Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

INTRODUCTION: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration.

INTRODUCTION: Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. METHODS: We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. RESULTS: Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). DISCUSSION: Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration.

INTRODUCTION: The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. METHODS: We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. RESULTS: Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. DISCUSSION: Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Atypical clinical features associated with mixed pathology in a case of non-fluent variant primary progressive aphasia.

A 66-year-old woman presented with agrammatism and apraxia of speech, meeting criteria for non-fluent/agrammatic variant primary progressive aphasia (nfvPPA). However, three years later, she developed frontal/executive, short-term phonological memory, visuospatial, and visual memory deficits suggesting involvement of multiple brain networks. Multimodal neuroimaging showed damage of both fronto-striatal and posterior brain regions. She was found to have multiple pathological processes: corticobasal degeneration (CBD), Alzheimer's disease (AD), and TAR DNA-binding protein (TDP)-43 type A. We hypothesize that cognitive and neuroimaging findings consistent with damage to multiple brain networks, each associated with vulnerability to certain molecular disease subtypes, could indicate mixed pathology.

Neuroanatomical correlations of visuospatial processing in primary progressive aphasia.

Clinical phenotyping of primary progressive aphasia has largely focused on speech and language presentations, leaving other cognitive domains under-examined. This study investigated the diagnostic utility of visuospatial profiles and examined their neural basis among the three main primary progressive aphasia variants. We studied the neuropsychological performances of 118 primary progressive aphasia participants and 30 cognitively normal controls, across 11 measures of visuospatial cognition, and investigated their neural correlates via voxel-based morphometry analysis using visuospatial composite scores derived from principal component analysis. The principal component analysis identified three main factors: visuospatial-executive, visuospatial-memory and visuomotor components. Logopenic variant primary progressive aphasia performed significantly worst across all components; nonfluent/agrammatic variant primary progressive aphasia showed deficits in the visuospatial-executive and visuomotor components compared with controls; and the semantic variant primary progressive aphasia scored significantly lower than nonfluent/agrammatic variant primary progressive aphasia and control in the visuospatial-memory component. Grey matter volumes over the right parieto-occipital cortices correlated with visuospatial-executive performance; volumetric changes in the right anterior parahippocampal gyrus and amygdala were associated with visuospatial-memory function, and visuomotor composite scores correlated significantly with the grey matter volume at the right precentral gyrus. Discriminant function analysis identified three visuospatial measures: Visual Object and Space Perception and Benson figure copy and recall test, which classified 79.7% (94/118) of primary progressive aphasia into their specific variant. This study shows that each primary progressive aphasia variant also carries a distinctive visuospatial cognitive profile that corresponds with grey matter volumetric changes and in turn can be largely represented by their performance on the visuomotor, visuospatial-memory and executive functions.

18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes.

BACKGROUND: The tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain. METHODS: We performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and ß-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 ß-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches. RESULTS: On qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of ß-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology. CONCLUSIONS: 18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

Altered topology of the functional speech production network in non-fluent/agrammatic variant of PPA.

Non-fluent/agrammatic primary progressive aphasia (nfvPPA) is caused by neurodegeneration within the left fronto-insular speech and language production network (SPN). Graph theory is a branch of mathematics that studies network architecture (topology) by quantifying features based on its elements (nodes and connections). This approach has been recently applied to neuroimaging data to explore the complex architecture of the brain connectome, though few studies have exploited this technique in PPA. Here, we used graph theory on functional MRI resting state data from a group of 20 nfvPPA patients and 20 matched controls to investigate topological changes in response to focal neurodegeneration. We hypothesized that changes in the network architecture would be specific to the affected SPN in nfvPPA, while preserved in the spared default mode network (DMN). Topological configuration was quantified by hub location and global network metrics. Our findings showed a less efficiently wired and less optimally clustered SPN, while no changes were detected in the DMN. The SPN in the nfvPPA group showed a loss of hubs in the left fronto-parietal-temporal area and new critical nodes in the anterior left inferior-frontal and right frontal regions. Behaviorally, speech production score and rule violation errors correlated with the strength of functional connectivity of the left (lost) and right (new) regions respectively. This study shows that focal neurodegeneration within the SPN in nfvPPA is associated with network-specific topological alterations, with the loss and gain of crucial hubs and decreased global efficiency that were better accounted for through functional rather than structural changes. These findings support the hypothesis of selective network vulnerability in nfvPPA and may offer biomarkers for future behavioral intervention.