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Background and ObjectivesGRNvariants are a frequent cause of familial frontotemporal dementia (FTD). Monitoring disease progression in asymptomatic carriers of genetic variants is a major challenge in delivering preventative therapies before clinical onset. This study aimed to assess the usefulness of fluorodeoxyglucose (FDG)–PET in identifying metabolic changes in presymptomaticGRNcarriers (PS-GRN+) and to trace their longitudinal progression.MethodsParticipants were longitudinally evaluated over 5 years in a prospective cohort study focused onGRNdisease (Predict-PGRN). They underwent cognitive/behavioral assessment, plasma neurofilament measurement, brain MRI, and FDG-PET. Voxel-wise comparisons of structural and metabolic imaging data between 2 groups were performed for each time point. Longitudinal PET changes were evaluated with voxel-wise comparisons and the metabolic percent annual changes method. The association of regional brain metabolism with plasma neurofilament and cognitive changes was analyzed.ResultsAmong the 80 individuals enrolled in the study, 58 (27 PS-GRN+ and 31 noncarriers) were included in the analyses. Cross-sectional comparisons between PS-GRN+ and controls found a significant hypometabolism in the left superior temporal sulcus (STS) region (encompassing the middle and superior temporal gyri), approximately 15 years before the expected disease onset, without significant cortical atrophy. The longitudinal metabolic decline over the following 5 years peaked around the right STS in carriers (p< 0.001), without significantly greater volume loss compared with that in controls. Their estimated annualized metabolic decrease (−1.37%) was higher than that in controls (−0.21%,p= 0.004). Lower glucose uptake was associated with higher neurofilament increase (p= 0.003) and lower frontal cognitive scores (p= 0.014) in PS-GRN+.DiscussionThis study detected brain metabolic changes in the STS region, preceding structural and cognitive alterations, thus contributing to the characterization of the pathochronology of preclinicalGRNdisease. Owing to the STS involvement in the perception of facially communicated cues, it is likely that its dysfunction contributes to social cognition deficits characterizing FTD. Overall, our study highlights brain metabolic changes as an early disease-tracking biomarker and proposes annualized percent decrease as a metric to monitor therapeutic response in forthcoming trials.

To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated withPatients with PPA carryingAmong the 235 patients with PPA, 45 (19%) carriedThis study shows that the most frequent PPA variant associated with

Objective: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes associated with posterior brain atrophy. We compared PCA and LPA to each other and to an age-matched group of patients with early age at onset of Alzheimer disease (EO-AD). We hypothesized that these 3 syndromes are part of a single clinical and biologic continuum. Methods: Voxel-based morphometry (VBM) was used to assess atrophy in 14 PCA, 10 LPA, and 16 EO-AD patients compared to 65 healthy controls. Genetic analysis for APOE was conducted in 30 patients and 44 controls. Four patients came to autopsy. An additional 14 were studied with the beta-amyloid specific PET with tracer 11 C-labeled Pittsburgh Compound-B (PIB). Results: VBM results demonstrated that, compared to controls, each patient group showed a large area of overlapping atrophy in bilateral parietal, occipital, precuneus, posterior cingulate, posterior temporal, and hippocampal regions. Surrounding this common area, group-specific atrophy was found in small, symptom-specific regions for each group: the right ventral-occipital and superior parietal regions in PCA, the left middle and superior temporal gyri in LPA, and the prefrontal cortex in EO-AD. APOE e4 frequency was higher in all patient groups compared to controls. Four PCA, 5 LPA, and 8 EO-AD patients showed evidence of cortical amyloid at pathology (n = 3) or on PIB-PET (n = 14). Conclusions: Logopenic progressive aphasia and posterior cortical atrophy showed largely overlapping anatomic and biologic features with early age at onset of Alzheimer disease, suggesting that these clinical syndromes represent the spectrum of clinical manifestation of the nontypical form of Alzheimer disease that presents at an early age. AD = Alzheimer disease; CBD = corticobasal degeneration; EO-AD = early age at onset of Alzheimer disease; LPA = logopenic progressive aphasia; MAC = Memory and Aging Center; PCA = posterior cortical atrophy; PIB = Pittsburgh Compound-B; PPA = primary progressive aphasia; UCSF = University of California San Francisco; VBM = voxel-based morphometry.

Objective: To describe a patient affected by the logopenic variant of primary progressive aphasia (lv-PPA) with a clinical evolution towards dementia with Lewy bodies (DLB). Background Lv-PPA is a progressive language disorder characterized by slow speech, word finding problems, sentence repetition and comprehension deficits, and relative sparing of motor speech, grammar, and single-word comprehension. Brain atrophy is located at the left temporo-parietal junction. Biological and neuropathological studies suggest that the main cause of lv-PPA is Alzheimer9s disease (AD). Design/Methods: Clinical, cognitive and language data were acquired in a 65-years-old patient with lv-PPA (right-handed man, disease duration at presentation 24 months). Furthermore, we analyzed cerebrospinal fluid (CSF) biomarkers, structural MRI, brain Single-photon emission computed tomography (SPECT) and dopamine transporter (DAT)-scan. Results: For the first two years (2006-2008), the patient demonstrated isolated language deficits with typical logopenic profile. In 2008: MRI was normal and SPECT showed hypoperfusion in left posterior temporal and inferior parietal regions. CSF analysis revealed a non-AD profile, with normal levels of beta-amyloid, tau and phosphorylated tau. On the basis of these elements, the diagnosis of lv-PPA was made. Two years later, visual hallucinations, cognitive fluctuations and parkinsonian signs appeared; neuroleptic medication was not tolerated. DAT-scan demonstrated a bilateral DAT loss. The second SPECT showed a posterior extension of cortical hypoperfusion including parietal, temporal and occipital regions, with involvement of the left primary visual cortex. Accordingly with this clinical and imaging evolution, the clinical diagnosis of DLB was made. Conclusions: We provided clinical, imaging and biological findings showing that the lv-PPA is not necessarily related to AD pathology. Hence, the medical community should not systematically lump together lv-PPA and AD. Conversely, DLB should be considered as a heterogeneous disease, which can initially present with a progressive aphasia profile, namely lv-PPA. Supported by: Dr. Migliaccio was funded by the Neuropole de Recherche Francilien (NeRF). Disclosure: Dr. Migliaccio has nothing to disclose. Dr. Roue-Jagot has nothing to disclose. Dr. Dubois has received personal compensation for activities with Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen as a consultantDr. Dubois has received personal compensation for serving on the advisory board of Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen.Dr. Dubois has received research support from Novartis and Sanofi-Aventis. Dr. Teichmann has nothing to disclose.