Marion Houot

Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study

BACKGROUNDnImproved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimers disease. We assessed associations between brain β-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimers disease.nnnMETHODSnThe INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid β deposition on 18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on 18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and 18F-FDG and 18F-florbetapir PET every 24 months. We assessed associations of amyloid β deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimers disease was defined as an amnestic syndrome of the hippocampal type.nnnFINDINGSnFrom May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid β deposition and the remainder did not. The amyloid β subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid β deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid β1-42 concentration in CSF significantly correlated with mean 18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid β1-42 to amyloid β1-40 (r=-0·61, p<0·0001), and identified amyloid β deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid β. Four participants (all positive for amyloid β deposition at baseline) progressed to prodromal Alzheimers disease. They were older than other participants positive for amyloid β deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater 18F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]).nnnINTERPRETATIONnBrain β-amyloidosis alone did not predict progression to prodromal Alzheimers disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent.nnnFUNDINGnInstitut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.

Evaluation of amyloid status in a cohort of elderly individuals with memory complaints: validation of the method of quantification and determination of positivity thresholds

ObjectiveOur aim is to validate the process steps implemented by the French CATI platform to assess amyloid status, obtained from 18F-Florbetapir PET scans, in a cohort of 318 cognitively normal subjects participating in the INSIGHT-preAD study. Our objective was to develop a method with partial volume effect correction (PVEC) on untransformed PET images, using an automated pipeline (“RACHEL”) adapted to large series of patients and including quality checks of results.MethodsWe compared RACHEL using different options (with and without PVEC, different sets of regions of interest), to two other methods validated in the literature, referred as the “AVID” and “CAEN” methods. A standard uptake value ratio (SUVR) was obtained with the different methods for participants to another French study, IMAP, including 26 normal elderly controls (NEC), 11 patients with mild cognitive impairment (MCI) and 16 patients with Alzheimer’s disease (AD). We determined two cutoffs for RACHEL method by linear correlation with the other methods and applied them to the INSIGHT-preAD subjects.ResultsRACHEL including PVEC and a combination of the whole cerebellum and the pons as a reference region allowed the best discrimination between NEC and AD participants. A strong linear correlation was found between RACHEL and the other two methods and yielded the two cutoffs of 0.79 and 0.88. According to the more conservative threshold, 19.8% of the INSIGHT-preAD subjects would be considered amyloid positive, and 27.7% according to the more liberal threshold.ConclusionsWith our method, we clearly discriminated between NEC with negative amyloid status and patients with clinical AD. Using a linear correlation with other validated cutoffs, we could infer our own positivity thresholds and apply them to an independent population. This method might be useful to the community, especially when the optimal cutoff could not be obtained from a population of healthy young adults or from correlation with post-mortem results.

Early cognitive, structural and microstructural changes in c9orf72 presymptomatic carriers before 40 years of age

Importance Presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. Objectives To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers. Design, Setting, and Participants The PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Eighty-four participants entered the study between October 2015 and April 2017; 80 (95%) were included in cross-sectional analyses of baseline data. All participants underwent neuropsychological testing and magnetic resonance imaging; 63 (79%) underwent diffusion tensor magnetic resonance imaging. Gray matter volumes and diffusion tensor imaging metrics were calculated within regions of interest. Anatomical and microstructural differences between individuals who carried the C9orf72 mutation (C9+) and those who did not carry the C9orf72 mutation (C9−) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017. Main Outcomes and Measures Differences in neuropsychological scores, gray matter volume, and white matter integrity between C9+ and C9− individuals. Results Of the 80 included participants, there were 41 C9+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39 C9− individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with C9− individuals, C9+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; Pu2009=u2009.01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5]; Pu2009=u2009.004), atrophy in 8 cortical regions of interest and in the right thalamus, and white matter alterations in 8 tracts. When restricting the analyses to participants younger than 40 years, compared with C9− individuals, C9+ individuals had lower praxis scores and intransitive gesture scores, atrophy in 4 cortical regions of interest and in the right thalamus, and white matter alterations in 2 tracts. Conclusions and Relevance Cognitive, structural, and microstructural alterations are detectable in young C9+ individuals. Early and subtle praxis alterations, underpinned by focal atrophy of the left supramarginal gyrus, may represent an early and nonevolving phenotype related to neurodevelopmental effects of C9orf72 mutation. White matter alterations reflect the future phenotype of frontotemporal lobar degeneration/amyotrophic lateral sclerosis, while atrophy appears more diffuse. Our results contribute to a better understanding of the preclinical phase of C9orf72 disease and of the respective contribution of magnetic resonance biomarkers. Trial Registration clinicaltrials.gov Identifier: NCT02590276

Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer’s Disease

BACKGROUNDnSubjective cognitive decline (SCD) may result from many conditions, including Alzheimers disease (AD).nnnOBJECTIVEnIn this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD.nnnMETHODSnCognitively normal older adults (Nu200a=u200a318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared.nnnRESULTSnScores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (nu200a=u200a19) and high (nu200a=u200a86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the low awareness group showed greater amyloid burden and lower cortical metabolism, compared to the high awareness group.nnnCONCLUSIONnThis study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.

Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in cognitively normal older adults with subjective memory complaints.

Observational multimodal neuroimaging studies indicate sex differences in Alzheimers disease pathophysiological markers.

Relationship between Basal Forebrain Resting-State Functional Connectivity and Brain Amyloid-β Deposition in Cognitively Intact Older Adults with Subjective Memory Complaints

Purpose To evaluate the association between the global fibrillary amyloid-β pathology and the basal forebrain connectivity at rest in cognitively intact older adults at risk for Alzheimer disease. Materials and Methods This retrospective study was approved by the local ethics committee and written informed consent was obtained from all participants. Resting-state functional connectivity (RSFC) of anterior and posterior basal forebrain seeds was investigated, as well as PET-measured global amyloid-β load by using standardized uptake value ratio (SUVR) in 267 older cognitively intact individuals with subjective memory complaints (age range, 70-85 years; overall mean age, 75.8 years; 167 women [mean age, 75.9 years] and 100 men [mean age, 75.8 years]). The participants were from the Investigation of Alzheimers Predictors in Subjective Memory Complainers (INSIGHT-preAD) cohort (date range, 2013-present). The relationship between SUVR and the basal forebrain RSFC was assessed, followed by the effects of apolipoprotein E (APOE) genotype and sex on the basal forebrain RSFC. Results Higher SUVR values correlated with lower posterior basal forebrain RSFC in the hippocampus and the thalamus (Pearson r =-0.23; P <.001 corrected for familywise error [FWE]). Both sex and APOE genotype impacted the associations between basal forebrain RSFC and the global amyloid deposition (t values >3.59; P <.05 corrected for FWE). Conclusion Data indicate a distinct in vivo association between posterior basal forebrain dynamics and global fibrillary amyloid-β pathology in cognitively intact older adults with subjective memory complaints; both apolipoprotein E and sex moderate such association.

DIFFERENCES IN SENSITIVITY TO AMYLOIDOSIS FOR STANDARD NEUROPSYCHOLOGICAL MEMORY TESTS

were administered. The levels of Ab and tau protein in the different diagnostic categories were analyzed with ANOVAs and by Tukey post-hoc tests. Multivariate regression models were computed to test whether cognitive performance was driven by the levels of amyloid load and NFT accumulation as determined by PET [F] NAV4694 and [F]MK6240. Results: The PET scans revealed that the Ab and tau protein levels were increased in AD patients (Ab 2.8360.60 SUVR; tau 3.6261.40 SUVR) compared with MCI and CH but were not different between MCI and CH. On both cognitive tests, the AD group performed worse than the MCI and the CH (p<0.001 to p1⁄40.001); the MCI performed worse than the CH on the verbal memory test (p1⁄40.029), but not on the semantic fluency test (p1⁄40.41). The regression analyses revealed that tau levels (but not Ab) were negatively linked to verbal memory (p1⁄4 0.001) and to semantic verbal fluency (p1⁄40.0002). Further analysis revealed that tau in the superior frontal lobewas associated with poor performance in semantic fluency (p1⁄40,004) and immediate recall of the logical memory task (p1⁄40.018) and tau in the hippocampus was strongly associated with poor delayed recall of the logical memory (p1⁄40.008). Conclusions: The cognitive decline was linked to tau protein but not to Ab. Furthermore, we found differential involvement of the frontal lobe and hippocampus in the cognitive performance.

EVOLUTION OF THE AWARENESS OF COGNITIVE DECLINE INDEX OVER 24 MONTHS IN PRECLINICAL ALZHEIMER'S DISEASE IS ASSOCIATED TO BASELINE BRAIN AMYLOID LOAD

bed-ridden by the spring of 2016with almost permanent drowsiness and still retains this state by the submission date of this abstract. Conclusions: To our knowledge, excluding one adolescent boy whose disease onset was at 13 years of age, this case is the youngest so far reported. Although extremely rare, this diagnosis must not be overlooked in a patient with chronic insomnia and subacute progressive cerebellar syndrome, when more likely and most often treatable causes like autoimmune encephalitides, such as Morvan’s syndrome or NMDAR encephalitis are excluded after a meticulous work-up.

THE NEURONAL COMPENSATION MODEL OF THE PRECLINICAL STAGE OF ALZHEIMER'S DISEASE: RESULTS FROM THE INSIGHT-PRE AD STUDY

N 1899 173 568 Age 55,31 (6,59) 56,46 (6,89) 57.14 (6,86) Education 13,51 (3,50) 12,38 (3,51) 13,14 (3,50) MMSE 29,09(1,04) 29,03(1,00) 28,82 (1,18) GADS Total .61 (1,35) .62 (1,24) 1,29 (2,03) % Females 64,1% 48,0% 65,0% % e4 Carriers 34,6% 37,6% 34.3,6% MBT-TPR M (SO) 24,42 (4,22) 23,19 (3.37) 23,28 (4.77) MBT-TFR M (SD) 16,94 (4,93) 15,17 (4.34) 15,53 (5.09) MBT-TDFR M (SD) 17,32 (5.0) 15,66 (4.52) 15,80 (5.43) MBT-TDPR M (SD) 24,26 (4,3) 22,94 (4.40) 23,07 (4.94) WAIS-Coding M (SD) 67,09 (14.54) 62,77 (14.63) 62,93 (14.75) WAIS-Visual Puzzles M (SD) 13,57 (4.27) 13,42 (4.32) 12,61 (4.07)

INCREASED RESILIENCE TO ALZHEIMER’S DISEASE PATHOPHYSIOLOGY IN MEN WITH SUBJECTIVE MEMORY COMPLAINTS COMPARED TO WOMEN

Constant 2730.3157 <0.001 1859.0788 3601.5525 1.5029 <0.001 1.4559 1.5498 APOE4 -327.9283 0.005 -556.4050 -99.4516 -0.0018 0.064 -0.0036 0.0001 Amyloid -283.8190 <0.001 -381.5672 -186.0708 -0.0423 <0.001 -0.0579 -0.0268 PA 22.3413 0.805 -155.8281 200.5108 0.0450 0.002 0.0163 0.0738 APOE4 x PA -143.7908 0.549 -615.2068 327.6252 0.0027 0.162 -0.0011 0.0065 Amyloid x PA 147.2199 0.126 -41.6790 336.1188 0.0002 0.987 -0.0288 0.0293 CA 103.9141 0.139 -33.7525 241.5806 0.0097 0.358 -0.0124 0.0319 APOE4x CA -356.6207 0.024 -665.8677 -47.3737 0.0002 0.876 -0.0021 0.0024 Amyloid x CA 69.0120 0.257 -50.5644 188.5883 -0.0038 0.669 -0.0215 0.0138 Sex -481.8246 <0.001 -669.3021 -294.3472 0.0088 0.565 -0.0212 0.0388 Age -50.9411 <0.001 -62.5039 -39.3783 -0.0024 0.229 -0.0064 0.0015 Educational year 0.4370 0.973 -24.5808 25.4548 -0.0157 0.389 -0.0516 0.0202