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.
Alzheimer disease; Frontotemporal lobar degeneration; Philadelphia Brief Assessment of Cognition; PBAC; MRI; Sparse canonical correlation analysis
Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TDP-43 proteinopathy.
A retrospective-cohort study using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43).
C9P cases had an earlier age of onset (p=0.047), and in the subset of deceased patients, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rankλ2=4.183,p=0.041), and C9P FTLD showed a significantly greater annualized rate of decline in letter fluency (4.5±1.3words/year) than C9N FTLD (1.4±0.8words/year, p=0.023). VBM revealed greater atrophy in the right fronto-insular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathologic analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance.
C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for ALS and FTLD patients.
Frontotemporal dementia; Amyotrophic lateral sclerosis; C9orf72; neuropsychological tests; neuroimaging
A significant portion of frontotemporal lobar degeneration (FTLD) is due to inherited gene mutations, and we are unaware of a large sequential series that includes a recently discovered inherited cause of FTLD. There is also great need to develop clinical tools and approaches that will assist clinicians in the identification and counseling of patients with FTLD and their families regarding the likelihood of an identifiable genetic cause.
To ascertain the frequency of inherited FTLD and develop validated pedigree classification criteria for FTLD that provide a standardized means to evaluate pedigree information and insight into the likelihood of mutation-positive genetic test results for C9orf72, MAPT, and GRN.
Information about pedigrees and DNA was collected from 306 serially assessed patients with a clinical diagnosis of FTLD. This information included gene test results for C9orf72, MAPT, and GRN. Pedigree classification criteria were developed based on a literature review of FTLD genetics and pedigree tools and then refined by reviewing mutation-positive and -negative pedigrees to determine differentiating characteristics.
Academic medical center.
Patients with FTLD.
MAIN OUTCOMES AND MEASURES
The rate of C9orf72, MAPT, or GRN mutation–positive FTLD in this series was 15.4%. Categories designating the risk level for hereditary cause were termed high, medium, low, apparent sporadic, and unknown significance. Thirty-nine pedigrees (12.7%)met criteria for high, 31 (10.1%) for medium, 46 (15.0%) for low, 91 (29.7%) for apparent sporadic, and 99 (32.4%) for unknown significance. The mutation-detection rates were as follows: high, 64.1%; medium, 29%; low, 10.9%; apparent sporadic, 1.1%; and unknown significance, 7.1%. Mutation-detection rates differed significantly between the high and other categories.
CONCLUSIONS AND RELEVANCE
Mutation rates are high in FTLD spectrum disorders, and the proposed criteria provide a validated standard for the classification of FTLD pedigrees. The combination of pedigree criteria and mutation-detection rates has important implications for genetic counseling and testing in clinical settings.
Frontotemporal lobar degeneration (FTLD) can manifest as a spectrum of clinical syndromes, ranging from behavioural impairment to language or motor dysfunction. Recently, revised diagnostic criteria have been proposed for the behavioural and progressive aphasia syndromes associated with frontotemporal degeneration. The present review will summarize these diagnostic guidelines and highlight some lingering controversies in the classification of FTLD clinical syndromes. We will discuss common tools and methods used to identify the insidious changes of behavioural variant frontotemporal dementia (bvFTD), the value of new, patient-based tasks of orbitofrontal function, and the issue of a benign or ‘phenocopy’ variant of bvFTD. With regard to primary progressive aphasia (PPA), we will discuss the scope of the semantic disorder in semantic-variant PPA, the nature of the speech disorder in non-fluent, agrammatic PPA, and the preliminary utility of a logopenic PPA classification.
Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) may have overlapping clinical presentations despite distinct underlying neuropathologies, thus making in vivo diagnosis challenging. In this study, we evaluate the utility of MRI as a noninvasive screening procedure for the differential diagnosis of AD and FTLD.
We recruited 185 patients with a clinically diagnosed neurodegenerative disease consistent with AD or FTLD who had a lumbar puncture and a volumetric MRI. A subset of 32 patients had genetic or autopsy-confirmed AD or FTLD. We used singular value decomposition to decompose MRI volumes and linear regression and cross-validation to predict CSF total tau (tt) and β-amyloid (Aβ1-42) ratio (tt/Aβ) in patients with AD and patients with FTLD. We then evaluated accuracy of MRI-based predicted tt/Aβ using 4 converging sources including neuroanatomic visualization and categorization of a subset of patients with genetic or autopsy-confirmed AD or FTLD.
Regression analyses showed that MRI-predicted tt/Aβ is highly related to actual CSF tt/Aβ. In each group, both predicted and actual CSF tt/Aβ have extensively overlapping neuroanatomic correlates: low tt/Aβ consistent with FTLD is related to ventromedial prefrontal regions while high tt/Aβ consistent with AD is related to posterior cortical regions. MRI-predicted tt/Aβ is 75% accurate at identifying underlying diagnosis in patients with known pathology and in clinically diagnosed patients with known CSF tt/Aβ levels.
MRI may serve as a noninvasive procedure that can screen for AD and FTLD pathology as a surrogate for CSF biomarkers.
Objective: To relate fractional anisotropy (FA) changes associated with the semantic and logopenic variants of primary progressive aphasia (PPA) to measures of lexical retrieval.
Methods: We collected neuropsychological testing, volumetric magnetic resonance imaging, and diffusion-weighted imaging on semantic variant PPA (svPPA) (n = 11) and logopenic variant PPA (lvPPA) (n = 13) patients diagnosed using published criteria. We also acquired neuroimaging data on a group of demographically comparable healthy seniors (n = 34). FA was calculated and analyzed using a white matter (WM) tract-specific analysis approach. This approach utilizes anatomically guided data reduction to increase sensitivity and localizes results within canonically defined tracts. We used non-parametric, cluster-based statistical analysis to relate language performance to FA and determine regions of reduced FA in patients.
Results: We found widespread FA reductions in WM for both variants of PPA. FA was related to both confrontation naming and category naming fluency performance in left uncinate fasciculus and corpus callosum in svPPA and left superior and inferior longitudinal fasciculi in lvPPA.
Conclusion: SvPPA and lvPPA are associated with distinct disruptions of a large-scale network implicated in lexical retrieval, and the WM disease in each phenotype may contribute to language impairments including lexical retrieval.
frontotemporal dementia; primary progressive aphasia; diffusion-weighted MRI; magnetic resonance imaging; neuropsychology
When making a decision, humans often have to ‘coordinate’—reach the same conclusion—as another individual without explicitly communicating. Relatively, little is known about the neural basis for coordination. Moreover, previous fMRI investigations have supported conflicting hypotheses. One account proposes that individuals coordinate using a ‘gut feeling’ and that this is supported by insula recruitment. Another account proposes that individuals recruit strategic decision-making mechanisms in prefrontal cortex in order to coordinate. We investigate the neural basis for coordination in individuals with behavioral-variant frontotemporal dementia (bvFTD) who have limitations in social decision-making associated with disease in prefrontal cortex. We demonstrate that bvFTD are impaired at establishing a focal point in a semantic task (e.g. ‘Tell me any boy's name’) that requires coordination relative to a similar, control semantic task that does not. Additionally, coordination limitations in bvFTD are related to cortical thinning in prefrontal cortex. These findings are consistent with behavioral economic models proposing that, beyond a ‘gut feeling’, strategic decision-making contributes to the coordination process, including a probabilistic mechanism that evaluates the salience of a response (e.g. is ‘John’ a frequent boy's name), a hierarchical mechanism that iteratively models an opponent's likely response and a mechanism involved in social perspective taking.
coordination; frontotemporal dementia; MRI; decision making; game theory
Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).
Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort.
ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP.
These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasize the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.
Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI).
We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974
100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group.
There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD.
Forest Research Institute
While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI).
Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide.
Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.
To examine whether frontal lobe abnormalities on magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) correlate with poor letter fluency (LF).
Twenty-five patients with ALS (20 with definite, probable, or possible ALS and 5 with progressive muscular atrophy) performed an LF task, involving F word generation in 1 minute, and underwent MRS. Comparisons were made between patients with ALS with impaired LF and unimpaired LF based on an empirically derived cutoff score. A Spearman correlation was performed between the patient's N-acetyl acetate/creatinine-phosphocreatinine ratio (NAA/Cr) and the number of F words generated.
LF was impaired in 50% of patients with ALS. Patients with impaired LF had reduced NAA/Cr in the DLPFC compared with those with unimpaired LF (p = 0.007). There was a significant correlation between LF and NAA/Cr in the DLPFC (r = 0.51, p = 0.0009). The ALS Functional Rating Scale score, clinical region of motor onset, and disease category had no effect on LF or NAA/Cr in the DLPFC.
A reduced NAA/Cr in the DLPFC of patients with ALS is a marker of neuronal dysfunction and correlates with impaired performance on a clinical measure of executive function.
To utilize values of cerebrospinal fluid (CSF) tau and ß-amyloid obtained from two different analytical immunoassays to differentiate Alzheimer’s disease (AD) from frontotemporal lobar degeneration (FTLD).
CSF values of total tau (t-tau) and ß-amyloid (Aß1-42) obtained using the INNOTEST® ELISA were transformed using a linear regression model to equivalent values obtained using the INNO-BIA AlzBio3™ (xMAP Luminex) assay. Cutoff values obtained from the xMAP assay were developed in a series of autopsy-confirmed cases and cross-validated in another series of autopsy-confirmed samples using transformed ELISA values to assess sensitivity and specificity for differentiating AD from FTLD.
Tertiary memory disorders clinics and neuropathological and biomarker core centers.
75 samples from patients with CSF data obtained from both assays were used for transformation of ELISA values. 40 autopsy-confirmed cases (30 AD, 10 FTLD) were used to establish diagnostic cutoff values, and then cross-validated in a second sample set of 21 autopsy-confirmed cases (11 AD, 10 FTLD) with transformed ELISA values.
Main outcome measure
Diagnostic accuracy using transformed biomarker values.
Data obtained from both assays were highly correlated. The t-tau:Aß1-42 ratio had the highest correlation between measures (r=0.928, p<0.001) and high reliability of transformation (ICC=0.89). A cutoff of 0.34 for the t-tau:Aß1-42 ratio had 90% and 100% sensitivity and 96.7% and 91% specificity to differentiate FTLD cases in the validation and cross-validation samples, respectively.
Values from two analytical platforms can be transformed into equivalent units, which can distinguish AD from FTLD more accurately than the clinical diagnosis.
Deficits in auditory perception compromise a range of linguistic processes in persons with Parkinson’s disease (PD), including speech perception and sensitivity to affective and linguistic prosody. An unanswered question is whether this deficit exists not only at the level of speech perception, but also at a more pervasive level of auditory perception. It is possible that PD produces a selective impairment in the perception of a salient acoustic feature such as frequency, amplitude, or duration.
Auditory perception in persons with PD was investigated using a tone discrimination task where clients (N = 12) and age-matched controls (N = 15) made same/different judgments for pairs of pure tones that were factorially varied by acoustic feature (i.e., frequency, amplitude, or duration) crossed with perceptual distance (i.e., close vs. far).
Relative to healthy age-matched controls, persons with PD showed marked impairment in tone discrimination. Persons with PD showed an acoustic feature by perceptual distance interaction that was characterized by deficits in detecting frequency and amplitude differences for perceptually near tones.
These results suggest that persons with PD show a reduced ability to notice change in frequency and amplitude as compared to normal older adults. More generally, these findings implicate a frontal–striatal contribution to auditory perception.
Parkinson’s disease; speech perception; auditory perception; tone detection; frontal lobe
Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease.
Since little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations.
Our data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP.
TMEM106B; Frontotemporal lobar degeneration; Frontotemporal dementia; TDP-43; Progranulin; FTLD-TDP
Amyotrophic Lateral Sclerosis (ALS) is associated with impaired executive control. The aim of the current research was to test the hypothesis that concept formation deficits associated with an extra-motor neurocognitive network involving executive and semantic resources can be found in some ALS patients.
Forty-one patients with clinically-definite ALS were assessed with Delis Kaplan Executive Function System Sorting Test (D-KEFS), a measure of concept formation requiring patients to manipulate verbal and visual semantic information and neuropsychological tests measuring naming, semantic memory, and executive control. Using D-KEFS scale scores, a k-mean cluster analysis specifying a 3-group solution was able to classify ALS patients into groups presenting with mildly impaired, average, and above average sorting test performance. High resolution T1 structural MRI was used to examine cortical thickness in a subset of 16 ALS patients.
Step-wise regression analyses related free and recognition sorting test performance to measures of action naming, single word semantic knowledge, and mental search/working memory. MRI studies found widespread cortical thinning involving bilateral frontal, temporal and parietal regions. Regression analyses related recognition sorting performance to reduced MRI cortical thickness involving the left prefrontal and left parietal cortex.
An extra-motor cognitive network is associated with impaired concept formation in ALS.
Amyotrophic Lateral Sclerosis (ALS); executive control; prefrontal cortex; neuropsychology; Delis-Kaplan Executive Function System (D-KEFS) Sorting Test
We propose to use the sparseness property of the gradient probability distribution to estimate the intensity nonuniformity in medical images, resulting in two novel automatic methods: a non-parametric method and a parametric method. Our methods are easy to implement because they both solve an iteratively re-weighted least squares problem. They are remarkably accurate as shown by our experiments on images of different imaged objects and from different imaging modalities.
In an era of disease-modifying treatments, the non-fluent/agrammatic variant of primary progressive aphasia (naPPA) may help screen for a specific cause of neurodegenerative disease. However, there are controversies surrounding the identification of naPPA. This review describes the characteristic features associated with this discrete, young-onset neurodegenerative condition. Patients with naPPA have a distinct limitation in language emphasizingtheir poor grammatical comprehension and expression, as well as a disorder of speech sound production. Imaging studies associate an impairment of this uniquely human language capacity with disruption of a large-scale neural network centered in left inferior frontal and anterior-superior temporal regions. This corresponds to thepathologic burden of disease anatomically focused in left inferior frontal and anterior-superior temporal regions. A review of the histopathology underlying naPPA relates this condition to frontotemporal lobar degeneration spectrum pathology involving the microtubule-associated protein tau in a majority of cases. While much work remains to be done, these observations point to unique clinical-pathological correlations that can advance care for an important class of diseases while supplementing our knowledge of human cognitive neuroscience.
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.
Alzheimer disease; Corticobasal degeneration; Frontotemporal dementia; Tauopathy; TDP-43
We contribute a novel and interpretable dimensionality reduction strategy, eigenanatomy, that is tuned for neuroimaging data. The method approximates the eigendecomposition of an image set with basis functions (the eigenanatomy vectors) that are sparse, unsigned and are anatomically clustered. We employ the eigenanatomy vectors as anatomical predictors to improve detection power in morphometry. Standard voxel-based morphometry (VBM) analyzes imaging data voxel-by-voxel—and follows this with cluster-based or voxel-wise multiple comparisons correction methods to determine significance. Eigenanatomy reverses the standard order of operations by first clustering the voxel data and then using standard linear regression in this reduced dimensionality space. As with traditional region-of-interest (ROI) analysis, this strategy can greatly improve detection power. Our results show that eigenanatomy provides a principled objective function that leads to localized, data-driven regions of interest. These regions improve our ability to quantify biologically plausible rates of cortical change in two distinct forms of neurodegeneration. We detail the algorithm and show experimental evidence of its efficacy.
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.
Patients with Lewy body spectrum disorders (LBSD) such as Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB) exhibit deficits in both narrative comprehension and narrative expression. The present research examines the hypothesis that these impairments are due to a material-neutral deficit in organizational executive resources rather than to impairments of language per se. We predicted that comprehension and expression of narrative would be similarly affected and that deficits in both expression and comprehension of narrative would be related to the same anatomic distribution of prefrontal disease.
We examined 29 LBSD patients and 26 healthy seniors on their comprehension and expression of narrative discourse. For comprehension, we measured accuracy and latency in judging events with high and low associativity from familiar scripts such as “going fishing.” The expression task involved maintaining the connectedness of events while narrating a story from a wordless picture book.
LBSD patients were impaired on measures of narrative organization during both comprehension and expression relative to healthy seniors. Measures of organization during narrative expression and comprehension were significantly correlated with each other. These measures both correlated with executive measures but not with neuropsychological measures of lexical semantics or grammar. Voxel-based morphometry revealed overlapping regressions relating frontal atrophy to narrative comprehension, narrative expression, and measures of executive control.
Difficulty with narrative discourse in LBSD stems in part from a deficit of organization common to comprehension and expression. This deficit is related to prefrontal cortical atrophy in LBSD.
Parkinson’s disease; speech; language; dementia with Lewy bodies
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.
language; quantifiers; fMRI; volumetric MRI; frontotemporal dementia
Pronouns are extraordinarily common in daily language yet little is known about the neural mechanisms that support decisions about pronoun reference. We propose a large-scale neural network for resolving pronoun reference that consists of two components. First, a core language network in peri-Sylvian cortex supports syntactic and semantic resources for interpreting pronoun meaning in sentences. Second, a frontal-parietal network that supports strategic decision-making is recruited to support probabilistic and risk-related components of resolving a pronoun’s referent. In an fMRI study of healthy young adults, we observed activation of left inferior frontal and superior temporal cortex, consistent with a language network. We also observed activation of brain regions not associated with traditional language areas. By manipulating the context of the pronoun, we were able to demonstrate recruitment of dorsolateral prefrontal cortex during probabilistic evaluation of a pronoun’s reference, and orbital frontal activation when a pronoun must adopt a risky referent. Together, these findings are consistent with a two-component model for resolving a pronoun’s reference that includes neuroanatomic regions supporting core linguistic and decision-making mechanisms.
decision-making; language processing; pronouns; fMRI; lexical semantic