Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias.

Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.

Distinct and shared neuropsychiatric phenotypes in FTLD-tauopathies.

Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau) commonly causes dementia syndromes that include primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD). Cognitive decline in PPA and bvFTD is often accompanied by debilitating neuropsychiatric symptoms. In 44 participants with PPA or bvFTD due to autopsy-confirmed FTLD-tau, we characterized neuropsychiatric symptoms at early and late disease stages and determined whether the presence of certain symptoms predicted a specific underlying FTLD-tauopathy. Participants completed annual research visits at the Northwestern University Alzheimer's Disease Research Center. All participants had an initial Global Clinical Dementia Rating (CDR) Scale score ≤ 2, and neuropsychiatric symptoms were evaluated via the Neuropsychiatric Inventory-Questionnaire (NPI-Q). We assessed the frequency of neuropsychiatric symptoms across all participants at their initial and final visits and performed logistic regression to determine whether symptoms predicted a specific FTLD-tau pathologic diagnosis. Across the FTLD-tau cohort, irritability and apathy were most frequently endorsed at initial and final visits, respectively, whereas psychosis was highly uncommon at both timepoints. Irritability at initial visit predicted greater odds of a 4-repeat compared to a 3-repeat tauopathy (OR = 3.95, 95% CI = 1.10-15.83, p < 0.05). Initial sleep disturbance predicted greater odds of progressive supranuclear palsy (PSP) compared to other FTLD-tau subtypes (OR = 10.68, 95% CI = 2.05-72.40, p < 0.01). Appetite disturbance at final evaluation predicted lower odds of PSP (OR = 0.15, 95% CI = 0.02-0.74, p < 0.05). Our findings suggest that characterization of neuropsychiatric symptoms can aid in the prediction of underlying FTLD-tauopathies. Given considerable pathologic heterogeneity underlying dementias, neuropsychiatric symptoms may be useful for differential diagnosis and treatment planning.

Differential vulnerability of the dentate gyrus to tauopathies in dementias.

The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles-3R Pick's disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p < 0.001), followed by CBD, AD, then PSP. PPA-AD cases showed more inclusions in hilar cells compared to granule cells, while the opposite was true in PiD and CBD. Inclusion-to-neuron ratios revealed, on average, 33% of all DG neurons in PiD cases contained a tau inclusion, compared to ~ 7% in CBD, 2% in AD, and 0.4% in PSP. There was no significant difference between DAT-AD and PPA-AD pathologic tau burden, suggesting that differences in DG burden are not specific to clinical phenotype. We conclude that the DG is differentially vulnerable to pathologic tau accumulation, raising intriguing questions about the structural integrity and functional significance of hippocampal circuits in neurodegenerative dementias.

Focal amyloid and asymmetric tau in an imaging-to-autopsy case of clinical primary progressive aphasia with Alzheimer disease neuropathology.

Quantification of in vivo amyloid and tau PET imaging relationships with postmortem measurements are critical for validating the sensitivity and specificity imaging biomarkers across clinical phenotypes with Alzheimer disease neuropathologic change (ADNC). This study examined the quantitative relationship between regional binding of in vivo 18F-florbetapir amyloid PET and 18F-flortaucipir tau PET with postmortem stereological counts of amyloid plaques and neurofibrillary tangles (NFT) in a case of primary progressive aphasia (PPA) with ADNC, where neurodegeneration asymmetrically targets the left hemisphere. Beginning 2 years prior to death, a 63-year-old right-handed man presenting with agrammatic variant PPA underwent a florbetapir and flortaucpir PET scan, and neuropsychological assessments and magnetic resonance imaging sessions every 6 months. Florbetapir and flortaucpir PET standard uptake value ratios (SUVRs) were quantified from 8 left and right hemisphere brain regions with stereological quantification of amyloid plaques and NFTs from corresponding postmortem sections. Pearson's correlations and measures of asymmetry were used to examine relationships between imaging and autopsy measurements. The three visits prior to death revealed decline of language measures, with marked progression of atrophy. Florbetapir PET presented with an atypical focal pattern of uptake and showed a significant positive correlation with postmortem amyloid plaque density across the 8 regions (r = 0.92; p = 0.001). Flortaucipir PET had a left-lateralized distribution and showed a significant positive correlation with NFT density (r = 0.78; p = 0.023). Flortaucipir PET and NFT density indicated a medial temporal lobe sparing presentation of ADNC, demonstrating that AD does not always target the medial temporal lobe. This study adds additional evidence, in a non-amnestic phenotype of ADNC, that there is a strong correlation between AD PET biomarkers, florbetapir and flortaucipir, with quantitative neuropathology. The atypical and focal presentation of plaque density and florbetapir PET uptake suggests not all amyloid pathology presents as diffuse across neocortex.

Eye movements as a measure of word comprehension deficits in primary progressive aphasia.

INTRODUCTION: Eye movement studies can uncover subtle aspects of language processing impairment in individuals with primary progressive aphasia (PPA), who may have difficulty understanding words. This study examined eye movement patterns on a word-object matching task in response to varying levels of word-knowledge in PPA. METHODS: Participants with semantic and non-semantic PPA completed an object-matching task, where a word was presented and participants then selected the corresponding pictured object from an array. Afterwards, participants defined words for trials to which they incorrectly pointed. Linear mixed-effects analyses examined fixation differences on targets and related and unrelated foils. RESULTS: On incorrectly-pointed trials, participants demonstrated greater fixation duration on related foils, demonstrating intra-category blurring. For words that could not be defined, there was similar fixation duration on related and unrelated foils, demonstrating inter-category semantic blurring. DISCUSSION: This study demonstrated that fixation patterns reflect varying levels of word knowledge in PPA.

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.

The Reliability of Telepractice Administration of the Western Aphasia Battery-Revised in Persons With Primary Progressive Aphasia.

PURPOSE: The use of telepractice in the field of communication disorders offers an opportunity to provide care for those with primary progressive aphasia (PPA). The Western Aphasia Battery-Revised (WAB-R) is used for differential diagnosis, to assess severity of aphasia, and to identify a language profile of strengths and challenges. Telehealth administration of the WAB-R is supported for those with chronic aphasia due to stroke but has not yet been systematically explored in neurodegenerative dementia syndromes. To fill this gap, in-person and telehealth performance on the WAB-R from participants with mild to moderate PPA was compared. METHOD: Nineteen participants with mild to moderate PPA were administered the WAB-R in person and over videoconferencing. Videoconferencing administration included modifications to the testing protocol to ensure smooth completion of the assessment. Subtest and Aphasia Quotient (WAB-AQ) summary scores were compared using concordance coefficients to measure the relationship between the administration modes. RESULTS: In-person and telehealth scores showed strong concordance for the WAB-AQ, Auditory Verbal Comprehension subtest, and Naming & Word Finding subtest. The Spontaneous Speech test summary score had slightly lower concordance, indicating the need for caution when comparing these scores across administration modes. CONCLUSION: These findings support extending the use of telehealth administration of the WAB-R via videoconferencing to those with mild to moderate PPA given appropriate modifications to testing protocol.

Communication Partner Engagement: A Relevant Factor for Functional Outcomes in Speech-Language Therapy for Aphasic Dementia.

OBJECTIVES: Previous reports established the feasibility of a telehealth model for delivering speech-language therapy via Internet videoconferencing, which connects individuals with primary progressive aphasia (PPA) to an expert speech and language pathologist for treatment. This study reports feasibility of the same telehealth intervention in a larger set of progressive aphasia participants and explores factors potentially influencing functional intervention outcomes. METHODS: Participants with PPA or progressive aphasia in the context of a neurodegenerative dementia syndrome and their communication partners were enrolled into an 8-session intervention, with 3 evaluations (baseline, 2 months, and 6 months postenrollment). Half of the participants were randomized into a "check-in" group and received 3-monthly half-hour sessions postintervention. Mixed linear models with post hoc testing and percent change in area under the curve were used to examine communication confidence over time, as well as the influence of check-in sessions and the role of communication partner engagement on communication confidence. RESULTS: Communication confidence improved at the 2-month evaluation and showed no significant decline at the 6-month evaluation. Item-level analysis revealed gains in communication confidence across multiple communication contexts. Gains and maintenance of communication confidence were only present for the engaged communication partner group and were not bolstered by randomization to the check-in group. DISCUSSION: Internet-based, person-centered interventions demonstrate promise as a model for delivering speech-language therapy to individuals living with PPA. Maintenance is possible for at least 6 months postenrollment and is better for those with engaged communication partners, which supports the use of dyadic interventions.

Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C.

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.

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.

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.

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.

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.

Nosology of Primary Progressive Aphasia and the Neuropathology of Language.

Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration (FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.

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.

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.

Montreal Cognitive Assessment (MoCA) Performance and Domain-Specific Index Scores in Amnestic Versus Aphasic Dementia.

OBJECTIVE: The Montreal Cognitive Assessment (MoCA) is a popular and simple-to-administer screening instrument to detect cognitive impairment. The MoCA generates a total score and six domain-specific index scores: (1) Memory, (2) Executive Functioning, (3) Attention, (4) Language, (5) Visuospatial, and (6) Orientation. It is unclear whether these MoCA scores can differentiate between distinct clinical dementia syndromes. This study compared MoCA Index scores between amnestic dementia of the Alzheimer's type (DAT) and primary progressive aphasia (PPA), a language-based dementia. METHOD: Baseline MoCA data were analyzed from 33 DAT, 37 PPA, and 83 cognitively normal individuals enrolled in the Clinical Core of the Northwestern Alzheimer's Disease Center. A one-way analysis of covariance adjusted for age was used to compare MoCA scores among groups. A logistic regression model was implemented to observe individual likelihood of group affiliation based on MoCA Index scores. RESULTS: The mean MoCA total score was significantly higher in controls compared to both patient groups (p < .001) but did not differ between DAT and PPA groups. However, in accordance with salient clinical features commonly observed in DAT versus PPA, Memory and Orientation Index scores were lowest in the DAT group (p < .001), whereas Language and Attention Index scores were lowest in the PPA group (p < .001). Multivariate logistic regression analysis showed that the individual effects of Memory (p = .001), Language (p = .002), and Orientation (p = .025) Indices were significant. CONCLUSIONS: MoCA Index scores can help differentiate among distinct cognitive syndromes, suggesting it may be a useful brief screening tool to detect domain-specific cognitive impairment.

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.