Global Clinical Dementia Rating Research Articles

The relationship between blood‐brain barrier permeability and cerebral blood flow in cognitive impairment

AbstractBackgroundThe contribution of cerebral microvascular dysfunction to early cognitive impairment and dementia is increasingly recognized. Here we investigated cerebral blood flow (CBF) and blood–brain barrier (BBB) permeability in relation to early cognitive decline in APOE3‐homozygotes (ε3/ε3) and APOE4‐carriers (ε3/ε4; ε4/ε4).MethodA total of 237 participants underwent neuropsychological evaluations, venipuncture, and magnetic resonance imaging (MRI). The global Clinical Dementia Rating (CDR) was used to classify participants in cognitively unimpaired (CU, CDR=0) and mild cognitive impairment (CDR=0.5). APOE genotyping was performed via polymerase chain reaction‐based retention fragment length polymorphism analysis on DNA extracted from buffy coat. BBB permeability and CBF were estimated from dynamic contrast‐enhanced and 3D pseudo‐continuous arterial spin labeling (pCASL) MRI data, respectively, using in‐house pipelines. After excluding APOE2‐carriers and participants with CDR>0.5, 143 participants (86 females [60.1%]) were included in the analysis. (Table 1)ResultStandardized CBF levels in grey matter (GM), hippocampus (HC), and parahippocampal gyrus (PHG) were not significantly different in APOE3‐homozygotes and APOE4‐carriers, after controlling for age and sex. (Figure 1) Our results of BBB permeability in 52 CU participants (27 APOE3‐homozygotes and 25 APOE4‐carriers) confirm a significantly higher BBB permeability in the HC of APOE4‐carriers compared with APOE3‐homozygotes (p<0.001), as previously reported (Montagne et al., Nature, 2020), and show no relationship between BBB permeability and CBF. (Figure 2) In a subgroup of 46 participants (21 CU APOE3‐homozygotes, 18 CU APOE4‐carriers, and 7 APOE4‐carriers with CDR=0.5) who underwent a second MRI approximately 2 years after the first MRI, we observed a significant reduction (p=0.008) of CBF in APOE4‐carriers with mild cognitive impairment, but not in CU individuals.ConclusionAPOE4 is associated with higher BBB permeability in CU participants compared with APOE3‐homozygotes, but CBF is not different between the two genotypes. In the future, longitudinal data will be collected to confirm whether BBB breakdown precedes CBF alterations and to assess their relationship with cognitive decline, amyloid‐β and tau pathology.

The effects of robot‐based cognitive intervention on resting‐state EEG in patients with mild Alzheimer's disease dementia

AbstractBackgroundCognitive intervention (CI) has been known to improve cognition and to delay cognitive decline in patients with dementia. The purpose of this study was to investigate the effects of our newly developed, robot‐based CI for 12 weeks on brain function and cognitive performance in patients with mild Alzheimer's disease dementia (ADD).MethodsA single‐blind randomized controlled trial was conducted in 37 patients with ADD. ADD patients met the criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA). Mild dementia was determined if global clinical dementia rating of the patients was 0.5 or 1. All participants were randomized into the two groups: the home based cognitive intervention with robot (Robot) and waitlist control without cognitive intervention (control). A total of 20 cognitive training programs were settled in the robot, which targeted training for specific cognitive domains including attention, memory, visuospatial, calculation, language and frontal executive functions. The robot‐based cognitive intervention comprised 60‐min‐session per day for 12 weeks. The primary outcome was the changes in brain function measured by resting state electroencephalogram (EEG) with a 19‐channel wireless EEG device. The secondary outcome was the changes of cognitive function measured using the Cambridge Neuropsychological Test Automated Battery.ResultsThere were no baseline demographic and clinical differences between the two groups. EEG analysis after 12‐week cognitive intervention showed decreased theta wave on the frontal areas in the Robot group, while increased theta wave on the frontal areas in the control group. In addition, Robot group also demonstrated improvement in the attention domain compared to the control group.ConclusionGiven that increased theta wave on the frontal areas is associated with cognitive decline, our results suggest that 12‐week robot based cognitive intervention could help improve brain function and attention in patients with mild ADD.

Neuroimaging and clinical characteristics of cognitive migration in community‐dwelling older adults

AbstractBackgroundLongitudinal studies in cognitively unimpaired older adults have identified a wide range of neuroimaging and clinical biomarkers that predict cognitive decline and clinical progression to mild cognitive impairment (MCI) or dementia. However, early biomarkers associated with progression from normal to impaired brain functioning and cognition (cognitive migration) in ADRD require further validation. We investigated the impacts of baseline neuroimaging and clinical biomarkers on functional and cognitive migration in a community‐dwelling cohort of older adults.MethodParticipants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort who completed their baseline and 1‐year follow‐up clinical visits with available neuropsychological and MRI data were evaluated. Each participant was categorized to a functional/cognitive state based on baseline global CDR (Clinical Dementia Rating); CDR=0 (n=120) indicates normal function and CDR=0.5 (n=57) corresponds to MCI. Cognitive measures included MoCA (Montreal Cognitive Assessment) and preclinical Alzheimer's cognitive composite (PACC5) scores. Oral Glucose Tolerance Testing (OGTT) assessed blood glucose 120‐minute post‐challenge; OGTT >140 mg/dl indicates impaired glucose tolerance. The primary outcome measure was cognitive migration determined by CDR increase/decrease between baseline and follow‐up (mean difference=13.8 months): CDR‐0 Stables (maintained CDR=0), CDR‐0.5 Stables (maintained CDR=0.5), CDR‐0 to CDR‐0.5 (Migrators), and CDR‐0.5 to CDR‐0 (Reverters). Baseline T1 MRI scans were assessed for gray‐matter volume and analyzed using voxel‐based morphometry in SPM12 for group differences. Statistical design was a two‐sample t‐test controlling for age, sex, education and whole brain volume in contrasts of interest (thresholded at k=25 voxels, p<0.01 uncorrected).ResultTable lists the baseline demographic and clinical characteristics for significant differences between groups. CDR‐0.5 Stables and Migrators had lower gray‐matter density (GMD) than CDR‐0 Stables and Reverters, most significantly in hippocampal (HC), temporal pole (BA38) and angular (BA39) regions (Figure).ConclusionOur analyses suggest that lower GMD in HC and BA38/39 may predict cognitive migration in early stages of disease pathology. OGTT tracks cognitive migration status in this cohort with Reverters having the lowest and Migrators having the highest mean OGTT. Validating these biomarkers may guide clinical diagnosis and treatments in ADRD. Cognitive and functional changes identified within one year can inform disease profiling.

Design of a patient‐ and investigator‐blind, randomized, placebo‐controlled study to evaluate efficacy, safety, and tolerability of bepranemab, UCB0107, in prodromal to mild Alzheimer’s disease: The TOGETHER Study, AH0003

AbstractBackgroundBepranemab is a recombinant, humanized, full‐length immunoglobulin G4 monoclonal antibody that binds to a central tau epitope (amino acids 235–250). Bepranemab is being developed to block or reduce the spread of tau pathology in people living with tau‐mediated diseases, like Alzheimer’s disease (AD).MethodTOGETHER (AH0003; NCT04867616) is a global, multicenter, patient‐blind, investigator‐blind, placebo‐controlled, parallel‐group study, investigating the efficacy, safety, and tolerability of bepranemab (intravenously, every 4 weeks) versus placebo in patients with prodromal (40%) or mild (60%) AD over an 80‐week treatment period, followed by an optional 48‐week open‐label extension (OLE). The primary objective is the change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score. Secondary objectives include: pharmacokinetics (PK); safety and tolerability; the effect of bepranemab on tau positron emission tomography (PET) imaging at Weeks 56 and 80; and the changes from baseline in the 14‐item Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog14), Amsterdam‐Instrumental Activities of Daily Living, and Mini‐Mental State Examination (MMSE) at Weeks 56 and 80. The OLE will assess the long‐term safety and tolerability of bepranemab. Approximately 150 patients per arm will be enrolled across 3 study arms (low‐dose and high‐dose bepranemab, and placebo; randomized 1:1:1). Eligible patients will meet the National Institute of Aging‐Alzheimer’s Association (NIA‐AA) 2018 Stage 3 or 4 definitions of prodromal or mild AD, respectively. Patients will have a global CDR score indicative of prodromal AD (0.5) or mild AD (0.5 or 1.0) and a CDR‐Memory Box score ≥0.5 at screening and baseline. Patients will have a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status, MMSE ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read PET scan or a positive cerebrospinal fluid pTau181/Aβ1‐42 ratio.ResultPatient enrollment and assessment will begin in Quarter 2 2021.ConclusionTOGETHER is a proof‐of‐concept study that will employ clinical outcome measures, imaging, PK, biomarkers, and safety to assess the ability of bepranemab to slow the progression of AD when administered in the prodromal/mild stages of disease.

156 POTENTIAL ELIGIBILITY FOR ADUCANUMAB THERAPY IN A REGIONAL SPECIALIST MEMORY SERVICE UTILISING AD PHENOTYPE, CSF BIOMARKERS AND APPROPRIATE USE CRITERIA

Abstract Background Aducanumab, the first monoclonal antibody directed against amyloid beta peptide has recently been licensed for use by the FDA for treatment of patients with mild cognitive impairment (MCI) due to Alzheimer’s Disease (ad) or mild ad dementia. Appropriate use criteria (AUC) for Aducanumab have recently been released. In light of these AUC, the aim of this study was to review patients in our specialist memory service with positive CSF biomarkers for ad [low amyloid- beta-42 (AB-42), high phosphorylated tau (p-tau)] to assess their hypothetical eligibility for Aducanumab therapy. Methods Retrospective database analysis was undertaken of patients with positive (high p-tau, low AB-42) ad-biomarker CSF analysis. Demographic, neuropsychological performance, neuro-radiological, laboratory, and clinical phenotype diagnosis data were reviewed at time of CSF analysis to determine hypothetical eligibility for Aducanumab. Data was extracted and analysed using SPSS v.25. Results Forty-nine patients had positive ad-CSF biomarkers, 41/49 (84%) of whom presented with common ad phenotypes. 28/49 (57%) were male. Mean patient age was 71.2 (±5.9) RBANS delayed memory index score mean was 80.2 (±14.5) and mean EXIT-25 scores were 13.2 (±6.7). 63.2% (31/49) patients met eligibility criteria for Aducanumab therapy by AUC guidelines. 12.2% (6/49) wouldn’t have qualified due to abnormal laboratory findings and 14.2% (7/49) due to MMSE <21 or MoCA <17. Two patients would not have qualified due to underlying medical conditions and two were prescribed therapeutic anticoagulation. However by FDA guidelines, a further 30.6% (15/49) of patients may have been unsuitable due to global Clinical Dementia Rating Scale ≥0.5. Conclusion AUC for Aducanumab address some of the controversial aspects in its licencing. This report highlights the presence of patients eligible for Aducanumab therapy should a European licence be granted, and the need to develop a system readiness and capacity to deliver this and other emerging disease-modifying ad therapies.

Differences in Symptomatic Presentation and Cognitive Performance Among Participants With LATE-NC Compared to FTLD-TDP.

Transactive response DNA-binding protein 43 kDa (TDP-43) is aberrantly aggregated and phosphorylated in frontotemporal lobar degeneration of the TDP-43 type (FTLD-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). We examined data from the National Alzheimer's Coordinating Center to compare clinical features of autopsy-confirmed LATE-NC and FTLD-TDP. A total of 265 LATE-NC and 92 FTLD-TDP participants were included. Cognitive and behavioral symptoms were compared, stratified by level of impairment based on global clinical dementia rating (CDR) score. LATE-NC participants were older at death, more likely to carry APOE ε4, more likely to have Alzheimer disease neuropathology, and had lower (i.e. less severe) final CDR global scores than those with FTLD-TDP. Participants with FTLD-TDP were more likely to present with primary progressive aphasia, or behavior problems such as apathy, disinhibition, and personality changes. Among participants with final CDR score of 2-3, those with LATE-NC were more likely to have visuospatial impairment, delusions, and/or visual hallucinations. These differences were robust after sensitivity analyses excluding older (≥80 years at death), LATE-NC stage 3, or severe Alzheimer cases. Overall, FTLD-TDP was more globally severe, and affected younger participants, whereas psychoses were more common in LATE-NC.

Evaluation of the Cost-effectiveness of Drug Treatment for Alzheimer Disease in a Simulation Model That Includes Caregiver and Societal Factors

The possibility of widespread use of a novel effective therapy for Alzheimer disease (AD) will present important clinical, policy, and financial challenges. To describe how including different patient, caregiver, and societal treatment-related factors affects estimates of the cost-effectiveness of a hypothetical disease-modifying AD treatment. In this economic evaluation, the Alzheimer Disease Archimedes Condition Event Simulator was used to simulate the prognosis of a hypothetical cohort of patients selected from the Alzheimer Disease Neuroimaging Initiative database who received the diagnosis of mild cognitive impairment (MCI). Scenario analyses that varied costs and quality of life inputs relevant to patients and caregivers were conducted. The analysis was designed and conducted from June 15, 2019, to September 30, 2020. A hypothetical drug that would delay progression to dementia in individuals with MCI compared with usual care. Incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life-year (QALY) gained. The model included a simulated cohort of patients who scored between 24 and 30 on the Mini-Mental State Examination and had a global Clinical Dementia Rating scale of 0.5, with a required memory box score of 0.5 or higher, at baseline. Using a health care sector perspective, which included only individual patient health care costs, the ICER for the hypothetical treatment was $192 000 per QALY gained. The result decreased to $183 000 per QALY gained in a traditional societal perspective analysis with the inclusion of patient non-health care costs. The inclusion of estimated caregiver health care costs produced almost no change in the ICER, but the inclusion of QALYs gained by caregivers led to a substantial reduction in the ICER for the hypothetical treatment, to $107 000 per QALY gained in the health sector perspective. In the societal perspective scenario, with the broadest inclusion of patient and caregiver factors, the ICER decreased to $74 000 per added QALY. The findings of this economic evaluation suggest that policy makers should be aware that efforts to estimate and include the effects of AD treatments outside those on patients themselves can affect the results of the cost-effectiveness analyses that often underpin assessments of the value of new treatments. Further research and debate on including these factors in assessments that will inform discussions on fair pricing for new treatments are needed.

Differences in Brain Morphology between Hydrocephalus Ex Vacuo and Idiopathic Normal Pressure Hydrocephalus.

ObjectiveThe distinction between idiopathic normal pressure hydrocephalus (iNPH) and hydrocephalus ex vacuo caused by encephalic volume loss remains to be established. This study aims to investigate radiological parameters as clinically useful tools to discriminate iNPH from hydrocephalus ex vacuo caused by Alzheimer’s disease (AD). MethodsA total of 54 patients with ventriculomegaly (iNPH, 25; hydrocephalus ex vacuo, 29) were recruited in this study. Consequently, nine radiological parameters were compared between iNPH and hydrocephalus ex vacuo using magnetic resonance imaging (MRI). ResultsA small callosal angle (CA), the Sylvian fissure dilatation, and absence of narrowing of superior parietal sulci discriminated the iNPH group from the hydrocephalus ex vacuo group (p<0.05). The final binary logistic regression model included narrowing of superior parietal sulci, degrees of the CA, and height of the Sylvian fissure after controlling for age and global Clinical Dementia Rating (CDR). The composite score made from these three indicators (narrowing of superior parietal sulci, degrees of the CA, and height of the Sylvian fissure) was statistically different between iNPH and hydrocephalus ex vacuo. ConclusionThe narrowing of the CA, dilatation of the Sylvain fissure, and narrowing of superior parietal sulci may be used as radiological key indices and noninvasive tools for the differential diagnosis of iNPH from hydrocephalus ex vacuo.

Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity.

ObjectiveTo investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.MethodsIndividuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a “placebo” and “treatment” group and subsequently computed group differences on the CDR–sum of boxes (CDR-SB), Alzheimer’s Disease Assessment Scale–cognitive subscale–13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes.ResultsIndividual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).ConclusionsIndividuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.

Neuropsychiatric symptoms in early stage of Alzheimer's and non-Alzheimer's dementia, and the risk of progression to severe dementia.

Neuropsychiatric symptoms (NPSs) in early dementia have been suggested to predict a higher risk of dementia progression. However, the literature is not yet clear whether the risk is similar across Alzheimer's dementia (AD) and non-Alzheimer's dementia (non-AD), as well as across different NPSs. This study examined the association between NPSs in early dementia and the risk of progression to severe dementia, specifically in AD and non-AD, as well as across various NPSs. This cohort study included 7,594 participants who were ≥65years and had early dementia (global Clinical Dementia Rating [CDR] = 1). Participants completed Neuropsychiatric-Inventory-Questionnaire at baseline and were followed-up almost annually for progression to severe dementia (global CDR = 3) (median follow-up = 3.5years; interquartile range = 2.1-5.9years). Cox regression was used to examine progression risk, stratified by AD and non-AD. The presence of NPSs was associated with risk of progression to severe dementia, but primarily in AD (HR 1.4, 95% confidence interval [CI]: 1.1-1.6) and not in non-AD (HR 0.9, 95% CI: 0.5-1.5). When comparing across various NPSs, seven NPSs in AD were associated with disease progression, and they were depression, anxiety, apathy, delusions, hallucinations, irritability and motor disturbance (HR 1.2-1.6). In contrast, only hallucinations and delusions were associated with disease progression in non-AD (HR 1.7-1.9). NPSs in early dementia-especially among individuals with AD-can be useful prognostic markers of disease progression. They may inform discussion on advanced care planning and prompt clinical review to incorporate evidence-based interventions that may address disease progression.

Cognitive indices correlate with [18F]GTP1 tau PET signal and white matter hyperintensities in prodromal‐to‐mild Alzheimer's disease: Baseline data from the Tauriel Study

AbstractBackgroundIn prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer’s disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD.MethodWe analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression.ResultUnivariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p’s&lt;0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p&lt;0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p’s&lt;0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR.ConclusionAmongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline.

Associations of truncal body composition with cognitive status in patients with dementia

AbstractBackgroundCognitive impairment is one of the most common age‐related diseases, and there are many modifiable risk factors, such as obesity and sarcopenia, which are extensively researched these days. Although many studies examined the relationship between obesity and cognitive impairment, the common methods to measure obesity have a limitation that they do not accurately measure truncal fat. Moreover, as truncal muscles are an indispensable component for movement for activity, it could be expected that the many truncal muscles are related to better cognitive functions. The objective of this study is to investigate the relationship between truncal body composition (fat and muscle) and cognitive impairment in patients with dementia in Korea.MethodFemale over 60 years of age with probable Alzheimer’s Disease were recruited between November 2014 and September 2015. The Mini‐Mental state examination, Global deterioration scale and Clinical dementia rating scale were used to assess the cognitive functions. Both truncal fat and muscle mass were measured using body dual energy X‐ray absorptiometry, and used as a percentage of body weight (TMM% and TFM%). Correlations between truncal composition and cognitive status were assessed by simple correlation analysis, which was followed by partial correlation analysis with age, educational years.ResultTFM% was not related to cognitive impairment. In contrast, TMM% had a significantly negative correlation with all three cognitive assessment scores. After further adjusting for age and educational years, there was still a relationship between TMM% and cognitive functionsConclusionWhile truncal fat mass showed no relevance with cognitive functions, the truncal muscle mass was negatively correlated with cognitive status. The truncal muscle mass is thought to affect cognitive status in dementia patients somehow.

Intracellular signal changes in the anterosuperior medial temporal lobe associated with early cognitive decline

AbstractBackgroundHippocampal degeneration and loss of white matter integrity both play a role in AD pathology. The anterosuperior part of the medial temporal lobe (MTL) acts as a white matter connecting point between the fontal and temporal lobes. Loss of white matter integrity in tracts passing through this region has been associated with AD [1,2]. Our aim was to use diffusion MRI to investigate changes in microstructure of white matter tracts passing through this region corresponding with cognitive impairment.Method120 subjects from the ADNI 3 cohort with multi‐shell diffusion MRI were analyzed [3]. Tractography through the anterosuperior MTL (asMTL) tracts were performed using the Quantitative Imaging Toolkit (QIT), using HCP‐derived atlas data [4,5]. Three tracts were selected for analysis including the uncinate and inferior fronto‐occipital fasciculi and the anterior commissure. . Subjects with global clinical dementia rating of 0 (N=71) and 1 (N=39) were grouped as cognitively normal (CN) and mild cognitive impairment (MCI), respectively. Intracellular signal fraction, isotropic signal fraction (free water) were obtained using NODDI [6] and mean diffusivity were obtained using DTI [7] estimated using QIT. The association between cognitive impairment and imaging features were assessed using logistic regression with age, sex, and brain volume as covariates.ResultThe intracellular signal fraction was reduced to a significant extent bilaterally in the uncinate and inferior fronto‐occipital fasciculi and anterior commissure among MCI compared to CN individuals (Figure 2.a). No significant difference in isotropic signal was observed (Figure 2.b). We also observed significantly increased mean diffusivity among MCI bilaterally in the uncinate fasciculi and the anterior commissure and trended towards significance bilaterally in the inferior fronto‐occipital fasciculi (Figure 2.c).ConclusionWe found significant microstructural alteration in early cognitive decline in tracts passing through the asMTL region. Among these tracts, the left inferior fronto‐occipital fasciculus showed the largest microstructural changes (Cohen’s D=0.525721). Identifying early white matter changes could aid early diagnosis or disease progression monitoring, as it has been suggested that white matter atrophy precede symptom onset [2]. Results suggest that decreased intracellular signal fraction in these tracts passing through the asMTL as a potential driving factor of this increased diffusivity.

Clinical Profiles of Arteriolosclerosis and Alzheimer Disease at Mild Cognitive Impairment and Mild Dementia in a National Neuropathology Cohort.

We sought to evaluate early clinical differences between cerebral arteriolosclerosis (pARTE), Alzheimer disease (pAD), and AD with arteriolosclerosis (ADARTE). Using National Alzheimer's Coordinating Center neuropathology diagnoses, we defined pARTE (n=21), pAD (n=203), and ADARTE (n=158) groups. We compared demographics, medical history, psychometrics, neuropsychiatric symptoms, and apolipoprotein E (APOE) allele variants across neuropathology groups. Retrospective timepoints were first evaluation with Global Clinical Dementia Rating (CDR) score of 0.5 and 1.0, via the CDR Dementia Staging Instrument, corresponding to mild cognitive impairment (MCI) and mild dementia, respectively. In MCI, clinical differences were minimal but pARTE subjects were older, had later onset cognitive decline, and progressed less severely than pAD. In mild dementia, pAD subjects were younger and had earlier onset of decline. Neuropsychiatric (depression) and psychometric (Logical Memory Delayed Recall, Trails B) differences also emerged between the groups. In MCI, APOE4 associated with worse Logical Memory Delayed Recall in pAD and ADARTE. In mild dementia, APOE4 associated with better animal fluency in pAD, but with better Trails A performance and more neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire) in ADARTE. Differences between pARTE, pAD, and ADARTE emerge at mild dementia rather than MCI. APOE4 has varied cognitive and psychiatric impact dependent on neuropathology group and stage.

Regional Cerebral Associations Between Psychometric Tests and Imaging Biomarkers in Alzheimer's Disease.

Recently, imaging biomarkers have gained importance for the characterization of patients with Alzheimer’s disease; however, the relationship between regional biomarker expression and cognitive function remains unclear. In our study, we investigated associations between scores on CERAD neuropsychological assessment battery (CERAD-NAB) subtests with regional glucose metabolism, cortical thickness and amyloid deposition in patients with early Alzheimer’s disease (AD) using [18F]-fluorodeoxyglucose (FDG), structural MRI, and 11C-Pittsburgh Compound B (PiB) positron emission tomography (PET), respectively. A total of 76 patients (mean age 68.4 ± 8.5 years, 57.9% male) with early AD (median global clinical dementia rating (CDR) score = 0.5, range: 0.5–2.0) were studied. Associations were investigated by correlation and multiple regression analyses. Scores on cognitive subtests were most closely predicted by regional glucose metabolism with explained variance up to a corrected R² of 0.518, followed by cortical thickness and amyloid deposition. Prediction of cognitive subtest performance was increased up to a corrected R² of 0.622 for Word List—Delayed Recall, when biomarker information from multiple regions and multiple modalities were included. For verbal, visuoconstructive and mnestic domains the closest associations with FDG-PET imaging were found in the left lateral temporal lobe, right parietal lobe, and posterior cingulate cortex, respectively. Decreased cortical thickness in parietal regions was most predictive of impaired subtest performance. Remarkably, cerebral amyloid deposition significantly predicted cognitive function in about half of the subtests but with smaller extent of variance explained (corrected R² ≤ 0.220). We conclude that brain metabolism and atrophy affect cognitive performance in a regionally distinct way. Significant predictions of cognitive function by PiB-PET in half of CERAD-NAB subtests suggest functional relevance even in symptomatic patients with AD, challenging the concept of plateauing cortical amyloid deposition early in the disease course. Our results underscore the complex spatial relationship between different imaging biomarkers.

Cerebroarterial pulsatility and resistivity indices are associated with cognitive impairment and white matter hyperintensity in elderly subjects: A phase-contrast MRI study

Increased cerebroarterial pulsations are thought to be contributing factors in microvascular damage and cognitive impairment. In this study, we assessed the utility of two-dimensional (2D) phase-contrast MRI (PC-MRI) in quantifying cerebroarterial pulsations and evaluated the associations of pulsatile and non-pulsatile hemodynamic measures with cognitive performance and white matter hyperintensities (WMH). Neurocognitive assessments on 50 elderly subjects were performed using clinical dementia rating (CDR) and Montreal cognitive assessment (MoCA). An electrocardiogram-gated 2D PC-MRI sequence was used to calculate mean flow rate, pulsatility index (PI), and resistivity index (RI) of the internal carotid artery. For each subject, whole brain global cerebral blood flow (gCBF) and relative WMH volume were also quantified. Elevated RI was significantly associated with reduced cognitive performance quantified using MoCA (p = 0.04) and global CDR (p = 0.02). PI and RI were both significantly associated with relative WMH volume (p = 0.01, p < 0.01, respectively). However, non-pulsatile hemodynamic measures were not associated with cognitive impairment or relative WMH volume. This study showed that the cerebroarterial pulsatile measures obtained using PC-MRI have stronger association with the measures of cognitive impairment compared to global blood flow measurement and as such, might be useful as potential biomarkers of cerebrovascular dysfunction in preclinical populations.

Expanded Demographic Norms for Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set.

Norms for the Uniform Data Set Version 3 Neuropsychological Battery are available for cognitively normal individuals based on age, education, and sex; however, these norms do not include race. We provide expanded norms for African Americans and whites. Data from 32 Alzheimer's Disease Centers (ADCs) and ADC affiliated cohorts with global Clinical Dementia Rating Scale (CDR) Dementia Staging Instrument scores of 0 were included. Descriptive statistics for each test were calculated by age, sex, race, and education. Multiple linear regressions were conducted to estimate the effect of each demographic variable; squared semipartial correlation coefficients measured the relative importance of variables. There were 8313 participants (16% African American) with complete demographic information, ranging from 6600 to 7885 depending on the test. Lower scores were found for older and less educated groups, and African Americans versus whites. Education was the strongest predictor for most tests, followed in order by age, race, and sex. Quadratic terms were significant for age and education, indicating some nonlinearity, but did not substantially increase R. Although race-based norms represent incomplete proxies for other sociocultural variables, the appropriate application of these norms is important given the potential to improve diagnostic accuracy and to reduce misclassification bias in cognitive disorders of aging such as Alzheimer disease.

Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD

IntroductionDemonstrating the “clinical meaningfulness” of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid-β (Aβ+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression. MethodsCox regression analyses were used to determine whether 3-year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aβ+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative. ResultsSteeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta-analytic estimates were 5.47 (95% CI: 3.25–9.18) for MCI diagnosis and 4.49 (95% CI: 2.84–7.09) for Clinical Dementia Rating>0 in those with subtle decline (>−.14 to −.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing. DiscussionEarly “subtle cognitive decline” among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment.

Global Clinical Dementia Rating Score of 0.5 May Not Be an Accurate Criterion to Identify Individuals with Mild Cognitive Impairment.

Many studies use the global clinical dementia rating (CDR) of 0.5 as a criterion for mild cognitive impairment, but past studies have not fully discussed its validity. The authors developed the ABC Dementia Scale (ABC-DS) to accurately monitor the changes in activities for daily living, behavioral and psychological symptoms of dementia, and cognitive function. When we carried out a cluster analysis of ABC-DS scores of 110 individuals for whom global CDR was 0.5, there were three groups with different levels of activities for daily living and cognitive function. O’Bryant et al. proposed a new guideline to stage dementia using the CDR sum of boxes scores (CDR-SOB). We used their proposal and ABC-DS scores to evaluate the validity of CDR 0.5 as a definition of mild cognitive impairment (MCI). We concluded that the CDR-SOB scores and ABC-DS score are more accurate than global CDR of 0.5 for specifying individuals with MCI.

Effects of Anserine/Carnosine Supplementation on Mild Cognitive Impairment with APOE4.

Background: Oral supplementation of anserine/carnosine helps preserve cognitive functions in healthy older adults. Mild cognitive impairment (MCI) is a transition between cognitive-normal and dementia. Therefore, it needs to investigate whether anserine/carnosine supplementation (ACS) has effects on subjects with MCI. Methods: A randomized, double-blind, placebo-controlled 12-week trial was performed. Fifty-four subjects with MCI were randomized to an active group ingesting 750 mg of anserine and 250 mg of carnosine per day or a placebo (1:1). Evaluation of cognitive change was conducted utilizing a psychometric test battery. Results: The score improvement in the global Clinical Dementia Rating (gloCDR) was superior in the active group than placebo (p = 0.023). No beneficial effect in the active group was detected in the other psychometric tests including the Mini-Mental State Examination (MMSE), the Wechsler Memory Scale, and the Alzheimer’s Disease Assessment Scale (ADAS). When APOE4 positive (APOE4 (+)) or negative (APOE4 (-)) subjects were separately analyzed, beneficial change in the APOE4 (+) subjects was observed in MMSE (p = 0.025) as well as in gloCDR (p = 0.026). Conclusions: The present study might suggest that protective effects against cognitive decline in APOE4 (+) MCI subjects exist.