Sparse canonical correlation analysis relates network-level atrophy to multivariate cognitive measures in a neurodegenerative population.

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, non-fluent/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.

A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank.

Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.

Neuropsychologic assessment in collaborative Parkinson's disease research: a proposal from the National Institute of Neurological Disorders and Stroke Morris K. Udall Centers of Excellence for Parkinson's Disease Research at the University of Pennsylvania and the University of Washington.

Cognitive impairment (CI) and behavioral disturbances can be the earliest symptoms of Parkinson's disease (PD), ultimately afflict the vast majority of PD patients, and increase caregiver burden. Our two Morris K. Udall Centers of Excellence for Parkinson's Disease Research were supported by the National Institute of Neurological Disorders and Stroke (NINDS) in an effort to recommend a comprehensive yet practical approach to cognitive and behavioral assessment to further collaborative research. We recommend a stepwise approach with two levels of standardized evaluation to establish a common battery, as well as an alternative testing recommendation for severely impaired subjects, and review supplemental tests that may be useful in specific research settings. Our flexible approach may be applied to studies with varying emphasis on cognition and behavior, does not place undue burden on participants or resources, and has a high degree of compatibility with existing test batteries to promote collaboration.

Sentence processing in Lewy body spectrum disorder: the role of working memory.

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 inferior prefrontal, 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.

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.

Regional brain amyloid-ß accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia.

Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-ß accumulation to these problems is unclear. We hypothesized that amyloid-ß PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-ß plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients. We assessed 61 non-demented Parkinson disease patients with detailed cognitive assessments and 18F-florbetapir PET brain imaging. Scans were interpreted qualitatively (positive or negative) by two independent nuclear medicine physicians blinded to clinical data, and quantitatively by a novel volume-weighted method. The presence of mild cognitive impairment was determined through an expert consensus process using Level 1 criteria from the Movement Disorder Society. Nineteen participants (31.2%) were diagnosed with mild cognitive impairment and the remainder had normal cognition. Qualitative 18F-florbetapir PET imaging was positive in 15 participants (24.6%). Increasing age and presence of an APOE ε4 allele were associated with higher composite 18F-florbetapir binding. In multivariable models, an abnormal 18F-florbetapir scan by expert rating was not associated with a diagnosis of mild cognitive impairment. However, 18F-florbetapir retention values in the posterior cingulate gyrus inversely correlated with verbal memory performance. Retention values in the frontal cortex, precuneus, and anterior cingulate gyrus retention values inversely correlated with naming performance. Regional cortical amyloid-ß amyloid, as measured by 18F-florbetapir PET, may be a biomarker of specific cognitive deficits in non-demented Parkinson disease patients.

Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome.

OBJECTIVE: To use multimodal neuroimaging to evaluate the influence of heterogeneous underlying pathology in corticobasal syndrome (CBS) on the neuroanatomical distribution of disease. METHODS: We performed a retrospective evaluation of 35 patients with CBS with T1-weighted MRI, diffusion tensor imaging, and neuropathologic, genetic, or CSF evidence of underlying pathology. Patients were assigned to 2 groups: those with evidence of Alzheimer pathology (CBS-AD) and those without Alzheimer pathology (CBS-non-AD). Group comparisons of CBS-AD and CBS-non-AD assessed clinical features, gray matter (GM) cortical thickness, and white matter (WM) fractional anisotropy. RESULTS: CBS-AD was found in 34% (n = 12) and CBS-non-AD in 66% (n = 23) of CBS patients. Clinical evaluations revealed that CBS-non-AD had a higher frequency of asymmetric rigidity compared to CBS-AD, but groups otherwise did not differ in dementia severity, impairments in cognition, or rates of extrapyramidal symptoms. We found frontoparietal GM and WM disease in each group compared to healthy, demographically comparable controls, as well as multimodal neuroimaging evidence of a double dissociation: CBS-non-AD had WM disease in the corpus callosum, corticospinal tract, and superior longitudinal fasciculus relative to CBS-AD, and CBS-AD had reduced temporoparietal GM relative to CBS-non-AD, including the precuneus and posterior cingulate. CONCLUSIONS: Patients with CBS have a pathology-mediated dissociation of GM and WM disease. Multimodality neuroimaging may be useful for improving in vivo pathologic diagnosis of CBS.

Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy.

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).

Corticobasal syndrome: Five new things.

Corticobasal syndrome (CBS) is characterized by asymmetric involuntary movements including rigidity, tremor, dystonia, and myoclonus, and often associated with apraxia, cortical sensory deficits, and alien limb phenomena. Additionally, there are various nonmotor (cognitive and language) deficits. CBS is associated with several distinct histopathologies, including corticobasal degeneration, other forms of tau-related frontotemporal lobar degeneration such as progressive supranuclear palsy, and Alzheimer disease. Accurate antemortem diagnosis of underlying pathology in CBS is challenging, though certain clinical and imaging findings may be helpful. Five recent advances in the understanding of CBS are reviewed, including clinical and pathologic features, imaging and CSF biomarkers, the role of specific genes, and the concept of a spectrum of tauopathies.

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.

Impairment of script comprehension in Lewy body spectrum disorders.

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.

Difficulty processing temporary syntactic ambiguities in Lewy body spectrum disorder.

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.

Impairments of speech fluency in Lewy body spectrum disorder.

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.

The organization of narrative discourse in Lewy body spectrum disorder.

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.

Some is not enough: quantifier comprehension in corticobasal syndrome and behavioral variant frontotemporal dementia.

Quantifiers are very common in everyday speech, but we know little about their cognitive basis or neural representation. The present study examined comprehension of three classes of quantifiers that depend on different cognitive components in patients with focal neurodegenerative diseases. Patients evaluated the truth-value of a sentence containing a quantifier relative to a picture illustrating a small number of familiar objects, and performance was related to MRI grey matter atrophy using voxel-based morphometry. We found that patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA) are significantly impaired in their comprehension of cardinal quantifiers (e.g. "At least three birds are on the branch"), due in part to their deficit in quantity knowledge. MRI analyses related this deficit to temporal-parietal atrophy found in CBS/PCA. We also found that patients with behavioral variant frontotemporal dementia (bvFTD) are significantly impaired in their comprehension of logical quantifiers (e.g. "Some of the birds are on the branch"), associated with a simple form of perceptual logic, and this correlated with their deficit on executive measures. This deficit was related to disease in rostral prefrontal cortex in bvFTD. These patients were also impaired in their comprehension of majority quantifiers (e.g. "At least half of the birds are on the branch"), and this too was correlated with their deficit on executive measures. This was related to disease in the basal ganglia interrupting a frontal-striatal loop critical for executive functioning. These findings suggest that a large-scale frontal-parietal neural network plays a crucial role in quantifier comprehension, and that comprehension of specific classes of quantifiers may be selectively impaired in patients with focal neurodegenerative conditions in these areas.

The Philadelphia Brief Assessment of Cognition (PBAC): a validated screening measure for dementia.

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.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is 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 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified 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.

Executive resources.

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.