Much research has focused on neurodegeneration in aging and Alzheimer's disease (AD). We developed Scoring by Nonlocal Image Patch Estimator (SNIPE), a non-local patch-based measure of anatomical similarity and hippocampal segmentation to measure hippocampal change. While SNIPE shows enhanced predictive power over hippocampal volume, it is unknown whether SNIPE is more strongly associated with group differences between normal controls (NC), early MCI (eMCI), late (lMCI), and AD than hippocampal volume. Alzheimer's Disease Neuroimaging Initiative older adults were included in the first analyses (N = 1666, 513 NCs, 269 eMCI, 556 lMCI, and 328 AD). Sub-analyses investigated amyloid positive individuals (N = 834; 179 NC, 148 eMCI, 298 lMCI, and 209 AD) to determine accuracy in those on the AD trajectory. We compared SNIPE grading, SNIPE volume, and Freesurfer volume as features in seven different machine learning techniques classifying participants into their correct cohort using 10-fold cross-validation. The best model was then validated in the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). SNIPE grading provided the highest classification accuracy for all classifications in both the full and amyloid positive sample. When classifying NC:AD, SNIPE grading provided an 89% accuracy (full sample) and 87% (amyloid positive sample). Freesurfer volume provided much lower accuracies of 65% (full sample) and 46% (amyloid positive sample). In the AIBL validation cohort, SNIPE grading provided a 90% classification accuracy for NC:AD. These findings suggest SNIPE grading provides increased classification accuracy over both SNIPE and Freesurfer volume. SNIPE grading offers promise to accurately identify people with and without AD.

Can a failure in the error-monitoring system explain unawareness of memory deficits in Alzheimer’s disease?

WMH and biomarker heterogeneity of individuals on the amyloid pathway

Increased Expression of Kif11/Kinesin‐5 mRNA Offsets Cognitive Deficits In An Alzheimer’s Mouse Model, Blocks Aβ‐Mediated Decreases in Long‐Term Potentiation and Spine Density, and is Associated With Better Cognitive Performance in Alzheimer’s Patients

Interaction effect of sex and diagnosis on functional connectivity within the default network in healthy controls, mild cognitive impairment and Alzheimer Disease

Background and ObjectivesSleep disordered breathing (SDB) has been related to amyloid deposition and an increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions, and episodic memory performance in cognitively unimpaired older adults.MethodsData were acquired between 2016 and 2020 in the context of the Age-Well randomized controlled trial of the Medit-Aging European project. Participants older than 65 years who were free of neurologic, psychiatric, or chronic medical diseases were recruited from the community. They completed a neuropsychological evaluation, in-home polysomnography, a Florbetapir PET, and an MRI, including a specific high-resolution assessment of the medial temporal lobe and hippocampal subfields. Multiple linear regressions were conducted to test interactions between amyloid status and SDB severity on the volume of MTL subregions, controlling for age, sex, education, and the ApoE4 status. Secondary analyses aimed at investigating the links between SDB, MTL subregional atrophy, and episodic memory performance at baseline and at a mean follow-up of 20.66 months in the whole cohort and in subgroups stratified according to amyloid status.ResultsWe included 122 cognitively intact community-dwelling older adults (mean age ± SD: 69.40 ± 3.85 years, 77 women, 26 Aβ+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (β = −0.81, p < 0.001, pη2 = 0.19), whole hippocampal (β = −0.61, p < 0.001, pη2 = 0.10), subiculum (β = −0.56, p = 0.002, pη2 = 0.08), CA1 (β = −0.55, p = 0.002, pη2 = 0.08), and DG (β = −0.53, p = 0.003, pη2 = 0.08) volumes such that a higher sleep apnea severity was related to lower MTL subregion volumes in amyloid-positive individuals, but not in those who were amyloid negative. In the whole cohort, lower whole hippocampal (r = 0.27, p = 0.005) and CA1 (r = 0.28, p = 0.003) volumes at baseline were associated with worse episodic memory performance at follow-up.DiscussionOverall, we showed that SDB was associated with MTL atrophy in cognitively asymptomatic older adults engaged in the Alzheimer continuum, which may increase the risk of developing memory impairment over time.Trial Registration InformationClinicalTrials.gov Identifier: NCT02977819.

<h3>Objective:</h3> To evaluate the concordance of tPACC scores from in-person and remote testing. <h3>Background:</h3> The clinical trial landscape in Alzheimer’s disease (AD) and related dementias is focused on targeting individuals in preclinical stages. The preclinical Alzheimer’s cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline in amyloid positive individuals compared to amyloid negative. It is desirable to have a transportable, composite measurement sensitive to detecting cognitive changes across cognitively normal (NC) and impaired (MCI and dementia) participants. <h3>Design/Methods:</h3> We examined in-person cognitive data from 662 adults (70.2±8.1y) from the Wake Forest AD Research Center’s Clinical Core, who received clinical evaluation, cognitive testing, and adjudication. The PACC in-person only was calculated using RAVLT Delayed Recall, Digit Symbol Coding (DSC), semantic fluency, Craft Story Delayed Verbatim, and MMSE total scores using baseline NC participants as a reference. The tPACC used measurements that were available at both in-person and remote visits with modifications from the in-person PACC; Montreal Cognitive Assessment (MoCA) was used in place of MMSE, and DSC was not included. A subset analysis with PACC in-person and tPACC remote from a pilot study examined reliability between in-person and remote testing. We performed correlation analysis and generated Bland-Altman plots. <h3>Results:</h3> Of the 662 adults studied, 434 (66%) were female, 522 (79%) were White, 206 (34%) were <i>APOE</i>4 carriers, and mean education was 15.9±4.1 years. At baseline, there is a significant positive relationship between in-person tPACC and PACC (Overall group; r²=0.94, p=&lt;0.0001, n=640). Although there is a good agreement in both subgroups (Impaired: r²=0.86, p=&lt;0.0001, n=301 and NC: r²=0.90, p=&lt;0.0001, n=328), tPACC overestimates cognitive performance compared to PACC for those with lower scores. We also found good agreement between in-person PACC and remote tPACC (r²=0.83, p=&lt;0.0001, n=38). <h3>Conclusions:</h3> There is generally good agreement between tPACC and PACC for NC and impaired individuals. <b>Disclosure:</b> Miss Duran has nothing to disclose. The institution of Ms. Gaussoin has received research support from NIH. The institution of Dr. Lockhart has received research support from NIH. Dr. Rundle has nothing to disclose. The institution of Dr. Espeland has received research support from Alzheimer’s Association. The institution of Dr. Espeland has received research support from National Institutes of Health. Dr. Espeland has received personal compensation in the range of $500-$4,999 for serving as a Consultant with National Institutes of Health. Dr. Williams has nothing to disclose. Tim Hughes has nothing to disclose. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cognito Therapeutics. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D Therapeutics. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cyclerion Therapeutics. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving as a member, Board of Scientific Counselors with NIA. Bonnie Sachs has received research support from NIH. Bonnie Sachs has received research support from Alzheimer’s Association. The institution of Dr. Bateman has received research support from NIA.

To evaluate the progression of brain glucose metabolism among participants with biological signature of Alzheimer's disease (AD) and its relevance to cognitive decline. We studied 602 amyloid positive individuals who underwent 18F-fluorodeoxyglucose PET (FDG-PET) scan, 18F-AV-45 amyloid PET (AV45-PET) scan, structural MRI scan and neuropsychological examination, including 116 cognitively normal (CN) participants, 314 participants diagnosed as mild cognitive impairment (MCI), and 172 participants diagnosed as AD dementia. The first FDG-PET scan satisfying the inclusion criteria was considered as the baseline scan. Cross-sectional analysis were conducted with the baseline FDG-PET data to compare the regional differences between diagnostic groups after adjusting confounding factors. Among these participants, 229 participants (55 CN, 139 MCI, and 35 AD dementia) had two-year follow-up FDG-PET data available. Regional glucose metabolism was computed and the progression rates of regional glucose metabolism were derived from longitudinal FDG-PET scans. Then the group differences of regional progression rates were examined to assess whether glucose metabolism deficit accelerates or becomes stable with disease progression. The association of cognitive decline rate with baseline regional glucose metabolism, and progression rate in longitudinal data, were evaluated. Participants with AD dementia showed substantial glucose metabolism deficit than CN and MCI at left hippocampus, in addition to the traditionally reported frontal and parietal-temporal lobe. More substantial metabolic change was observed with the contrast AD - MCI than the contrast MCI - CN, even after adjusting time duration since cognitive symptom onset. With the longitudinal data, glucose metabolism was observed to decline the most rapidly in the AD dementia group and at a slower rate in MCI. Lower regional glucose metabolism was correlated to faster cognitive decline rate with mild-moderate correlations, and the progression rate was correlated to cognitive decline rate with moderate-large correlations. Hippocampus was identified to experience hypometabolism in AD pathology. Hypometabolism accelerates with disease progression toward AD dementia. FDG-PET, particularly longitudinal scans, could potentially help predict how fast cognition declines and assess the impact of treatment in interventional trials.

BackgroundAmyloid deposition is a primary predictor of Alzheimer’s disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI).MethodsvERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time–frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT).ResultsNeurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r = − .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%.DiscussionvERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition.

BackgroundIn preclinical Alzheimer’s disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions.MethodsWe tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol.ResultsIn asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs.ConclusionsThese data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.

BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder with β-amyloid pathology as a key underlying process. The relevance of cerebrospinal fluid (CSF) and brain imaging biomarkers is validated in clinical practice for early diagnosis. Yet, their cost and perceived invasiveness are a limitation for large-scale implementation. Based on positive amyloid profiles, blood-based biomarkers should allow to detect people at risk for AD and to monitor patients under therapeutics strategies. Thanks to the recent development of innovative proteomic tools, the sensibility and specificity of blood biomarkers have been considerably improved. However, their diagnosis and prognosis relevance for daily clinical practice is still incomplete.MethodsThe Plasmaboost study included 184 participants from the Montpellier’s hospital NeuroCognition Biobank with AD (n = 73), mild cognitive impairments (MCI) (n = 32), subjective cognitive impairments (SCI) (n = 12), other neurodegenerative diseases (NDD) (n = 31), and other neurological disorders (OND) (n = 36). Dosage of β-amyloid biomarkers was performed on plasma samples using immunoprecipitation-mass spectrometry (IPMS) developed by Shimadzu (IPMS-Shim Aβ42, Aβ40, APP669–711) and Simoa Human Neurology 3-PLEX A assay (Aβ42, Aβ40, t-tau). Links between those biomarkers and demographical and clinical data and CSF AD biomarkers were investigated. Performances of the two technologies to discriminate clinically or biologically based (using the AT(N) framework) diagnosis of AD were compared using receiver operating characteristic (ROC) analyses.ResultsThe amyloid IPMS-Shim composite biomarker (combining APP669–711/Aβ42 and Aβ40/Aβ42 ratios) discriminated AD from SCI (AUC: 0.91), OND (0.89), and NDD (0.81). The IPMS-Shim Aβ42/40 ratio also discriminated AD from MCI (0.78). IPMS-Shim biomarkers have similar relevance to discriminate between amyloid-positive and amyloid-negative individuals (0.73 and 0.76 respectively) and A−T−N−/A+T+N+ profiles (0.83 and 0.85). Performances of the Simoa 3-PLEX Aβ42/40 ratio were more modest. Pilot longitudinal analysis on the progression of plasma biomarkers indicates that IPMS-Shim can detect the decrease in plasma Aβ42 that is specific to AD patients.ConclusionsOur study confirms the potential usefulness of amyloid plasma biomarkers, especially the IPMS-Shim technology, as a screening tool for early AD patients.

Changes in self- and study partner-perceived cognitive functioning in relation to amyloid status and future clinical progression: Findings from the SCIENCe project.

MRI‐guided Clustering of Alzheimer’s Disease patients: A post‐hoc analysis of Phase 3 Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally. In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time. This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (nCU- = 197); CU Aβ-positive (nCU+ = 55), mild cognitively impaired (MCI) Aβ-negative (nMCI- = 228), MCI Aβ-positive (nMCI+ = 193), and AD dementia Aβ-positive (nAD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (p = 0.01), worse brain atrophy (p = 8.8 × 10-27), and worse MMSE scores (p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, p = 1.5 × 10-14]). Despite the significant association with Aβ pathology (η2 Aβ PET = 0.09, P Aβ PET < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η2 pTau-181 = 0.53, P pTau-181 < 0.001; η2 tTau = 0.59, P tTau < 0.001). High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.

The APOE-ε4 allele is known to predispose to amyloid deposition and consequently is strongly associated with Alzheimer's disease (AD) risk. There is debate as to whether the APOE gene accounts for all genetic variation of the APOE locus. Another question which remains is whether APOE-ε4 carriers have other genetic factors influencing the progression of amyloid positive individuals to AD. We conducted a genome-wide association study in a sample of 5,390 APOE-ε4 homozygous (ε4ε4) individuals (288 cases and 5102 controls) aged 65 or over in the UK Biobank. We found no significant associations of SNPs in the APOE locus with AD in the sample of ε4ε4 individuals. However, we identified a novel genome-wide significant locus associated to AD, mapping to DAB1 (rs112437613, OR = 2.28, CI = 1.73–3.01, p = 5.4 × 10−9). This identification of DAB1 led us to investigate other components of the DAB1-RELN pathway for association. Analysis of the DAB1-RELN pathway indicated that the pathway itself was associated with AD, therefore suggesting an epistatic interaction between the APOE locus and the DAB1-RELN pathway.

BackgroundWe previously identified four Alzheimer’s disease (AD) subgroups with increasingly higher cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p-tau). These subgroups included individuals across the cognitive spectrum, suggesting p-tau subgroups could reflect distinct biological changes in AD, rather than disease severity. Therefore, in the current study, we further investigated which potential processes may be related with p-tau subgroups, by comparing individuals on CSF markers for presynaptic structure [vesicle-associated membrane protein 2 (VAMP2)], postsynaptic structure [neurogranin (NRGN)], axonal damage [neurofilament light (NfL)], and amyloid production [beta-secretase 1 (BACE1) and amyloid-beta 1–40 (Aβ40)].MethodsWe selected 348 amyloid-positive (A+) individuals (53 preclinical, 102 prodromal, 193 AD dementia) and 112 amyloid-negative (A−) cognitively normal (CN) individuals from the Amsterdam Dementia Cohort (ADC). Individuals were labeled according to their p-tau subgroup (subgroup 1: p-tau ≤ 56 pg/ml; subgroup 2: 57–96 pg/ml; subgroup 3: 97–159 pg/ml; subgroup 4: > 159 pg/ml). CSF protein levels were measured with ELISA (NRGN, BACE1, Aβ40, NfL) or single-molecule array (Simoa) (VAMP2). We tested whether protein levels differed between the p-tau subgroups within A+ individuals with linear models corrected for age and sex and whether disease stage influenced these relationships.ResultsAmong A+ individuals, higher p-tau subgroups showed a higher percentage of AD dementia [subgroup 1: n = 41/94 (44%); subgroup 2: n = 81/147 (55%); subgroup 3: n = 59/89 (66%); subgroup 4: n = 7/11 (64%)]. Relative to controls, subgroup 1 showed reduced CSF levels of BACE1, Aβ40, and VAMP2 and higher levels of NfL. Subgroups 2 to 4 showed gradually increased CSF levels of all measured proteins, either across the first three (NfL and Aβ40) or across all subgroups (VAMP2, NRGN, BACE1). The associations did not depend on the clinical stage (interaction p-values ranging between 0.19 and 0.87).ConclusionsThe results suggest that biological heterogeneity in p-tau levels in AD is related to amyloid metabolism and synaptic integrity independent of clinical stage. Biomarkers reflecting amyloid metabolism and synaptic integrity may be useful outcome measures in clinical trials targeting tau pathology.

Background: Characterizing self- and informant-reported cognitive complaints, as well as awareness of cognitive decline (ACD), is useful for an early diagnosis of Alzheimer’s disease (AD). However, complaints and ACD related to cognitive functions other than memory are poorly studied. Furthermore, it remains unclear which source of information is the most useful to distinguish various groups on the AD spectrum.Methods: Self- and informant-reported complaints were measured with the Everyday Cognition questionnaire (ECog-Subject and ECog-StudyPartner) in four domains (memory, language, visuospatial, and executive). ACD was measured as the subject-informant discrepancy in the four ECog scores. We compared the ECog and ACD scores across cognitive domains between four groups: 71 amyloid-positive individuals with amnestic AD, 191 amnestic mild cognitive impairment (MCI), or 118 cognitively normal (CN), and 211 amyloid-negative CN controls, selected from the ADNI database. Receiver operating characteristic curves analysis was performed to evaluate the accuracy of the ECog and ACD scores in discriminating clinical groups.Results: Self- and informant-reported complaints were generally distributed as follows: memory, language, executive, and visuospatial (from the most severe to the least severe). Both groups of CN participants presented on average more memory and language complaints than their informant. MCI participants showed good agreement with their informants. AD participants presented anosognosia in all domains, but especially for the executive domain. The four ECog-StudyPartner sub-scores allowed excellent discrimination between groups in almost all classifications and performed significantly better than the other two classifiers considered. The ACD was excellent in distinguishing the participants with AD from the two groups of CN participants. The ECog-Subject was the least accurate in discriminating groups in four of the six classifications performed.Conclusion: In research, the study of complaint and anosognosia should not be reduced solely to the memory domain. In clinical practice, non-amnestic complaints could also be linked to Alzheimer’s disease. The presence of an informant also seems necessary given its accuracy as a source of information.

BackgroundAlzheimer’s disease (AD) neuropathology reveals progressive microstructural alterations of cortical architecture. Recent studies reported intriguing biphasic trajectories of cortical structural changes in the early stages of Alzheimer’s disease (AD), comprising decreased mean diffusivity (MD) and increased cortical thickness in cognitively normal amyloid-positive individuals, ahead of increases and decreases, respectively, in subsequent disease stages.ObjectiveTo better understand the cytoarchitectural correlates of these observations, we assessed novel cortical diffusion tensor imaging (DTI) metrics that are correlated with disruption of cortical minicolumns and protein deposition.DesignCross-sectional and longitudinal analysis of whole brain and temporal lobe cortical diffusivity measures. Investigation of associations between baseline cortical diffusivity values and 24-month longitudinal structural-MRI changes. Investigations of the relationships between cortical diffusivity measures and biomarkers of neuroinflammation.SettingAlzheimer’s Disease Neuroimaging Initiative (ADNI).ParticipantsTwenty-four amyloid-negative controls (CN-), 28 amyloid-positive controls (CN+), 46 amyloid-positive subjects with mild cognitive impairment (MCI+) and 22 amyloid-positive subjects with AD were included.Measurements3DT1 and DTI scans at baseline and approximately 24-month follow-up were used to calculate cortical MD and three novel cortical diffusivity measures: the angle between the radial minicolumnar axis and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD+), and the principal diffusion component parallel with the minicolumns (ParlPD). Cortical macrostructural measurements (cortical volume fraction and cortical thickness), were used to test the hypothesis that baseline cortical diffusivity values can predict change in structural MRI outcomes over approximately 24 months. CSF soluble TREM2 and progranulin (PGRN) concentrations were used to investigate associations with microglial activity and potentially other aspects of neuroinflammation.ResultsCortical diffusivity metrics revealed a dependence on disease stage, with AngleR and PerpPD+ displaying biphasic relationships and ParlPD a monotonic relationship with clinical severity. The novel metrics were able to differentiate between Amyloid+ and Amyloid- controls (AngleR) and to differentiate among disease stages along the AD continuum (PerpPD+). Linear regression revealed significant associations between baseline cortical diffusivity values and subsequent 24-month longitudinal structural-MRI changes. AngleR values were significantly associated with CSF sTREM2 and PGRN concentrations.ConclusionsCortical diffusivity parameters reflecting minicolumnar organization and neuroinflammation may provide a sensitive and biologically interpretable measurement of cortex quality and microstructure across the AD continuum.

A novel link between locus coeruleus activity and amyloid-related cognitive decline