Subjective Memory Complainers Research Articles

Theta Band-Power Shapes Amyloid-Driven Longitudinal EEG Changes in Elderly Subjective Memory Complainers At-Risk for Alzheimer's Disease.

Alzheimer's disease (AD) includes progressive symptoms spread along a continuum of preclinical and clinical stages. Although numerous studies uncovered the neuro-cognitive changes of AD, very little is known on the natural history of brain lesions and modifications of brain networks in elderly cognitively-healthy memory complainers at risk of AD for carrying pathophysiological biomarkers (amyloidopathy and tauopathy). We analyzed resting-state electroencephalography (EEG) of 318 cognitively-healthy subjective memory complainers from the INSIGHT-preAD cohort at the time of their first visit (M0) and two-years later (M24). Using 18F-florbetapir PET-scanner, subjects were stratified between amyloid negative (A-; n = 230) and positive (A+; n = 88) groups. Differences between A+ and A- were estimated at source-level in each band-power of the EEG spectrum. At M0, we found an increase of theta power in the mid-frontal cortex in A+ compared to A-. No significant association was found between mid-frontal theta and the individuals' cognitive performance. At M24, theta power increased in A+ relative to A- individuals in the posterior cingulate cortex and the pre-cuneus. Alpha band revealed a peculiar decremental trend in posterior brain regions in the A+ relative to the A- group only at M24. Theta power increase over the mid-frontal and mid-posterior cortices suggests an hypoactivation of the default-mode network in the A+ individuals and a non-linear longitudinal progression at M24. We provide the first source-level longitudinal evidence on the impact of brain amyloidosis on the EEG dynamics of a large-scale, monocentric cohort of elderly individuals at-risk for AD.

Clinical performance of the beta‐amyloid 1‐42/1‐40 ratio determined from automated Lumipulse G1200 cerebrospinal fluid Abeta1‐42 and Abeta1‐40 assays, assessed by concordance with PET imaging status

AbstractBackgroundβ‐amyloid measured in cerebrospinal fluid (CSF) has been widely used to assess Alzheimer’s disease (AD) patients. Reduced concentrations of Aβ1‐42 (Aβ42) in CSF are inversely correlated with increased retention of Aβ tracers in brain amyloid plaques observed with positron emission tomography (PET). Multiple studies, including those applying automated immunoassay platforms, have reported increased diagnostic accuracy of the CSF Aβ1‐42/Aβ1‐40 ratio (Aβ42/Aβ40 ratio) over Aβ42 levels alone. In the present study, the concordance between calculated CSF Aβ42/Aβ40 ratios derived from individual Lumipulse G1200 CSF Aβ42 and Aβ40 assays and PET imagining status was determined utilizing a well characterized patient cohort.MethodA subset of n=171 patient CSF samples from the Australian Imaging, Biomarkers and Lifestyle study (AIBL), and n=24 samples from an independent study cohort were included for a total of n=195 patients having amyloid PET status. Amyloid PET‐positivity was 51%. Clinical diagnosis groups included AD (n=43; 95% PET+), mild cognitive impairment (MCI; n=46; 67% PET+); subjective memory complainers (SMC; n=59; 39% PET+), non‐memory complainers (NMC; n=45; 9% PET+), and non‐AD dementia (frontotemporal dementia; n=2; 0% PET+). CSF Aβ42 and Aβ40 were measured with analytically validated Lumipulse G1200 immunoassays (Fujirebio Diagnostics), performed by state‐certified laboratory scientists under CLIA conditions, and the ratio calculated. An optimal cutoff for the Aβ42/Aβ40 ratio was determined from the maximal Youden J index.ResultThe median Aβ42/Aβ40 ratios for PET+ (0.088) and PET‐ (0.042) patient groups were significantly different (Wilcoxon p<0.001). An optimal Aβ42/Aβ40 ratio cutoff of 0.058 was determined, resulting in a sensitivity, specificity, PPV and NPV of 96.0% (CI 90.0%‐98.4%); 96.9% (CI 91.2%‐98.9%), 96.9% (CI 91.3%‐98.9%), and 95.9% (CI 89.9%‐98.4%), respectively. Receiver operating characteristics area under the curve (ROC‐AUC) was 0.968.ConclusionExcellent concordance was observed between amyloid PET status and Aβ42/Aβ40 ratio determined from Lumipulse G1200 assays, including results from patients diagnosed with earlier stage disease. The sensitivity and specificity of the CSF Aβ42/Aβ40 ratio determined with the Lumipulse system, together with high analytical performance, support its clinical utility as a biomarker of amyloid status and clinical assessment.

Cortical microstructural changes and amyloid beta burden in cognitively normal subjective memory complainers

AbstractBackgroundThe aim of the present study was to investigate the association between brain amyloid β (Aβ) accumulation and cortical microstructural changes in cognitively normal individuals with subjective memory complaints.MethodA total of 258 individuals (100 males,158 females) from the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study [Dubois et al., 2018], were included. The 18F‐florbetapir PET images were used to compute whole brain and regional standard uptake value ratios (SUVr), while T1 structural and diffusion tensor imaging (DTI) scans were analysed to calculate 3 novel cortical grey matter diffusion measures (AngleR, PerpPD and ParlPD) and the mean diffusivity (MD) [McKavanagh et al., 2019]. A linear regression model was used to study the association between the global SUVr value and whole brain cortical diffusion measures, by including the diffusion measure as the dependent variable, and age, sex, APOE genotype and global amyloid SUVr as independent predictors. Partial correlation analysis, controlling for sex, was used to investigate regional associations between SUVr and diffusion values in 6 regions of interest (bilateral anterior cingulate, posterior cingulate, frontal superior orbital, inferior parietal, precuneus, middle temporal cortex). Results were considered statistically significant after false discovery rate correction (FDR <0.05).ResultLinear regression revealed that whole brain amyloid SUVr values were positively associated with whole brain AngleR (the angle between the principal diffusion direction and the radial minicolumn direction within the cortical grey matter) (β = 0.23, p<0.001). Regional partial correlations indicated significant associations between SUVr and AngleR regional values in left anterior cingulate cortex (r=0.168;p=0.010) and bilateral precuneus (left r=0.173;p=0.005; right r=0.178;p=0.004).ConclusionThese results showed a significant relationship between Aβ accumulation and cortical architectural change in subjective memory complainers. The regional associations revealed the presence of microstructural changes in key regions commonly affected in the early stage of AD [Palmqvist et al., 2017]. Our novel cortical DTI measures could offer additional information about cortical changes, playing a potential role as index of “neurodegeneration” in the ATN framework [Jack et al., 2018] of Alzheimer’s biomarkers.

Sex differences in cortical microstructural changes in asymptomatic individuals at risk for Alzheimer’s disease

AbstractBackgroundThe preclinical phase of Alzheimer’s disease (AD) is characterized by cortical microstructural changes before the appearance of clinical symptoms. Previous studies have shown that women can present significantly faster age‐related decline than men [Filon et al., 2016; Barnes et al., 2005; Ferretti et al., 2018]. The aim of the present study was to investigate the impact of sex in whole brain cortical changes in an asymptomatic population at risk for AD.MethodA total of 167 subjects (68 males and 99 females) recruited in the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study, were included in the present work. The T1 structural and diffusion tensor imaging (DTI) scans acquired at baseline and after 24 months, were analysed to calculate 3 novel cortical diffusion measures (AngleR, PerpPD and ParlPD) [McKavanagh et al., 2019] and the mean diffusivity (MD). An independent sample t‐test was used to assess group differences in demographic, clinical and MRI volumetric values. A linear regression analysis was performed to investigate the role of sex, age and APOE genotype on baseline cortical values. The repeated measures ANOVA was used to assess cortical diffusion differences at baseline and follow‐up.ResultMen compared with women showed higher angle between the principal diffusion direction and the radial minicolumn direction across the cortex at the baseline (p=0.001). No demographic, clinical nor brain volumetric differences between men and women were detected. The linear regression analysis revealed that only sex explains differences in AngleR values (p=0.001). The repeated measures ANOVA showed a significant effect of time (p=<0.001) and a significant interaction between time and sex (p=0.013), with a higher progression rate in women compare to men.ConclusionThese findings indicate that sex has a significant effect on cortical changes and in their progression rate. The DTI measures could have a central role in enabling individual’s specific characterization and may be informative for the development and assessment of potential drug targets that are specific for each subgroup.

Association of plasma YKL‐40 with brain amyloidosis, memory performance, and sex in subjective memory complainers

AbstractBackgroundNeuroinflammation – a crucial early pathomechanistic alteration of Alzheimer's disease (AD) – may represent either a detrimental or a compensatory mechanism or both, based on the disease stage. YKL‐40, a glycoprotein highly expressed in human glia cells, is a candidate biomarker to in vivo track glial‐related neuroinflammation in AD. Few studies explored, in cognitively healthy individuals, the potential influence of key biological factors – age, sex, Apolipoprotein E (APOE) ε4 allele – on YKL‐40 plasma concentrations as well as its association with other AD pathophysiological mechanisms and cognitive scores.MethodWe assessed the cross‐sectional and longitudinal impact of relevant biological factors – sex, age, APOE ε4 allele – on YKL‐40. Moreover, we explored the cross‐sectional and longitudinal association of YKL‐40 with: 1) global/regional brain amyloid beta (Aβ) deposition using Aβ‐positron emission tomography (PET) imaging; 2) synaptic loss, using [18F]‐fluorodeoxyglucose‐PET ([18F]‐FDG‐PET); 3) neurodegeneration using magnetic resonance imaging (MRI), i.e. hippocampal, entorhinal cortex, and basal forebrain volumes. We also sought for the potential association between YKL‐40 and the degree of cognitive performance. The study was performed in the INSIGHT‐preAD cohort (N=314, M=114, F=200, aged 70 to 85), a large observational monocentric French academic cohort (Pitié‐Salpêtrière University Hospital, Paris) of individuals with subjective memory complaints (SMC), a condition at risk for AD. We used mixed models with interaction of YKL‐40 with time.ResultMen displayed higher YKL‐40 concentrations than women at each time point investigated (b=0.171, t=2.434, P=0.015). YKL‐40 presented an age‐associated increase at each time point investigated (b=0.029, t=3.004, P=0.003). YKL‐40 was negatively associated with baseline Aβ deposition, at both global (b=‐0.025, t=‐1.992, P=0.047) and regional level. Besides, one‐year increase of YKL‐40 concentration was positively associated with memory performance, longitudinally (b=0.308, z=2.280, P=0.023). YKL‐40 showed no effect on synaptic loss or neurodegeneration.ConclusionPlasma YKL‐40 concentrations present an age‐associated increase with men showing higher levels than women, irrespective of the time point, thus indicating a potential sexual dimorphism in neuroinflammation. Moreover, the association of higher YKL‐40 concentrations with lower overall/regional cross‐sectional Aβ deposition and higher memory scores over time indicates a non‐clinical detrimental/potential protective effect of glia activation on incipient brain amyloidosis and synaptic network homeostasis.

Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers

Neuroinflammation, a key early pathomechanistic alteration of Alzheimer’s disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer’s disease exploring whether age, sex, and the apolipoprotein E ε4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis.

The meta-memory ratio: a new cohort-independent way to measure cognitive awareness in asymptomatic individuals at risk for Alzheimer\u2019s disease

BackgroundLack of awareness of cognitive decline (ACD) has been described at the preclinical and prodromal stages of Alzheimer’s disease (AD). In this study, we introduced a meta-memory ratio (MMR) and explored how it is associated with neuroimaging AD biomarkers in asymptomatic individuals at risk for AD.MethodFour hundred forty-eight cognitively healthy participants from two cohorts of subjective memory complainers (INSIGHT-PreAD and ADNI) were included. Regression models were used to assess the impact of AD biomarkers on the MMR.ResultIn both cohorts, there was a significant quadratic effect of cerebral amyloidosis on the MMR value. In particular, participants had a high ACD up to the amyloid positivity threshold, above which a decrease of ACD was eventually observed as the amyloid load increased.ConclusionThis nonlinear evolution of ACD in very early AD must be taken into account in clinical care and for trial enrollment as well.

Pre-trained MRI-based Alzheimer's disease classification models to classify memory clinic patients

Anatomical magnetic resonance imaging (MRI), diffusion MRI and resting state functional MRI (rs-fMRI) have been used for Alzheimer’s disease (AD) classification. These scans are typically used to build models for discriminating AD patients from control subjects, but it is not clear if these models can also discriminate AD in diverse clinical populations as found in memory clinics.To study this, we trained MRI-based AD classification models on a single centre data set consisting of AD patients (N = 76) and controls (N = 173), and used these models to assign AD scores to subjective memory complainers (N = 67), mild cognitive impairment (MCI) patients (N = 61), and AD patients (N = 61) from a multi-centre memory clinic data set. The anatomical MRI scans were used to calculate grey matter density, subcortical volumes and cortical thickness, the diffusion MRI scans were used to calculate fractional anisotropy, mean, axial and radial diffusivity, and the rs-fMRI scans were used to calculate functional connectivity between resting state networks and amplitude of low frequency fluctuations. Within the multi-centre memory clinic data set we removed scan site differences prior to applying the models.For all models, on average, the AD patients were assigned the highest AD scores, followed by MCI patients, and later followed by SMC subjects. The anatomical MRI models performed best, and the best performing anatomical MRI measure was grey matter density, separating SMC subjects from MCI patients with an AUC of 0.69, MCI patients from AD patients with an AUC of 0.70, and SMC patients from AD patients with an AUC of 0.86. The diffusion MRI models did not generalise well to the memory clinic data, possibly because of large scan site differences. The functional connectivity model separated SMC subjects and MCI patients relatively good (AUC = 0.66). The multimodal MRI model did not improve upon the anatomical MRI model.In conclusion, we showed that the grey matter density model generalises best to memory clinic subjects. When also considering the fact that grey matter density generally performs well in AD classification studies, this feature is probably the best MRI-based feature for AD diagnosis in clinical practice.

Association of brain network dynamics with plasma biomarkers in subjective memory complainers

Using a single integrated analysis, we examined the relationship between brain networks and molecular pathways in a cohort of elderly individuals at risk for Alzheimer's disease. In 205 subjective memory complainers (124 females, mean age: 75.7 ± 3.4), individual functional connectome was computed for a total of 3081 functional connections (set A) and 6 core plasma biomarkers of Alzheimer's disease (set B) were assessed. Partial least squares correlation analysis identified one dimension of population covariation between the 2 sets (p < 0.006), which we named bioneural mode. Five core plasma biomarkers and 190 functional connections presented bootstrap ratios greater than the critical value |1.96|. T-tau protein showed a trend toward significance (bootstrap resampling = 1.64). The salience, the language, the visuospatial, and the default mode networks were the strongest significant networks. We detected a strong association between network dynamics and core pathophysiological blood biomarkers. Innovative composite biomarkers, such as the bioneural mode, are promising to provide outcomes and better inform drug development and clinical practice for neurodegenerative diseases.

Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease.

To investigate whether baseline concentrations of plasma total tau (t-tau) and neurofilament light (NfL) chain proteins are associated with annual percent change (APC) of the basal forebrain cholinergic system (BFCS) in cognitively intact older adults at risk for Alzheimer disease (AD). This was a large-scale study of 276 cognitively intact older adults from the monocentric INSIGHT-preAD (Investigation of Alzheimer's Predictors in Subjective Memory Complainers) cohort. Participants underwent baseline assessment of plasma t-tau and NfL concentrations as well as baseline and 24-month follow-up MRI scans. Linear models with and without influential observations (calculated using the Cook distance) were carried out to investigate the effect of plasma NfL and t-tau concentrations, and their interaction effect with β-amyloid status and APOE genotype, on the APC of the whole BFCS and its anterior (Ch1/2) and posterior (Ch4) subdivisions separately. Higher plasma t-tau concentrations at baseline were associated with higher BFCS rate of atrophy (model without influencers: n = 251, F value = 4.6815; p value = 0.031). Subregional analyses showed similar results for both the APC of the Ch1/2 (model without influencers: n = 256, F value = 3.9535, p corrected = 0.047) and Ch4 BFCS sectors (model without influencers: n = 253, F value = 4.9090, p corrected = 0.047). Baseline NfL, β-amyloid load, and APOE ε4 carrier status did not affect APC of the BFCS. Increased concentrations of baseline plasma t-tau may predict in vivo structural BFCS atrophy progression in older adults at risk for AD, independently of β-amyloid status and APOE genotype.

Biomarker-guided clustering of Alzheimer's disease clinical syndromes

Alzheimer's disease (AD) neuropathology is extremely heterogeneous, and the evolution from preclinical to mild cognitive impairment until dementia is driven by interacting genetic/biological mechanisms not fully captured by current clinical/research criteria. We characterized the heterogeneous “construct” of AD through a cerebrospinal fluid biomarker-guided stratification approach. We analyzed 5 validated pathophysiological cerebrospinal fluid biomarkers (Aβ1-42, t-tau, p-tau181, NFL, YKL-40) in 113 participants (healthy controls [N = 20], subjective memory complainers [N = 36], mild cognitive impairment [N = 20], and AD dementia [N = 37], age: 66.7 ± 10.4, 70.4 ± 7.7, 71.7 ± 8.4, 76.2 ± 3.5 years [mean ± SD], respectively) using Density-Based Spatial Clustering of Applications with Noise, which does not require a priori determination of the number of clusters. We found 5 distinct clusters (sizes: N = 38, 16, 24, 14, and 21) whose composition was independent of phenotypical groups. Two clusters showed biomarker profiles linked to neurodegenerative processes not associated with classical AD-related pathophysiology. One cluster was characterized by the neuroinflammation biomarker YKL-40. Combining nonlinear data aggregation with informative biomarkers can generate novel patient strata which are representative of cellular/molecular pathophysiology and may aid in predicting disease evolution and mechanistic drug response.

The Impact of Self-Reported Hearing Difficulties on Memory Collaboration in Older Adults.

Cognitive scientists and philosophers recently have highlighted the value of thinking about people at risk of or living with dementia as intertwined parts of broader cognitive systems that involve their spouse, family, friends, or carers. By this view, we rely on people and things around us to “scaffold” mental processes such as memory. In the current study, we identified 39 long-married, older adult couples who are part of the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Ageing; all were cognitively healthy but half were subjective memory complainers. During two visits to their homes 1 week apart, we assessed husbands’ and wives’ cognitive performance across a range of everyday memory tasks working alone (Week 1) versus together (Week 2), including a Friends Task where they provided first and last names of their friends and acquaintances. As reported elsewhere, elderly couples recalled many more friends’ names working together compared to alone. Couples who remembered successfully together used well-developed, rich, sensitive, and dynamic communication strategies to boost each other’s recall. However, if one or both spouses self-reported mild-to-moderate or severe hearing difficulties (56% of husbands, 31% of wives), couples received less benefit from collaboration. Our findings imply that hearing loss may disrupt collaborative support structures that couples (and other intimate communicative partners) hone over decades together. We discuss the possibility that, cut off from the social world that scaffolds them, hearing loss may place older adults at greater risk of cognitive decline and dementia.

Relationships between objectives sleep parameters and brain amyloid load in subjects at risk for Alzheimer's disease: the INSIGHT-preAD Study.

Sleep changes have been associated with increased risks of developing cognitive disturbances and Alzheimer's disease (AD). A bidirectional relation is underlined between amyloid-beta (Aß) and sleep disruptions. The sleep profile in participants at risk to develop AD is not fully deciphered. We aim to investigate sleep-wake changes with objective sleep measurements in elderly participants without cognitive impairment depending on their brain amyloid status, positive (Aß+) or negative (Aß-) based on standard absorption ratios (SUVr) positron emission tomography-florbetapir imaging. Sixty-eight participants without cognitive impairment who have accepted to be involved in the sleep ancillary study from the InveStIGation of Alzheimer's Predictors in Subjective Memory Complainers (INSIGHT-pre AD) cohort, aiming to record sleep profile based on the analyses of an ambulatory accelerometer-based assessment (seven consecutive 24-hour periods). Neuropsychological tests were performed and sleep parameters have been individualized by actigraph. Participants also underwent a magnetic resonance imaging scan to assess their hippocampal volume. Based on SUVr PET-florbetapir imaging, two groups Aß+ and Aß- were compared. Participants were divided into two groups: Aß+ (n = 24) and Aß- (n = 44). Except for the SUVr, the two subgroups were comparable. When looking to sleep parameters, increased sleep latency, sleep fragmentation (wake after sleep onset [WASO] score and awakenings) and worst sleep efficiency were associated with cortical brain amyloid load. Actigraphic sleep parameters were associated with cortical brain amyloid load in participants at risk to develop AD. The detection of sleep abnormalities in those participants may be of interest to propose some preventive strategies.

SEXUAL DIMORPHISM IN PLASMA BETA-SECRETASE 1 CONCENTRATIONS IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR AD: CROSS-SECTIONAL AND LONGITUDINAL STUDIES

The development of effective disease-modifying treatments for early Alzheimer's disease (AD) and targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted requires biomarker-drug co-development strategies, including the validation and qualification of accessible and non-invasive biological markers for different contexts of use. Cross-sectional and longitudinal studies demonstrated that plasma and cerebrospinal fluid (CSF) concentrations of BACE1 closely correlate with each other. We conducted both cross-sectional and longitudinal explorative studies in a cohort of individuals with subjective memory complaint (SMC), a condition at risk for AD, to investigate whether key biological factors such as sex, APOE ε4allele, and age affect plasma BACE1 concentrations. SMC individuals were recruited from the “INveStIGation of AlzHeimer's PredicTors in Subjective Memory Complainers” (INSIGHT-preAD) study, a university-based cohort which is part of the Alzheimer Precision Medicine Initiative (APMI) and its Cohort Program (APMI-CP). In the cross-sectional analysis, we found that baseline plasma BACE1 concentrations were highly significantly increased in females compared to males (p<0.001). Women showed a highly significantly increased plasma BACE1 concentrations compared to men, at all the three investigated time intervals (p<0.001). No difference regarding the longitudinal trajectories of plasma BACE1 concentrations was found between women and men. There was no significant effect of age and APOE ε4carrier status neither on overall BACE1 concentrations nor on BACE1 concentrations evolution. There was a highly significant decrease in plasma BACE1 concentrations in the whole sample of SMC individuals over time (p<0.001). We did not find any significant impact of two-way interactions between age and sex, age and APOE ε4 allele, sex and APOE ε4 allele on BACE1 plasma concentrations either at baseline or longitudinally. Thus, we demonstrate that the impact of a sexual-dimorphism on plasma BACE1 concentrations is irrespective of age and time. Evidence of the potential impact of a sexual dimorphism on the concentration and activity of BACE1 may be a relevant missing design component contributing to the failure of negative clinical BACE1 inhibitor therapy trial outcomes. Our results indicate that the impact of a sexual dimorphism on plasma BACE1 should be considered in further biomarker validation and qualification studies and in clinical BACE1 trials.

LATENT CLASS ANALYSIS IDENTIFIES FUNCTIONAL DECLINE WITH AMSTERDAM IADL IN PRE-CLINICAL ALZHEIMER’S DISEASE

Introduction: Trials in Alzheimer's disease (AD) now include participants at the earliest stages to prevent further decline. However, the lack of tools sensitive to subtle functional changes in early-stage AD hinders the development of new therapies as it is difficult to prove their clinical relevance. Methods: We assessed functional changes over three years in 289 elderly memory complainers from the Investigation of Alzheimer's Predictors in subjective memory complainers cohort using the Am-sterdam Instrumental-Activities-of-Daily-Living questionnaire (A-IADL-Q). Results: No overall functional decline related to AD imaging markers was evidenced. However, five distinct classes of A-IADL-Q trajectories were identified. The largest class (212 [73.4%]) had stable A-IADL-Q scores over 3 years. A second group (23 [8.0%]) showed a persistent functional decline, higher amyloid load (P 5 .0005), and lower education (P 5 .0392). Discussion: The A-IADL-Q identified a subtle functional decline in asymptomatic at-risk AD individuals. This could have important implications in the field of early intervention in AD.

Latent class analysis identifies functional decline with Amsterdam IADL in preclinical Alzheimer's disease

IntroductionTrials in Alzheimer's disease (AD) now include participants at the earliest stages to prevent further decline. However, the lack of tools sensitive to subtle functional changes in early-stage AD hinders the development of new therapies as it is difficult to prove their clinical relevance. MethodsWe assessed functional changes over three years in 289 elderly memory complainers from the Investigation of Alzheimer's Predictors in subjective memory complainers cohort using the Amsterdam Instrumental-Activities-of-Daily-Living questionnaire (A-IADL-Q). ResultsNo overall functional decline related to AD imaging markers was evidenced. However, five distinct classes of A-IADL-Q trajectories were identified. The largest class (212 [73.4%]) had stable A-IADL-Q scores over 3 years. A second group (23 [8.0%]) showed a persistent functional decline, higher amyloid load (P = .0005), and lower education (P = .0392). DiscussionThe A-IADL-Q identified a subtle functional decline in asymptomatic at-risk AD individuals. This could have important implications in the field of early intervention in AD.

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 Alzheimer's 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. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Caspers in this issue.

Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

IntroductionSeveral neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. MethodsThe pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). ResultsWe found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. DiscussionAnimal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.

Effect of Alzheimer's disease risk and protective factors on cognitive trajectories in subjective memory complainers: An INSIGHT-preAD study

IntroductionCognitive change in people at risk of Alzheimer's disease (AD) such as subjective memory complainers is highly variable across individuals. MethodsWe used latent class growth modeling to identify distinct classes of nonlinear trajectories of cognitive change over 2 years follow-up from 265 subjective memory complainers individuals (age 70 years and older) of the INSIGHT-preAD cohort. We determined the effect of cortical amyloid load, hippocampus and basal forebrain volumes, and education on the cognitive trajectory classes. ResultsLatent class growth modeling identified distinct nonlinear cognitive trajectories. Education was associated with higher performing trajectories, whereas global amyloid load and basal forebrain atrophy were associated with lower performing trajectories. DiscussionDistinct classes of cognitive trajectories were associated with risk and protective factors of AD. These associations support the notion that the identified cognitive trajectories reflect different risk for AD that may be useful for selecting high-risk individuals for intervention trials.

Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants.

The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood. Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults. Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire. Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC. Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.