[Show abstract][Hide abstract] ABSTRACT: 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).
[Show abstract][Hide abstract] ABSTRACT: We often estimate an unknown value based on available relevant information, a process known as cognitive estimation. In this study, we assess the cognitive and neuroanatomic basis for quantitative estimation by examining deficits in patients with focal neurodegenerative disease in frontal and parietal cortex. Executive function and number knowledge are key components in cognitive estimation. Prefrontal cortex has been implicated in multilevel reasoning and planning processes, and parietal cortex has been associated with number knowledge required for such estimations. We administered the Biber cognitive estimation test (BCET) to assess cognitive estimation in 22 patients with prefrontal disease due to behavioral variant frontotemporal dementia (bvFTD), to 17 patients with parietal disease due to corticobasal syndrome (CBS) or posterior cortical atrophy (PCA) and 11 patients with mild cognitive impairment (MCI). Both bvFTD and CBS/PCA patients had significantly more difficulty with cognitive estimation than controls. MCI were not impaired on BCET relative to controls. Regression analyses related BCET performance to gray matter atrophy in right lateral prefrontal and orbital frontal cortices in bvFTD, and to atrophy in right inferior parietal cortex, right insula, and fusiform cortices in CBS/PCA. These results are consistent with the hypothesis that a frontal-parietal network plays a crucial role in cognitive estimation.
Frontiers in Human Neuroscience 06/2015; 9(317). DOI:10.3389/fnhum.2015.00317 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death. Mode values of C9orf72 expansion size were significantly shorter in FTD compared to ALS (p = 0.0001) but were not associated with age at onset in either FTD or ALS. A multivariate regression model correcting for patient's age at DNA collection and disease phenotype revealed that C9orf72 expansion size is significantly associated with shorter disease duration (p = 0.0107) for individuals with FTD, but not with ALS. Despite considerable somatic instability of the C9orf72 expansion, semi-automated expansion size measurements demonstrated an inverse relationship between C9orf72 expansion size and disease duration in patients with FTD. Our finding suggests that C9orf72 repeat size may be a molecular disease modifier in FTD linked to hexanucleotide repeat expansion.
[Show abstract][Hide abstract] ABSTRACT: The scope of reference of a word's meaning can be highly variable. We present a novel paradigm to investigate the flexible interpretation of word meaning. We focus on quantifiers such as "many" or "few," a class of words that depends on number knowledge but can be interpreted in a flexible manner. Healthy young adults performed a truth value judgment task on pictorial arrays of varying amounts of blue and yellow circles, deciding whether the sentence "Many/few of the circles are yellow" was an adequate description of the stimulus. The study consisted of two experiments, one focusing on "many," one on "few." Each experiment had three blocks. In a first "baseline" block, each individual's criterion for "many" and "few" was assessed. In a second "adaptation" block, subjects received feedback about their decisions that was different from their initial judgments in an effort to evaluate the flexibility of a subject's interpretation. A third "test" block assessed whether adaptation of quantifier meaning induced in block 2 then was generalized to alter a subject's baseline meaning for "many" and "few." In Experiment 1, a proportion of yellow circles as small as 40% was reinforced as "many"; in Experiment 2, a proportion of yellow circles as large as 60% was reinforced as "few." Subjects learned the new criterion for "many" in Experiment 1, which also affected their criterion for "few" although it had never been mentioned. Likewise, in Experiment 2, subjects changed their criterion for "few," with a comparable effect on the criterion for "many" which was not mentioned. Thus, the meaning of relational quantifiers like "many" and "few" is flexible and can be adapted. Most importantly, adapting the criterion for one quantifier (e.g., "many") also appeared to affect the reciprocal quantifier (in this case, "few"). Implications of this result for psychological interventions and for investigations of the neurobiology of the language-number interface are discussed.
Frontiers in Psychology 04/2015; 6:441. DOI:10.3389/fpsyg.2015.00441 · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Up to half of patients with amyotrophic lateral sclerosis (ALS) may have cognitive difficulty, but most cognitive measures are confounded by a motor component. Studies relating impaired cognition in ALS to disease in gray matter and white matter are rare. Our objective was to assess executive function in patients with ALS using a simple, untimed measure with minimal motor demands, and to relate performance to structural disease.
We gave the Visual-Verbal Test to 56 patients with ALS and 29 matched healthy controls. This brief, untimed measure of cognitive flexibility first assesses participants' ability to identify a feature shared by 3 of 4 simple geometric designs. The participants' cognitive flexibility is challenged when they are next asked to identify a different feature shared by another combination of 3 of the same 4 geometric designs. In a subset of 17 patients who underwent magnetic resonance imaging, regression analyses related test performance to gray matter atrophy and reduced white matter fractional anisotropy.
The patients with ALS showed significant impairment in cognitive flexibility (P<0.01), with 48.2% making an error on the test. Regression analyses related impaired cognitive flexibility to gray matter atrophy in inferior frontal and insular regions, and to reduced fractional anisotropy in white matter projections in the inferior fronto-occipital and uncinate fasciculi and corpus callosum.
Our patients with ALS had impaired cognitive flexibility on an untimed measure with minimal motor demands, a finding related in part to a large-scale frontal network that is degraded in ALS.
Cognitive and behavioral neurology: official journal of the Society for Behavioral and Cognitive Neurology 03/2015; 28(1):17-26. DOI:10.1097/WNN.0000000000000049 · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work toward the goal of defining clinical endophenotypes of FTD.
[Show abstract][Hide abstract] ABSTRACT: Quantitative examinations of speech production in amyotrophic lateral sclerosis (ALS) are rare. To identify language features minimally confounded by a motor disorder, we investigated linguistic and motor sources of impaired sentence expression in ALS, and we related deficits to gray matter (GM) and white matter (WM) MRI abnormalities. We analyzed a semi-structured speech sample in 26 ALS patients and 19 healthy seniors for motor- and language-related deficits. Regression analyses related grammaticality to GM atrophy and reduced WM fractional anisotropy (FA). Results demonstrated that ALS patients were impaired relative to controls on quantity of speech, speech rate, speech articulation errors, and grammaticality. Speech rate and articulation errors were related to the patients' motor impairment, while grammatical difficulty was independent of motor difficulty. This was confirmed in subgroups without dysarthria and without executive deficits. Regressions related grammatical expression to GM atrophy in left inferior frontal and anterior temporal regions and to reduced FA in superior longitudinal and inferior frontal-occipital fasciculi. In conclusion, patients with ALS exhibit multifactorial deficits in sentence expression. They demonstrate a deficit in grammatical expression that is independent of their motor disorder. Impaired grammatical expression is related to disease in a network of brain regions associated with syntactic processing.
[Show abstract][Hide abstract] ABSTRACT: To relate changes in fractional anisotropy associated with behavioral variant frontotemporal dementia to measures of apathy and disinhibition.
Apathy and disinhibition are the 2 most common behavioral features of behavioral variant frontotemporal dementia, and these symptoms are associated with accelerated patient decline and caregiver stress. However, little is known about how white matter disease contributes to these symptoms.
We collected neuropsychiatric data, volumetric magnetic resonance imaging, and diffusion-weighted imaging in 11 patients who met published criteria for behavioral variant frontotemporal dementia and had an autopsy-validated cerebrospinal fluid profile consistent with frontotemporal lobar degeneration. We also collected imaging data on 34 healthy seniors for analyses defining regions of disease in the patients. We calculated and analyzed fractional anisotropy with a white matter tract-specific method. This approach uses anatomically guided data reduction to increase sensitivity, and localizes results within canonically defined tracts. We used nonparametric, cluster-based statistical analysis to relate fractional anisotropy to neuropsychiatric measures of apathy and disinhibition.
The patients with behavioral variant frontotemporal dementia had widespread reductions in fractional anisotropy in anterior portions of frontal and temporal white matter, compared to the controls. Fractional anisotropy correlated with apathy in the left uncinate fasciculus and with disinhibition in the right corona radiata.
In patients with behavioral variant frontotemporal dementia, apathy and disinhibition are associated with distinct regions of white matter disease. The implicated fiber tracts likely support frontotemporal networks that are involved in goal-directed behavior.
Cognitive and behavioral neurology: official journal of the Society for Behavioral and Cognitive Neurology 12/2014; 27(4):206-14. DOI:10.1097/WNN.0000000000000044 · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Segmenting and quantifying gliomas from MRI is an important task for diagnosis, planning intervention, and for tracking tumor changes over time. However, this task is complicated by the lack of prior knowledge concerning tumor location, spatial extent, shape, possible displacement of normal tissue, and intensity signature. To accommodate such complications, we introduce a framework for supervised segmentation based on multiple modality intensity, geometry, and asymmetry feature sets. These features drive a supervised whole-brain and tumor segmentation approach based on random forest-derived probabilities. The asymmetry-related features (based on optimal symmetric multimodal templates) demonstrate excellent discriminative properties within this framework. We also gain performance by generating probability maps from random forest models and using these maps for a refining Markov random field regularized probabilistic segmentation. This strategy allows us to interface the supervised learning capabilities of the random forest model with regularized probabilistic segmentation using the recently developed ANTsR package-a comprehensive statistical and visualization interface between the popular Advanced Normalization Tools (ANTs) and the R statistical project. The reported algorithmic framework was the top-performing entry in the MICCAI 2013 Multimodal Brain Tumor Segmentation challenge. The challenge data were widely varying consisting of both high-grade and low-grade glioma tumor four-modality MRI from five different institutions. Average Dice overlap measures for the final algorithmic assessment were 0.87, 0.78, and 0.74 for "complete", "core", and "enhanced" tumor components, respectively.
[Show abstract][Hide abstract] ABSTRACT: C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether C9orf72 hypermethylation was associated with age at onset, disease duration, age at death, or hexanucleotide repeat expansion size. Permutation analysis was performed to determine whether C9orf72 methylation is heritable. We observed a high correlation between C9orf72 methylation across tissues including cerebellum, frontal cortex, spinal cord and peripheral blood. While C9orf72 methylation was not significantly different between ALS and FTD and did not predict age at onset, brain and blood C9orf72 hypermethylation was associated with later age at death in FTD (brain: β = 0.18, p = 0.006; blood: β = 0.15, p < 0.001), and blood C9orf72 hypermethylation was associated with longer disease duration in FTD (β = 0.03, p = 0.007). Furthermore, C9orf72 hypermethylation was associated with smaller hexanucleotide repeat length (β = -16.69, p = 0.033). Finally, analysis of pedigrees with multiple mutation carriers demonstrated a significant association between C9orf72 methylation and family relatedness (p < 0.0001). C9orf72 hypermethylation is associated with prolonged disease in C9orf72 repeat expansion carriers with FTD. The attenuated clinical phenotype associated with C9orf72 hypermethylation suggests that slower clinical progression in FTD is associated with reduced expression of mutant C9orf72. These results support the hypothesis that expression of the hexanucleotide repeat expansion is associated with a toxic gain of function.
[Show abstract][Hide abstract] ABSTRACT: A growing amount of empirical data is showing that the ability to manipulate quantities in a precise and efficient fashion is rooted in cognitive mechanisms devoted to specific aspects of numbers processing. The Analog number system (ANS) has a reasonable representation of quantities up to about 4, and represents larger quantities on the basis of a numerical ratio between quantities. In order to represent the precise cardinality of a number, the ANS may be supported by external algorithms such as language, leading to a “Precise Number System”. In the setting of limited language, other number-related systems can appear. For example the Parallel Individuation system (PIS) supports a “chunking mechanism” that clusters units of larger numerosities into smaller subsets. In the present study we investigated number processing in non-aphasic patients with Corticobasal Syndrome (CBS) and Posterior Cortical Atrophy (PCA), two neurodegenerative conditions that are associated with progressive parietal atrophy. The present study investigated these number systems in CBS and PCA by assessing the property of the ANS associated with smaller and larger numerosities, and the chunking property of the PIS. The results revealed that CBS/PCA patients are impaired in simple calculations (e.g., addition and subtraction) and that their performance strongly correlates with the size of the numbers involved in these calculations, revealing a clear magnitude effect. This magnitude effect correlated with gray matter atrophy in parietal regions. Moreover, a numeral-dots transcoding task showed that CBS/PCA patients are able to take advantage of clustering in the spatial distribution of the dots of the array. The relative advantage associated with chunking compared to a random spatial distribution correlated with both parietal and prefrontal regions. These results shed light on the properties of systems for representing number knowledge in non-aphasic patients with CBS and PCA.
[Show abstract][Hide abstract] ABSTRACT: Apathy, a reduction in goal-directed behavior (GDB), affects 90% of individuals with behavioral variant frontotemporal degeneration, which is a common cause of early onset neurodegenerative disease. The cognitive and neural impairments associated with apathy make it difficult to initiate, plan, and self-motivate activities toward a specific goal, such as dressing or bathing. These impairments are associated with significant decline in functional ability, caregiver burden, and increased cost of care due to early institutionalization. The current article reviews the evidence suggesting that apathy arises from the interruption of one or any combination of three GDB processes: initiation, planning, and motivation. From this perspective, three subtypes of apathy related to dysfunction at the level of GDB and the corresponding neuroanatomy are explored. Further research is required to confirm and measure these subtypes of apathy for use in clinical and research settings. A more precise classification of apathy by subtype will allow implementation of the most appropriate person-centered, individualized therapy. [Journal of Gerontological Nursing, xx(x), xx-xx.].