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1.  Impairment of script comprehension in Lewy body spectrum disorders 
Brain and language  2013;125(3):330-343.
A disabling impairment of higher-order language function can be seen in patients with Lewy body spectrum disorders such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). We focus on script comprehension in patients with Lewy body spectrum disorders. While scripts unfold sequentially, constituent events are thought to contain an internal organization. Executive dysfunction in patients with Lewy body spectrum disorders may interfere with comprehension of this internal structure. We examined 42 patients (30 non-demented PD and 12 mildly demented PDD/DLB patients) and 12 healthy seniors. We presented 22 scripts (e.g., “going fishing”), each consisting of six events. Pilot data from young controls provided the basis for organizing associated events into clusters and arranging them hierarchically into scripts. We measured accuracy and latency to judge the order of adjacent events in the same cluster versus adjacent events in different clusters. PDD/DLB patients were less accurate in their ordering judgments than PD patients and controls. Healthy seniors and PD patients were significantly faster to judge correctly the order of highly associated within-cluster event pairs relative to less closely associated different-cluster event pairs, while PDD/DLB patients did not consistently distinguish between these event-pair types. This relative insensitivity to the clustered-hierarchical organization of events was related to executive impairment and to frontal atrophy as measured by volumetric MRI. These findings extend prior work on script processing to patients with Lewy body spectrum disorders and highlight the potential impact of frontal/executive dysfunction on the daily lives of affected patients.
doi:10.1016/j.bandl.2013.02.006
PMCID: PMC3940934  PMID: 23566691
Parkinson's disease; Parkinson's disease dementia; Dementia with Lewy bodies; Frontal cortex; Executive function; Scripts; Organization; Discourse; Volumetric MRI
2.  Sparse canonical correlation analysis relates network-level atrophy to multivariate cognitive measures in a neurodegenerative population 
NeuroImage  2013;84:698-711.
This study establishes that sparse canonical correlation analysis (SCCAN) identifies generalizable, structural MRI-derived cortical networks that relate to five distinct categories of cognition. We obtain multivariate psychometrics from the domain-specific sub-scales of the Philadelphia Brief Assessment of Cognition (PBAC). By using a training and separate testing stage, we find that PBAC-defined cognitive domains of language, visuospatial functioning, episodic memory, executive control, and social functioning correlate with unique and distributed areas of gray matter (GM). In contrast, a parallel univariate framework fails to identify, from the training data, regions that are also significant in the left-out test dataset. The cohort includes164 patients with Alzheimer’s disease, behavioral-variant frontotemporal dementia, semantic variant primary progressive aphasia, nonfluent/agrammatic primary progressive aphasia, or corticobasal syndrome. The analysis is implemented with open-source software for which we provide examples in the text. In conclusion, we show that multivariate techniques identify biologically-plausible brain regions supporting specific cognitive domains. The findings are identified in training data and confirmed in test data.
doi:10.1016/j.neuroimage.2013.09.048
PMCID: PMC3911786  PMID: 24096125
Alzheimer disease; Frontotemporal lobar degeneration; Philadelphia Brief Assessment of Cognition; PBAC; MRI; Sparse canonical correlation analysis
3.  EXECUTIVE RESOURCES 
Continuum (Minneapolis, Minn.)  2010;16(4 0 0):140-152.
Executive resources allow for flexible, adaptive, goal-directed responses to environmental circumstances in essentially all facets of daily living. Executive function is composed of related, but separable, components. This article will highlight three essential aspects of executive function: (1) working memory, (2) planning and organizing, and (3) inhibitory control. Working memory is the system by which information is maintained in an active mental state so that it can be used for other purposes. Planning and organizing of behavior involves the way in which individuals optimize the execution of multistep tasks to achieve a goal. Inhibitory control allows an individual to inhibit inappropriate responses and to shift responses when necessary. These aspects of executive function appear to depend in part on large-scale neural networks that are centered in distinct areas of prefrontal cortex, working in concert with other brain regions, such as parietal cortex and the basal ganglia. Executive function is a fundamental aspect of human cognition that is compromised in patients with a wide range of medical conditions.
doi:10.1212/01.CON.0000368266.46038.0e
PMCID: PMC3652226  PMID: 22810519
4.  Converging Evidence for the Processing Costs Associated with Ambiguous Quantifier Comprehension 
Traditional neuroanatomic models of language comprehension have emphasized a core language network situated in peri-Sylvian cortex. More recent evidence appears to extend the neuroanatomic network beyond peri-Sylvian cortex to encompass other aspects of sentence processing. In this study, we evaluate the neuroanatomic basis for processing the ambiguity in doubly-quantified sentences. For example, a sentence like “All the dogs jumped in a lake” can be interpreted with a collective interpretation (e.g., several dogs jumping into a single lake) or a distributive interpretation (e.g., several dogs each jumping into a different lake). In Experiment 1, we used BOLD fMRI to investigate neuroanatomic recruitment by young adults during the interpretation of ambiguous doubly-quantified sentences in a sentence-picture verification task. We observed that young adults exhibited a processing cost associated with interpreting ambiguous sentences and this was related to frontal and parietal cortex recruitment. In Experiment 2, we investigate ambiguous sentence processing with the identical materials in non-aphasic patients with behavioral variant frontotemporal dementia (bvFTD) who have frontal cortex disease and executive and decision-making limitations. bvFTD patients are insensitive to ambiguity associated with doubly-quantified sentences, and this is related to the magnitude of their frontal cortex disease. These studies provide converging evidence that cortical regions that extend beyond peri-Sylvian cortex help support the processing costs associated with the interpretation of ambiguous doubly-quantified sentences.
doi:10.3389/fpsyg.2013.00153
PMCID: PMC3613595  PMID: 23565102
language; quantifiers; fMRI; volumetric MRI; frontotemporal dementia
5.  SENTENCE PROCESSING IN LEWY BODY SPECTRUM DISORDER: THE ROLE OF WORKING MEMORY 
Brain and Cognition  2012;78(2):85-93.
Prior work has related sentence processing to executive deficits in non-demented patients with Parkinson’s disease (PD). We extended this investigation to patients with dementia with Lewy bodies (DLB) and PD dementia (PDD) by examining grammatical and working memory components of sentence processing in the full range of patients with Lewy body spectrum disorder (LBSD). Thirty-three patients with LBSD were given a two-alternative, forced-choice sentence-picture matching task. Sentence type, working memory, and grammatical structure were systematically manipulated in the sentences. We found that patients with PDD and DLB were significantly impaired relative to non-demented PD patients and healthy controls. The deficit in PDD/DLB was most pronounced for sentences lengthened by the strategic placement of an additional prepositional phrase and for sentences with an additional proposition due to a center-embedded clause. However, there was no effect for subject-relative versus object-relative grammatical structure. An MRI voxel-based morphometry analysis in a subset of patients showed significant gray matter thinning in the frontal lobe bilaterally, and this extended to temporal, parietal and occipital regions. A regression analysis related sentence processing difficulty in LBSD to frontal neocortex, including inferiorprefrontal, premotor, and dorsolateral prefrontal regions, as well as right superior temporal cortex. These findings are consistent with the hypothesis that patients with PDD and DLB have difficulty processing sentences with increased working memory demands and that this deficit is related in part to their frontal disease.
doi:10.1016/j.bandc.2011.12.004
PMCID: PMC3265703  PMID: 22218297
Lewy body; Parkinson’s; sentence processing; working memory; MRI; prefrontal
6.  Impairments of Speech Fluency in Lewy Body Spectrum Disorder 
Brain and Language  2011;120(3):290-302.
Few studies have examined connected speech in demented and non-demented patients with Parkinson’s disease (PD). We assessed the speech production of 35 patients with Lewy body spectrum disorder (LBSD), including non-demented PD patients, patients with PD dementia (PDD), and patients with dementia with Lewy bodies (DLB), in a semi-structured narrative speech sample in order to characterize impairments of speech fluency and to determine the factors contributing to reduced speech fluency in these patients. Both demented and non-demented PD patients exhibited reduced speech fluency, characterized by reduced overall speech rate and long pauses between sentences. Reduced speech rate in LBSD correlated with measures of between-utterance pauses, executive functioning, and grammatical comprehension. Regression analyses related non-fluent speech, grammatical difficulty, and executive difficulty to atrophy in frontal brain regions. These findings indicate that multiple factors contribute to slowed speech in LBSD, and this is mediated in part by disease in frontal brain regions.
doi:10.1016/j.bandl.2011.09.004
PMCID: PMC3299896  PMID: 22099969
Parkinson’s disease; speech; language; fluency; dementia with Lewy bodies
7.  DIFFICULTY PROCESSING TEMPORARY SYNTACTIC AMBIGUITIES IN LEWY BODY SPECTRUM DISORDER 
Brain and Language  2011;120(1):52-60.
While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson’s disease (PD), Parkinson’s dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb’s statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.
doi:10.1016/j.bandl.2011.08.007
PMCID: PMC3253921  PMID: 21962945
Parkinson’s; Lewy body; syntactic ambiguity; working memory; frontal
8.  The Organization of Narrative Discourse in Lewy Body Spectrum Disorder 
Brain and language  2011;119(1):30-41.
Narrative discourse is an essential component of day-to-day communication, but little is known about narrative in Lewy Body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). We performed a detailed analysis of a semi-structured speech sample in 32 non-aphasic patients with LBSD, and we related their narrative impairments to gray matter (GM) atrophy using voxel-based morphometry. We found that patients with PDD and DLB have significant difficulty organizing their narrative speech. This was correlated with deficits on measures of executive functioning and speech fluency. Regression analyses associated this deficit with reduced cortical volume in inferior frontal and anterior cingulate regions. These findings are consistent with a model of narrative discourse that includes executive as well as language components and with an impairment of the organizational component of narrative discourse in patients with PDD and DLB.
doi:10.1016/j.bandl.2011.05.006
PMCID: PMC3163000  PMID: 21689852
Parkinson's disease; discourse; speech; language; Dementia with Lewy bodies
9.  The Philadelphia Brief Assessment of Cognition (PBAC): A Validated Screening Measure for Dementia 
The Clinical Neuropsychologist  2011;25(8):1314-1330.
The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer’s disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.
doi:10.1080/13854046.2011.631585
PMCID: PMC3297195  PMID: 22084867
Alzheimer’s disease; Frontotemporal lobar dementia; Frontotemporal dementia; FTD; Philadelphia Brief Assessment of the Cognition; PBAC; Neuropsychological assessment; Philadelphia (repeatable) Verbal Learning Test
10.  Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy 
Nature genetics  2011;43(7):699-705.
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component.
doi:10.1038/ng.859
PMCID: PMC3125476  PMID: 21685912
11.  Impaired Information Integration Contributes to Communication Difficulty in Corticobasal Syndrome 
Objective
To investigate the cognitive and neural correlates of discourse impairment in corticobasal syndrome (CBS).
Background
Difficulty communicating is a frequent clinical manifestation in patients with CBS. However, the mechanisms underlying this disabling problem are not well understood.
Methods
Twenty patients with CBS and 8 healthy seniors narrated a picture story. Narratives were analyzed for maintenance of the narrative theme, identification of the overall point of the story (global connectedness), and connectedness between consecutive events (local connectedness). Discourse measures were correlated with performance on cognitive tasks and with cortical atrophy as determined by magnetic resonance imaging voxel-based morphometry.
Results
Patients with CBS referred to the narrative theme significantly less frequently than controls. Global connectedness was intact in only 6 of 20 CBS patients (30%), but preserved in all controls. Local connectedness was significantly diminished in patients relative to controls. Discourse performance in CBS was related to tasks requiring higher-order integration of visual material, but not to basic visuospatial/visuoperceptual, language, or memory function. Discourse impairment was directly related to atrophy in the right parietal lobe and bilateral dorsolateral prefrontal cortex.
Conclusions
Our findings suggest that impaired information integration in CBS, related to parieto-frontal disease, interferes with patients’ ability to narrate a coherent story.
doi:10.1097/WNN.0b013e3181c5e2f8
PMCID: PMC2930985  PMID: 20299856
corticobasal syndrome; volumetric MRI; discourse; inferior parietal lobe; dorsolateral prefrontal cortex

Results 1-11 (11)