Frontotemporal Degeneration with Transactive Response DNA-Binding Protein Type C at the Anterior Temporal Lobe.

The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding protein type C (TDP-C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP-C patients has highlighted the importance of this region for complex cognitive and behavioral functions. This review includes observations on 28 TDP-C patients, 18 with semantic primary progressive aphasia and 10 with other syndromes. Longitudinal imaging allowed the delineation of progression trajectories. At post-mortem examination, the pathognomonic feature of TDP-C consisted of long, thick neurites found predominantly in superficial cortical layers. These neurites may represent dystrophic apical dendrites of layer III and V pyramidal neurons that are known to play pivotal roles in complex cortical computations. Other types of frontotemporal lobar degeneration TDP, such as TDP-A and TDP-B, are not associated with long dystrophic neurites in the cerebral cortex, and do not show similar predilection patterns for ATL. Research is beginning to identify molecular, structural, and immunological differences between pathological TDP-43 in TDP-C versus TDP-A and B. Parallel investigations based on proteomics, somatic mutations, and genome-wide association studies are detecting molecular features that could conceivably mediate the selective vulnerability of ATL to TDP-C. Future work will focus on characterizing the distinctive features of the abnormal TDP-C neurites, the mechanisms of neurotoxicity, initial cellular targets within the ATL, trajectory of spread, and the nature of ATL-specific markers that modulate vulnerability to TDP-C. ANN NEUROL 2023;94:1-12.

Neuropathological fingerprints of survival, atrophy and language in primary progressive aphasia.

Primary progressive aphasia is a neurodegenerative disease that selectively impairs language without equivalent impairment of speech, memory or comportment. In 118 consecutive autopsies on patients with primary progressive aphasia, primary diagnosis was Alzheimer's disease neuropathological changes (ADNC) in 42%, corticobasal degeneration or progressive supranuclear palsy neuropathology in 24%, Pick's disease neuropathology in 10%, transactive response DNA binding proteinopathy type A [TDP(A)] in 10%, TDP(C) in 11% and infrequent entities in 3%. Survival was longest in TDP(C) (13.2 ± 2.6 years) and shortest in TDP(A) (7.1 ± 2.4 years). A subset of 68 right-handed participants entered longitudinal investigations. They were classified as logopenic, agrammatic/non-fluent or semantic by quantitative algorithms. Each variant had a preferred but not invariant neuropathological correlate. Seventy-seven per cent of logopenics had ADNC, 56% of agrammatics had corticobasal degeneration/progressive supranuclear palsy or Pick's disease and 89% of semantics had TDP(C). Word comprehension impairments had strong predictive power for determining underlying neuropathology positively for TDP(C) and negatively for ADNC. Cortical atrophy was smallest in corticobasal degeneration/progressive supranuclear palsy and largest in TDP(A). Atrophy encompassed posterior frontal but not temporoparietal cortex in corticobasal degeneration/progressive supranuclear palsy, anterior temporal but not frontoparietal cortex in TDP(C), temporofrontal but not parietal cortex in Pick's disease and all three lobes with ADNC or TDP(A). There were individual deviations from these group patterns, accounting for less frequent clinicopathologic associations. The one common denominator was progressive asymmetric atrophy overwhelmingly favouring the left hemisphere language network. Comparisons of ADNC in typical amnestic versus atypical aphasic dementia and of TDP in type A versus type C revealed fundamental biological and clinical differences, suggesting that members of each pair may constitute distinct clinicopathologic entities despite identical downstream proteinopathies. Individual TDP(C) participants with unilateral left temporal atrophy displayed word comprehension impairments without additional object recognition deficits, helping to dissociate semantic primary progressive aphasia from semantic dementia. When common and uncommon associations were considered in the set of 68 participants, one neuropathology was found to cause multiple clinical subtypes, and one subtype of primary progressive aphasia to be caused by multiple neuropathologies, but with different probabilities. Occasionally, expected clinical manifestations of atrophy sites were absent, probably reflecting individual peculiarities of language organization. The hemispheric asymmetry of neurodegeneration and resultant language impairment in primary progressive aphasia reflect complex interactions among the cellular affinities of the degenerative disease, the constitutive biology of language cortex, familial or developmental vulnerabilities of this network and potential idiosyncrasies of functional anatomy in the affected individual.

Relationships among tau burden, atrophy, age, and naming in the aphasic variant of Alzheimer's disease.

INTRODUCTION: Examination of pathologic, anatomic, and cognitive relationships has been limited in primary progressive aphasia (PPA) with underlying Alzheimer's disease (AD) neuropathology. METHODS: Spatial relationships between tau positron emission tomography (PET), cortical thickness, age, and naming on the Boston Naming Test (BNT) in PPA with biomarker evidence of AD (PPA-AD) were examined. RESULTS: Higher tau PET burden was associated with atrophy and younger age. There was a significant left-lateralized relationship between lower BNT and more atrophy, and between lower BNT and increased tau burden. Variance in naming was primarily shared between tau and atrophy (51%), but naming was uniquely explained more by atrophy (32%) than tau (16%). Higher left anterior temporal tau burden was associated with greater 1-year rate of decline in naming. DISCUSSION: PPA-AD has a similar relationship between abnormal biomarkers as first described in amnestic AD, with differing spatial extent, reflecting the left-lateralized nature of the language network.

Functional decline in the aphasic variant of Alzheimer's disease.

INTRODUCTION: Primary progressive aphasia (PPA) is a clinical dementia syndrome associated with frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD). Impairment in activities of daily living is essential for dementia diagnosis, yet less is known about the neuropathologic impact on functional decline in PPA, especially over time. METHODS: Activities of Daily Living Questionnaire (ADLQ) ratings were compared by suspected underlying pathology between 17 PPAAß+ and 11 PPAAß- participants at 6-month intervals for 2 years using a linear mixed-effects model. A general linear model examined associations between functional decline and cortical thickness at baseline. RESULTS: Groups did not differ in demographics or aphasia severity at baseline, yet overall and subdomain scores of the ADLQ were significantly worse for PPAAß+ compared to PPAAß- (P = .015) at each interval across 18 months. DISCUSSION: Functional decline appears more pronounced and disrupts more aspects of life activities for individuals with non-semantic PPA with suspected AD versus non-AD neuropathology.

Clinical and cortical decline in the aphasic variant of Alzheimer's disease.

INTRODUCTION: Primary progressive aphasia (PPA) displays variable progression trajectories that require further elucidation. METHODS: Longitudinal quantitation of atrophy and language over 12 months was completed for PPA patients with and without positive amyloid PET (PPAAß+ and PPAAß-), an imaging biomarker of underlying Alzheimer's disease. RESULTS: Over 12 months, both PPA groups showed significantly greater cortical atrophy rates in the left versus right hemisphere, with a more widespread pattern in PPAAß+. The PPAAß+ group also showed greater decline in performance on most language tasks. There was no obligatory relationship between the logopenic PPA variant and amyloid status. Effect sizes from quantitative MRI data were more robust than neuropsychological metrics. DISCUSSION: Preferential language network neurodegeneration is present in PPA irrespective of amyloid status. Clinical and anatomical progression appears to differ for PPA due to Alzheimer's disease versus non-Alzheimer's disease neuropathology, a distinction that may help to inform prognosis and the design of intervention trials.

Functional Connectivity is Reduced in Early-stage Primary Progressive Aphasia When Atrophy is not Prominent.

Primary progressive aphasia (PPA) is a clinical syndrome of language decline caused by neurodegenerative pathology. Although language impairments in PPA are typically localized via the morphometric assessment of atrophy, functional changes may accompany or even precede detectable structural alterations, in which case resting state functional connectivity (RSFC) could provide an alternative approach. The goal of this study was to determine whether language network RSFC is reduced in early-stage PPA when atrophy is not prominent. We identified 10 individuals with early-stage agrammatic variant of PPA with no prominent cortical thinning compared with nonaphasic controls. RSFC between 2 nodes of the language network and 2 nodes of the default mode network were compared between agrammatic variant of PPA and healthy control participants. Language network connectivity was comparable with controls among patients with milder agrammatism, but was significantly reduced in patients with more pronounced agrammatism. No group differences were observed in default mode network connectivity, demonstrating specificity of findings. In early stages of PPA when cortical atrophy is not prominent, RSFC provides an alternative method for probing the neuroanatomic substrates of language impairment. RSFC may be of particular utility in studies on early interventions for neurodegenerative disease, either to identify anatomic targets for intervention or as an outcome measure of therapeutic efficacy.

SuperAging functional connectomics from resting-state functional MRI.

Understanding the relationship between functional connectivity (FC) of higher-order neurocognitive networks and age-related cognitive decline is a complex and evolving field of research. Decreases in FC have been associated with cognitive decline in persons with Alzheimer's disease and related dementias (ADRD). However, the contributions of FC have been less straightforward in typical cognitive aging. Some investigations suggest relatively robust FC within neurocognitive networks differentiates unusually successful cognitive aging from average aging, while others do not. Methodologic limitations in data processing and varying definitions of 'successful aging' may have contributed to the inconsistent results to date. The current study seeks to address previous limitations by optimized MRI methods to examine FC in the well-established SuperAging phenotype, defined by age and cognitive performance as individuals 80 and older with episodic memory performance equal to or better than 50-to-60-year-olds. Within- and between-network FC of large-scale neurocognitive networks were compared between 24 SuperAgers and 16 cognitively average older-aged control (OACs) with stable cognitive profiles using resting-state functional MRI (rs-fMRI) from a single visit. Group classification was determined based on measures of episodic memory, executive functioning, verbal fluency and picture naming. Inclusion criteria required stable cognitive status across two visits. First, we investigated the FC within and between seven resting-state networks from a common atlas parcellation. A separate index of network segregation was also compared between groups. Second, we investigated the FC between six subcomponents of the default mode network (DMN), the neurocognitive network commonly associated with memory performance and disrupted in persons with ADRD. For each analysis, FCs were compared across groups using two-sample independent t-tests and corrected for multiple comparisons. There were no significant between-group differences in demographic characteristics including age, sex and education. At the group-level, within-network FC, between-network FC, and segregation measurements of seven large-scale networks, including subcomponents of the DMN, were not a primary differentiator between cognitively average aging and SuperAging phenotypes. Thus, FC within or between large-scale networks does not appear to be a primary driver of the exceptional memory performance observed in SuperAgers. These results have relevance for differentiating the role of FC changes associated with cognitive aging from those associated with ADRD.

Disinhibition in dementia related to reduced morphometric similarity of cognitive control network.

Disinhibition is one of the most distressing and difficult to treat neuropsychiatric symptoms of dementia. It involves socially inappropriate behaviours, such as hypersexual comments, inappropriate approaching of strangers and excessive jocularity. Disinhibition occurs in multiple dementia syndromes, including behavioural variant frontotemporal dementia, and dementia of the Alzheimer's type. Morphometric similarity networks are a relatively new method for examining brain structure and can be used to calculate measures of network integrity on large scale brain networks and subnetworks such as the salience network and cognitive control network. In a cross-sectional study, we calculated morphometric similarity networks to determine whether disinhibition in behavioural variant frontotemporal dementia (n = 75) and dementia of the Alzheimer's type (n = 111) was associated with reduced integrity of these networks independent of diagnosis. We found that presence of disinhibition, measured by the Neuropsychiatric Inventory Questionnaire, was associated with reduced global efficiency of the cognitive control network in both dementia of the Alzheimer's type and behavioural variant frontotemporal dementia. Future research should replicate this transdiagnostic finding in other dementia diagnoses and imaging modalities, and investigate the potential for intervention at the level of the cognitive control network to target disinhibition.

Modularity and granularity across the language network-A primary progressive aphasia perspective.

Tests of grammar, repetition and semantics were administered to 62 prospectively enrolled right-handed participants with primary progressive aphasia (PPA). Structural brain images were obtained at the time of testing. Regression analyses uncovered 3 clearly delineated non-overlapping left hemisphere clusters where cortical thinning (atrophy) was significantly correlated with impaired performance. A morphosyntactic cluster associated with the grammaticality of sentence construction was located predominantly within the middle and inferior frontal gyri; a phonolexical cluster associated with language repetition was located in the temporoparietal junction; a lexicosemantic cluster associated with object naming and single word comprehension was located within the middle and anterior parts of the temporal lobe and extended into insular, orbitofrontal, and mediotemporal cortices. Commonality analyses were undertaken to explore whether these three clusters were as modular as indicated by the regression analyses or whether some underlying functional granularity could be uncovered. Modularity was defined as the exclusive association of an anatomical cluster with a single type of language task whereas granularity was defined as the association of a single anatomical cluster with more than one type of language task. The commonality analyses revealed a predominantly modular organization with quantitatively minor instances of inter-cluster granularity. The results also reconfirmed previous work on PPA which had shown that Wernicke's area is not essential for word comprehension, that naming impairments can be based either on deficits of lexical retrieval or word comprehension, and that the essential substrates of word comprehension encompass much wider areas of the temporal lobe than the temporal pole. The anatomy of the language network has traditionally been explored through patients with focal cerebrovascular accidents and experiments based on functional activation. Investigations on PPA are showing that focal neurodegenerations can add new perspectives to existing models of the language network.

Memory Resilience in Alzheimer Disease With Primary Progressive Aphasia.

OBJECTIVE: To determine whether memory is preserved longitudinally in primary progressive aphasia (PPA) associated with Alzheimer disease (AD) and to identify potential factors that maintain memory despite underlying neurofibrillary degeneration of mediotemporal memory areas. METHODS: Longitudinal memory assessment was done in 17 patients with PPA with autopsy or biomarker evidence of AD (PPA-AD) and 14 patients with amnestic dementia of the Alzheimer type with AD at autopsy (DAT-AD). RESULTS: In PPA-AD, episodic memory, tested with nonverbal items, was preserved at the initial testing and showed no decline at retesting 2.35 ± 0.78 years later, at which time symptoms had been present for 6.26 ± 2.21 years. In contrast, language functions declined significantly during the same period. In DAT-AD, both verbal memory and language declined with equal severity. Although imaging showed asymmetric left-sided mediotemporal atrophy in PPA-AD, autopsy revealed bilateral hippocampo-entorhinal neurofibrillary degeneration at Braak stages V and VI. Compared to DAT-AD, however, the PPA-AD group had lower incidence of APOE ε4 and of mediotemporal TAR DNA-binding protein 43 (TDP-43) pathology. CONCLUSIONS: Memory preservation in PPA is not just an incidental finding at onset but a core feature that persists for years despite the hippocampo-entorhinal AD neuropathology that is as severe as that of DAT-AD. Asymmetry of mediotemporal atrophy and a lesser impact of APOE ε4 and of TDP-43 on the integrity of memory circuitry may constitute some of the factors underlying this resilience. Our results also suggest that current controversies on memory in PPA-AD reflect inconsistencies in the diagnosis of logopenic PPA, the clinical variant most frequently associated with AD. CLINICALTRIALSGOV IDENTIFIER: NCT00537004 and NCT03371706.

Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer's disease.

The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non-amnestic clinical AD variants, including primary progressive aphasia (PPA-AD). PPA-AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language-dominant hemisphere. Here, a stereologic investigation of five PPA-AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA-DR) from bilateral language and non-language regions where in vivo cortical atrophy and Thioflavin-S-positive APs and NFTs were previously quantified. NeuN-positive neurons and morphologic subtypes of HLA-DR-positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA-AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA-AD.

Differential neurocognitive network perturbation in amnestic and aphasic Alzheimer disease.

OBJECTIVE: To determine if Alzheimer disease (AD) is associated with aphasic rather than amnestic dementias in certain circumstances related in part to perturbations in different networks. METHODS: Three groups were investigated: 14 participants suspected of having the neuropathology of AD based on clinically diagnosed amnestic dementia of the Alzheimer type (DAT), 26 individuals with primary progressive aphasia (PPA) with either a positive 18F-florbetapir amyloid PET scan or confirmed AD at autopsy, and 26 neurologically intact controls. The groups were compared using rs-fMRI. Seeds included the left hemisphere inferior frontal gyrus (IFG) for the language network, the left hippocampus for the episodic memory network, and the left posterior cingulate for the default mode network (DMN). RESULTS: Greater connectivity perturbations were found from the hippocampus for the DAT group and from the IFG for the PPA group. Furthermore, connectivity alterations in the PPA group were more asymmetric and favored the language-dominant left hemisphere. Loss of connectivity from the DMN seed was of a similar magnitude in the PPA and DAT groups. CONCLUSIONS: Despite the presumptive common underlying neuropathology of amyloid plaques and neurofibrillary tangles, the 2 groups displayed 2 different patterns of network perturbation, each concordant with the clinical presentation and the anatomy of neurodegeneration.

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease.

The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7-30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

Familial language network vulnerability in primary progressive aphasia.

OBJECTIVE: To investigate evidence of the potential role of early cortical vulnerability in the development of primary progressive aphasia (PPA). METHOD: A woman with a diagnosis of PPA and her 9 adult siblings, 7 with developmental language disabilities, underwent neuropsychological testing, structural MRI, and resting-state fMRI. Whole-exome sequencing was conducted for genes associated with dyslexia or with neurodegenerative dementia. RESULTS: The siblings demonstrated lower verbal than nonverbal cognitive test scores in a developmental dyslexia pattern. On structural MRI, although the siblings did not differ from controls in total brain volume, the left hemisphere language area volume was significantly smaller than the right. Furthermore, cortical connectivity between the left superior temporal area, previously identified as the region of peak atrophy in the proband early in the course of illness, and adjacent language network components, including the planum temporale, was decreased in the siblings. No distinctive genetic signatures were identified. CONCLUSION: This report further supports the hypothesis that at least some cases of PPA may be based on a familial language network vulnerability that interferes with the acquisition of language in some members and that makes the language network a locus of least resistance to the effects of an independently late-arising neurodegenerative disease in others. This association offers a conceptual model to explain why identical neurodegenerative diseases may selectively target the language network in some individuals while targeting networks that regulate memory or behavior in others. The genetic basis for this vulnerability remains to be determined.

Anatomical evidence of an indirect pathway for word repetition.

OBJECTIVE: To combine MRI-based cortical morphometry and diffusion white matter tractography to describe the anatomical correlates of repetition deficits in patients with primary progressive aphasia (PPA). METHODS: The traditional anatomical model of language identifies a network for word repetition that includes Wernicke and Broca regions directly connected via the arcuate fasciculus. Recent tractography findings of an indirect pathway between Wernicke and Broca regions suggest a critical role of the inferior parietal lobe for repetition. To test whether repetition deficits are associated with damage to the direct or indirect pathway between both regions, tractography analysis was performed in 30 patients with PPA (64.27 ± 8.51 years) and 22 healthy controls. Cortical volume measurements were also extracted from 8 perisylvian language areas connected by the direct and indirect pathways. RESULTS: Compared to healthy controls, patients with PPA presented with reduced performance in repetition tasks and increased damage to most of the perisylvian cortical regions and their connections through the indirect pathway. Repetition deficits were prominent in patients with cortical atrophy of the temporo-parietal region with volumetric reductions of the indirect pathway. CONCLUSIONS: The results suggest that in PPA, deficits in repetition are due to damage to the temporo-parietal cortex and its connections to Wernicke and Broca regions. We therefore propose a revised language model that also includes an indirect pathway for repetition, which has important clinical implications for the functional mapping and treatment of neurologic patients.

Word comprehension in temporal cortex and Wernicke area: A PPA perspective.

OBJECTIVE: To explore atrophy-deficit correlations of word comprehension and repetition in temporoparietal cortices encompassing the Wernicke area, based on patients with primary progressive aphasia (PPA). METHODS: Cortical thickness in regions within and outside the classical Wernicke area, measured by FreeSurfer, was correlated with repetition and single word comprehension scores in 73 right-handed patients at mild to moderate stages of PPA. RESULTS: Atrophy in the Wernicke area was correlated with repetition (r = 0.42, p = 0.001) but not single word comprehension (r = -0.072, p = 0.553). Correlations with word comprehension were confined to more anterior parts of the temporal lobe, especially its anterior third (r = 0.60, p < 0.001). A single case with postmortem autopsy illustrated preservation of word comprehension but not repetition 6 months prior to death despite nearly 50% loss of cortical volume and severe neurofibrillary degeneration in core components of the Wernicke area. CONCLUSIONS: Temporoparietal cortices containing the Wernicke area are critical for language repetition. Contrary to the formulations of classic aphasiology, their role in word and sentence comprehension is ancillary rather than critical. Thus, the Wernicke area is not sufficient to sustain word comprehension if the anterior temporal lobe is damaged. Traditional models of the role of the Wernicke area in comprehension are based almost entirely on patients with cerebrovascular lesions. Such lesions also cause deep white matter destruction and acute network diaschisis, whereas progressive neurodegenerative diseases associated with PPA do not. Conceptualizations of the Wernicke area that appear to conflict, therefore, can be reconciled by considering the hodologic and physiologic differences of the underlying lesions.

A nonverbal route to conceptual knowledge involving the right anterior temporal lobe.

The semantic variant of primary progressive aphasia (PPA-S) is diagnosed based on impaired single-word comprehension, but nonverbal impairments in face and object recognition can also be present, particularly in later disease stages. PPA-S is associated with focal atrophy in the left anterior temporal lobe (ATL), often accompanied by a lesser degree of atrophy in the right ATL. According to a dual-route account, the left ATL is critical for verbal access to conceptual knowledge while nonverbal access to conceptual knowledge depends upon the integrity of right ATL. Consistent with this view, single-word comprehension deficits in PPA-S have consistently been linked to the degree of atrophy in left ATL. In the current study we examined object processing and cortical thickness in 19 patients diagnosed with PPA-S, to evaluate the hypothesis that nonverbal object impairments would instead be determined by the amount of atrophy in the right ATL. All patients demonstrated inability to access conceptual knowledge on standardized tests with word stimuli: they were unable to match spoken words with their corresponding pictures on the Peabody Picture Vocabulary Test. Only a minority of patients, however, performed abnormally on an experimental thematic verification task, which requires judgments as to whether pairs of object pictures are thematically-associated, and does not rely on auditory or visual word input. The entire PPA-S group showed cortical thinning in left ATL, but atrophy in right ATL was more prominent in the subgroup with low verification scores. Thematic verification scores were correlated with cortical thickness in the right rather than left ATL, an asymmetric mapping which persisted when controlling for the degree of atrophy in the contralateral hemisphere. These results are consistent with a dual-route account of conceptual knowledge: breakdown of the verbal left hemispheric route produces an aphasic syndrome, which is only accompanied by visual object processing impairments when the nonverbal right hemispheric route is also compromised.

Aphasic variant of Alzheimer disease: Clinical, anatomic, and genetic features.

OBJECTIVE: To identify features of primary progressive aphasia (PPA) associated with Alzheimer disease (AD) neuropathology. A related objective was to determine whether logopenic PPA is a clinical marker for AD. METHODS: A total of 139 prospectively enrolled participants with a root diagnosis of PPA constituted the reference set. Those with autopsy or biomarker evidence of AD, and who had been evaluated at mild disease stages (Aphasia Quotient ≥85), were included (n = 19). All had quantitative language testing and APOE genotyping. Fifteen had MRI morphometry. RESULTS: Impaired word-finding was the universal presenting complaint in the aphasic AD group. PPA clinical subtype was logopenic (n = 13) and agrammatic (n = 6). Fluency, repetition, naming, and grammaticality ranged from preserved to severely impaired. All had relative preservation of word comprehension. Eight of the 15 aphasic participants with AD showed no appreciable cortical atrophy at the individual level on MRI. As a group, atrophy was asymmetrically concentrated in the left perisylvian cortex. APOE ε4 frequency was not elevated. CONCLUSIONS: There is a close, but not obligatory, association between logopenic PPA and AD. No language measure, with the possible exception of word comprehension, can confirm or exclude AD in PPA. Biomarkers are therefore essential for diagnosis. Asymmetry of cortical atrophy and normal APOE ε4 prevalence constitute deviations from typical AD. These and additional neuropathologic features suggest that AD has biological subtypes, one of which causes PPA. Better appreciation of this fact should promote the inclusion of individuals with PPA and positive AD biomarkers into relevant clinical trials.

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials.

BACKGROUND: Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures. METHODS: We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski et al. [Neurology 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al. [Pharmaceutical Statistics 2015;14:418-426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints. RESULTS: The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint. CONCLUSIONS: Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease.