Corey T. McMillan

The Neural Basis for Categorization in Semantic Memory

We asked young adults to categorize written object descriptions into one of two categories, based on a rule or on overall similarity, while we monitored regional brain activity with functional magnetic resonance imaging (fMRI). We found significantly greater recruitment of left dorsolateral prefrontal cortex for rule-based categorization in direct comparison with similarity-based categorization. Recruitment of right ventral frontal cortex and thalamus was uniquely associated with rule-based categorization as well. These observations lend support to the claim that executive functions such as working memory, inhibitory control, and selective attention contribute to rule-based categorization. Right inferior parietal activation was uniquely associated with similarity-based categorization. This region may play an important role in overall feature configuration that is important for this form of categorization. We found other brain regions recruited for both rule-based and similarity-based categorization: Anterior cingulate cortex may support the implementation of executive functions during situations with competing response alternatives; and left inferior parietal cortex may be related to the integration of feature knowledge about objects represented in modality-specific association cortices. We also administered a degraded-similarity condition where the task of categorizing a written object description was made more difficult by perceptually degrading the stimulus materials. The degraded condition and the rule-based condition, but not the similarity-based condition, were associated with caudate activation. The caudate may support resource demands that are not specific for a particular categorization process. These findings associate partially distinct large-scale neural networks with different forms of categorization in semantic memory.

Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine

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.

Non-fluent speech in frontotemporal lobar degeneration

We investigated the cognitive and neural bases of impaired speech fluency, a central feature of primary progressive aphasia. Speech fluency was assessed in 35 patients with frontotemporal lobar degeneration (FTLD) who presented with progressive non-fluent aphasia (PNFA, n=11), semantic dementia (SemD, n=12), or a social and executive disorder without aphasia (SOC/EXEC, n=12). Fluency was quantified as the number of words per minute in an extended, semi-structured speech sample. This was related to language characteristics of the speech sample and to neuropsychological measures. PNFA patients were significantly less fluent than controls and other FTLD patients. Fluency correlated with grammatical expression but not with speech errors or executive difficulty. SemD and SOC/EXEC patients were also less fluent than controls. In SemD, fluency was associated with semantically limited content. In SOC/EXEC, fluency was associated with executive limitations. Voxel-based morphometry analyses of high-resolution MRI related fluency to gray matter volume in left inferior frontal, insula, and superior temporal regions for the entire cohort of FTLD patients. This region overlapped partially distinct atrophic areas in each FTLD subgroup. It thus appears to play a crucial role in speech fluency, which can be interrupted in different ways in different FTLD subgroups.

Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia

Objective: Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are hypothesized to cause clinically distinct forms of primary progressive aphasia (PPA) that predominantly affect expressive speech. AD is thought to cause logopenic progressive aphasia (LPA), and FTLD may cause progressive nonfluent aphasia (PNFA). We sought to determine the value of clinical characterization, neuropsychological analysis, and MRI atrophy in predicting pathology of LPA and PNFA. Methods: Patients with LPA (n = 19) and patients with PNFA (n = 19) were evaluated with neuropsychological assessments, structural MRI, CSF analysis, and neuropathologic examination. Results: Twelve of 19 patients with LPA (63%) and 6 of 19 patients with PNFA (32%) had neuropathologic findings or CSF biomarkers consistent with AD. Neuropsychological testing showed that naming was more impaired in patients with AD, and letter-guided fluency was more affected in patients with a non-AD disorder. Voxel-based morphometry analysis revealed that in patients with AD, patients with LPA and PNFA had significant posterior-superior temporal atrophy; in patients with non-AD, patients with LPA had peri-Sylvian atrophy and patients with PNFA had dorsolateral prefrontal and insular atrophy. Receiver operator characteristic curve analysis showed that combining neuropsychological testing with MRI atrophy pattern had 90% specificity for pathology or CSF biomarkers consistent with AD, and combining clinical features with neuropsychological analysis had 100% sensitivity for pathology or CSF biomarkers consistent with AD. Conclusions: Neither PPA phenotyping nor imaging alone is a reliable predictor of pathology. Multimodal predictors, such as combining neuropsychological testing with MRI analysis, can improve noninvasive prediction of underlying pathology in nonfluent forms of PPA.

Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis

Background 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 TAR DNA-binding protein 43 (TDP-43) proteinopathy. Methods A retrospective case-control study was carried out 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). Results C9P cases had an earlier age of onset (p=0.047) and, in the subset of patients who were deceased, 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-rank λ2=4.183, p=0.041), and C9P FTLD showed a significantly greater annualised rate of decline in letter fluency (4.5±1.3 words/year) than C9N FTLD (1.4±0.8 words/year, p=0.023). VBM revealed greater atrophy in the right frontoinsular, 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. Neuropathological 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. Conclusions 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 patients with ALS and FTLD.

Dissociable Patterns of Brain Activity during Comprehension of Rapid and Syntactically Complex Speech: Evidence from fMRI.

Sentence comprehension is a complex task that involves both language-specific processing components and general cognitive resources. Comprehension can be made more difficult by increasing the syntactic complexity or the presentation rate of a sentence, but it is unclear whether the same neural mechanism underlies both of these effects. In the current study, we used event-related functional magnetic resonance imaging (fMRI) to monitor neural activity while participants heard sentences containing a subject-relative or object-relative center-embedded clause presented at three different speech rates. Syntactically complex object-relative sentences activated left inferior frontal cortex across presentation rates, whereas sentences presented at a rapid rate recruited frontal brain regions such as anterior cingulate and premotor cortex, regardless of syntactic complexity. These results suggest that dissociable components of a large-scale neural network support the processing of syntactic complexity and speech presented at a rapid rate during auditory sentence processing.

The neural basis for novel semantic categorization.

We monitored regional cerebral activity with BOLD fMRI during acquisition of a novel semantic category and subsequent categorization of test stimuli by a rule-based strategy or a similarity-based strategy. We observed different patterns of activation in direct comparisons of rule- and similarity-based categorization. During rule-based category acquisition, subjects recruited anterior cingulate, thalamic, and parietal regions to support selective attention to perceptual features, and left inferior frontal cortex to helps maintain rules in working memory. Subsequent rule-based categorization revealed anterior cingulate and parietal activation while judging stimuli whose conformity with the rules was readily apparent, and left inferior frontal recruitment during judgments of stimuli whose conformity was less apparent. By comparison, similarity-based category acquisition showed recruitment of anterior prefrontal and posterior cingulate regions, presumably to support successful retrieval of previously encountered exemplars from long-term memory, and bilateral temporal-parietal activation for perceptual feature integration. Subsequent similarity-based categorization revealed temporal-parietal, posterior cingulate, and anterior prefrontal activation. These findings suggest that large-scale networks support relatively distinct categorization processes during the acquisition and judgment of semantic category knowledge.

White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration

Background 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). Methods 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. Results 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. Conclusions These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasise the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.

Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration

Objective: To test the hypothesis that different neurocognitive networks underlie verbal fluency deficits in frontotemporal lobar degeneration (FTLD). Methods: Letter (“FAS”) and semantic (“animal”) fluency tests were administered to patients with a behavioral/dysexecutive disorder (bvFTLD; n = 71), semantic dementia (SemD; n = 21), and progressive nonfluent aphasia (PNFA; n = 26). Tests measuring working memory, naming/lexical retrieval, and semantic knowledge were also obtained. MRI voxel-based morphometry (VBM) studies were obtained on a subset of these patients (bvFTLD, n = 51; PNFA, n = 11; SemD, n = 10). Results: Patients with SemD were disproportionately impaired on the semantic fluency measure. Reduced output on this test was correlated with impaired performance on naming/lexical retrieval tests. VBM analyses related reduced letter and semantic fluency to anterior and inferior left temporal lobe atrophy. Patients with bvFTLD were equally impaired on both fluency tests. Poor performance on both fluency tests was correlated with low scores on working memory and naming/lexical retrieval measures. In this group, MRI-VBM analyses related letter fluency to bilateral frontal atrophy and semantic fluency to left frontal/temporal atrophy. Patients with PNFA were also equally impaired on fluency tests. Reduced semantic fluency output was correlated with reduced performance on naming/lexical retrieval tests. MRI-VBM analyses related semantic fluency to the right frontal lobe and letter fluency to left temporal atrophy. Conclusions: Distinct neurocognitive networks underlie impaired performance on letter and semantic fluency tests in frontotemporal lobar degeneration subgroups.

Comparison of Cerebrospinal Fluid Levels of Tau and Aβ 1-42 in Alzheimer Disease and Frontotemporal Degeneration Using 2 Analytical Platforms

OBJECTIVE To use values of cerebrospinal fluid tau and β-amyloid obtained from 2 different analytical immunoassays to differentiate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). DESIGN Cerebrospinal fluid values of total tau (T-tau) and β-amyloid 1-42 (Aβ 1-42) obtained using the Innotest enzyme-linked immunosorbent assay 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 enzyme-linked immunosorbent assay values to assess sensitivity and specificity for differentiating AD from FTLD. SETTING Tertiary memory disorder clinics and neuropathologic and biomarker core centers. PARTICIPANTS Seventy-five samples from patients with cerebrospinal fluid data obtained from both assays were used for transformation of enzyme-linked immunosorbent assay values. Forty autopsy-confirmed cases (30 with AD and 10 with FTLD) were used to establish diagnostic cutoff values and then cross validated in a second sample set of 21 autopsy-confirmed cases (11 with AD and 10 with FTLD) with transformed enzyme-linked immunosorbent assay values. MAIN OUTCOME MEASURE Diagnostic accuracy using transformed biomarker values. RESULTS Data obtained from both assays were highly correlated. The T-tau to Aβ 1-42 ratio had the highest correlation between measures (r = 0.928, P < .001) and high reliability of transformation (intraclass correlation coefficient= 0.89). A cutoff of 0.34 for the T-tau to Aβ 1-42 ratio had 90% and 100% sensitivity and 96.7% and 91% specificity to differentiate FTLD cases in the validation and cross-validation samples, respectively. CONCLUSIONS Values from 2 analytical platforms can be transformed into equivalent units, which can distinguish AD from FTLD more accurately than the clinical diagnosis.