphere. Correlation with naming in both AD and FTD was seen in the left anterior temporal cortex, suggesting that this area may play a role in the lexical retrieval component of naming. We also observed several unique areas of cortical atrophy in temporal and frontal cortices of these patients. Right anterior temporal and left posterolateral temporal regions of atrophy correlated with naming difficulty in FTD, suggesting that these areas may contribute to the semantic memory component of naming. Cortical areas correlating with naming that are not atrophic may represent regions that play an optional role in naming. CONCLUSION: VBM provides an important first step in analyzing brain-behavior relations in vivo in patients with neurodegenerative diseases. More refined analyses of brain morphology via high-dimensional normalization methods that are capable of modeling local as well as global variability in neuroanatomical structure promise to be even more informative.

Grossman M, Smith EE, Koenig PL, Glosser G, Rhee J, Dennis K. · Department of Neurology-2 Gibson, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, USA. · Cogn Affect Behav Neurosci. · Pubmed #12943327 links to  free full text

Abstract: Studies of semantic memory in probable Alzheimer's disease (AD) have focused on the degradation of semantic knowledge, but other work in AD suggests an impairment in the semantic categorization processes that operate on this knowledge. We examined the categorization of object descriptions, where semantic category membership judgments were based on rule-based or similarity-based categorization processes. We found that AD patients were selectively limited in their semantic categorization under conditions requiring a rule-based approach. However, AD patients did not differ from healthy seniors under conditions based on judgments of overall similarity. We showed that this was not due to nonspecific or overall task-related difficulty associated with the rule condition by asking the subjects to use similarity-based judgments of perceptually degraded versions of the stimuli. The results of this condition did not differ from other similarity-based judgments but did differ from the rule-based condition in AD. Rule-based judgments of semantic category membership correlated with executive measures of inhibitory control and mental search, but not with measures of episodic memory or overall dementia severity, suggesting a contribution of executive resources to rule-based semantic categorization. Moreover, the pattern of limited rule-based categorization in AD closely resembled the performance profile of patients with frontotemporal dementia, further implying that executive resource limitations underlie AD patients' limited rule-based semantic categorization. These findings suggest that semantic memory difficulty in AD is due in part to a deficit in executive processes that are central to rule-based categorization in semantic memory.