Fazekas scale magnetic resonance imaging assessment in Alzheimer's disease and primary age-related tauopathy.

BACKGROUND: Brain vascular pathology is an important comorbidity in Alzheimer's disease (AD), with white matter damage independently predicting cognitive impairment. However, it is still unknown how vascular pathology differentially impacts primary age-related tauopathy (PART) compared to AD. Therefore, our objectives were to compare the brain microangiopathic burden in patients with PART and AD, evaluated by MRI, while assessing its relation with neuropathological findings, patterns of brain atrophy and degree of clinical impairment. METHODS: Clinical information, brain MRI (T1 and T2-FLAIR) and neuropathological data were obtained from the National Alzheimer's Coordinating Centre ongoing study, with a total sample of 167 patients identified, that were divided according to the presence of neuritic plaques in Consortium to Establish a Registry for Alzheimer's disease (CERAD) 0 to 3. Microangiopathic burden and brain atrophy were evaluated by two certified neuroradiologists, using, respectively, the Fazekas score and previously validated visual rating scales to assess brain regional atrophy. RESULTS: Significant correlations were found between the Fazekas score and atrophy in the fronto-insular and medial temporal regions on both groups, with PART showing overall stronger positive correlations than in AD, especially in the fronto-insular region. For this specific cohort, no significant correlations were found between the Fazekas score and the degree of clinical impairment. CONCLUSION: Our results show that PART presents different pathological consequences at the brain microvascular level compared with AD and further supports PART as an independent pathological entity from AD.

Personality predictors of dementia diagnosis and neuropathological burden: An individual participant data meta-analysis.

INTRODUCTION: The extent to which the Big Five personality traits and subjective well-being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia-related neuropathology is unclear. METHODS: Using data from eight independent studies (Ntotal = 44,531; Ndementia = 1703; baseline Mage = 49 to 81 years, 26 to 61% female; Mfollow-up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia. RESULTS: Synthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long-term dementia diagnosis. There were no consistent associations with neuropathology. DISCUSSION: This multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy. HIGHLIGHTS: N(+), C(-), E(-), PA(-), and NA(+) were associated with incident diagnosis. Results were consistent despite self-report versus clinical diagnosis of dementia. Psychological factors were not associated with neuropathology at autopsy. Individuals with higher conscientiousness and no diagnosis had less neuropathology. High C individuals may withstand neuropathology for longer before death.

Associations between urinary caffeine and caffeine metabolites and cognitive function in older adults.

BACKGROUND: The effects of caffeine on cognitive impairment have not been conclusively determined. This study aimed to objectively assess the correlation between the urinary caffeine and caffeine metabolites and cognitive decline in older adults. METHODS: Data on urinary caffeine and caffeine metabolites and the cognitive performance of participants aged 60 years and older were extracted from the National Health and Nutrition Examination Surveys 2011-2014. Binary logistic regression and restricted cubic splines (RCS) analyses were used to evaluate the association between urinary caffeine and caffeine metabolites and cognitive performance. RESULTS: Eight hundred twenty-seven individuals were enrolled in this cross-sectional study. We observed that 1-methylxanthine, 3-methylxanthine, 7-methylxanthine, 1,3-dimethylxanthine, 1,7-dimethylxanthine, and 3,7-dimethylxanthine levels were significantly and inversely associated with cognitive decline. The RCS results suggested an approximately linear dose-response relationship between the aforementioned metabolites and cognitive performance. Moreover, the effects of urinary caffeine and caffeine metabolites on cognitive function assessed using the AFT were more evident in men. CONCLUSIONS: Our study suggested that urinary caffeine and caffeine metabolite levels were associated with a reduced risk of cognitive impairment in a linear manner, especially in men.

Multisite study of the relationships between antemortem [11C]PIB-PET Centiloid values and postmortem measures of Alzheimer's disease neuropathology.

INTRODUCTION: We sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [11C]PIB-positron emission tomography ([11C]PIB-PET) analyzed with the Centiloid (CL) method, a standardized scale for Aß-PET quantification. METHODS: Four centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings. RESULTS: CL values increased with each CERAD neuritic plaque score increment (median -3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aß phases (increases were detected starting at phase 2) with overlap between scores/phases. PET-pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate-to-frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate-to-high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%). DISCUSSION: Our study demonstrated the robustness of a multisite Centiloid [11C]PIB-PET study and established a range of pathology-based CL thresholds.

Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease.

INTRODUCTION: Neuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential. METHODS: We compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB-PET), 18F-fluorodeoxyglucose PET (FDG-PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed. RESULTS: PiB-PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG-PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with "none" or "sparse" neuritic plaque scores had elevated PiB-PET signal due to diffuse amyloid plaque. Participants with findings characterized as "suspected non-Alzheimer's pathophysiology" represented 15% of the group. DISCUSSION: PiB-PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG-PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non-Alzheimer's pathophysiology most commonly had primary age-related tauopathy.

The CERAD Neuropsychological Assessment Battery Is Sensitive to Alcohol-Related Cognitive Deficiencies in Elderly Patients: A Retrospective Matched Case-Control Study.

OBJECTIVES: Adverse effects of heavy drinking on cognition have frequently been reported. In the present study, we systematically examined for the first time whether clinical neuropsychological assessments may be sensitive to alcohol abuse in elderly patients with suspected minor neurocognitive disorder. METHODS: A total of 144 elderly with and without alcohol abuse (each group n=72; mean age 66.7 years) were selected from a patient pool of n=738 by applying propensity score matching (a statistical method allowing to match participants in experimental and control group by balancing various covariates to reduce selection bias). Accordingly, study groups were almost perfectly matched regarding age, education, gender, and Mini Mental State Examination score. Neuropsychological performance was measured using the CERAD (Consortium to Establish a Registry for Alzheimer's Disease). Classification analyses (i.e., decision tree and boosted trees models) were conducted to examine whether CERAD variables or total score contributed to group classification. RESULTS: Decision tree models disclosed that groups could be reliably classified based on the CERAD variables "Word List Discriminability" (tapping verbal recognition memory, 64% classification accuracy) and "Trail Making Test A" (measuring visuo-motor speed, 59% classification accuracy). Boosted tree analyses further indicated the sensitivity of "Word List Recall" (measuring free verbal recall) for discriminating elderly with versus without a history of alcohol abuse. CONCLUSIONS: This indicates that specific CERAD variables seem to be sensitive to alcohol-related cognitive dysfunctions in elderly patients with suspected minor neurocognitive disorder. (JINS, 2018, 24, 360-371).

Dietary inflammatory index and memory function: population-based national sample of elderly Americans.

The objective of this study was to examine the association between dietary inflammatory potential and memory and cognitive functioning among a representative sample of the US older adult population. Cross-sectional data from the 2011-2012 and 2013-2014 National Health and Nutrition Examination Survey were utilised to identify an aggregate sample of adults 60-85 years of age (n 1723). Dietary inflammatory index (DII®) scores were calculated using 24-h dietary recall interviews. Three memory-related assessments were employed, including the Consortium to Establish a Registry for Alzheimer's disease (CERAD) Word Learning subset, the Animal Fluency test and the Digit Symbol Substitution Test (DSST). Inverse associations were observed between DII scores and the different memory parameters. Episodic memory (CERAD) (b adjusted=-0·39; 95 % CI -0·79, 0·00), semantic-based memory (Animal Fluency Test) (b adjusted=-1·18; 95 % CI -2·17, -0·20) and executive function and working-memory (DSST) (b adjusted=-2·80; 95 % CI -5·58, -0·02) performances were lowest among those with the highest mean DII score. Though inverse relationships were observed between DII scores and memory and cognitive functioning, future work is needed to further explore the neurobiological mechanisms underlying the complex relationship between inflammation-related dietary behaviour and memory and cognition.

The effect of exercise combined with a cognitive-enhancement group training program on cognition and depression in the community-dwelling elderly.

[Purpose] In this study, we investigated the effects of combining exercise with a cognitive-enhancement group program on cognition and depression in a group of community-dwelling elderly people. [Subjects and Methods] The study's subjects consisted of 30 community-dwelling elderly people of both genders, whose average age was 78 years. They participated in a program of physical exercise combined with a cognitive-enhancement group training program. This consisted of sessions lasting 60 minutes that took place once a week over 3 months. To assess the participants' levels of cognition and depression, we conducted batteries of tests using, respectively, the Korean versions of the Consortium to Establish a Registry for Alzheimer's Disease assessment packet (CERAD-K) and the Geriatric Depression Scale-Short Form (GDS-SF). [Results] The Verbal Fluency test, Word List Memory test, Modified Boston Naming test, Mini Mental Status Examination (Korean Version) (MMSE-KC), Constructional Praxis task and Constructional Recall task showed significant improvement, but improvement in the Word List Recall and Word List Recognition tests did not achieve significant levels. Meanwhile, the symptoms of depression were shown to decrease significantly. [Conclusion] Physical exercise combined with a cognitive-enhancement group training program was effective in improving, some of the components of cognition, as well as alleviating depression. This program should be used for the prevention of dementia in community-dwelling elderly, through the intervention should be complemented in order to improve more of the components of cognition.

Diagnostic accuracy of CERAD total score in a Colombian cohort with mild cognitive impairment and Alzheimer's disease affected by E280A mutation on presenilin-1 gene.

BACKGROUND: This study aimed to determine Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Assessment Battery total score diagnostic accuracy in the diagnosis of mild cognitive impairment (MCI) and dementia in familial Alzheimer's disease (FAD) with E280A mutation on presenilin-1 gene (PSEN1). METHODS: A cross-sectional study was conducted in a cohort of PSEN1 E280A carriers and non-carriers assessed between January 1995 and February 2013. During the first neuropsychological assessment, 76 were having dementia, 46 had MCI, and 1,576 were asymptomatic. CERAD cut-off points were established for MCI and dementia using a Receiver Operating Characteristics (ROC) analysis, and were further analyzed according to education level in two groups: low education level (eight years or less), and high education level (over eight years). RESULTS: The area under curve-ROC CERAD total score for dementia was 0.994 (95% CI = 0.989-0.999), and that for MCI was 0.862 (95% CI = 0.816-0.908). The dementia diagnosis cut-off point for the low education group was 54, (98.4% sensitivity, 92.6% specificity), and that for the high education group was 67 (100% sensitivity, 94.1% specificity). The MCI diagnosis cut-off point for the low education group was 66 (91.2% sensitivity, 56.4% specificity), and that for the high education group was 72 (91.7% sensitivity, 76.3% specificity). CONCLUSIONS: The CERAD total score is a useful screening tool for dementia and MCI in a population at risk of FAD.

Applicability of digital analysis and imaging technology in neuropathology assessment.

Alzheimer's disease (AD) is a progressive neurological disorder that affects more than 30 million people worldwide. While various dementia-related losses in cognitive functioning are its hallmark clinical symptoms, ultimate diagnosis is based on manual neuropathological assessments using various schemas, including Braak staging, CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and Thal phase scoring. Since these scoring systems are based on subjective assessment, there is inevitably some degree of variation between readers, which could affect ultimate neuropathology diagnosis. Here, we report a pilot study investigating the applicability of computer-driven image analysis for characterizing neuropathological features, as well as its potential to supplement or even replace manually derived ratings commonly performed in medical settings. In this work, we quantitatively measured amyloid beta (Aß) plaque in various brain regions from 34 patients using a robust digital quantification algorithm. We next verified these digitally derived measures to the manually derived pathology ratings using correlation and ordinal logistic regression methods, while also investigating the association with other AD-related neuropathology scoring schema commonly used at autopsy, such as Braak and CERAD. In addition to successfully verifying our digital measurements of Aß plaques with respective categorical measurements, we found significant correlations with most AD-related scoring schemas. Our results demonstrate the potential for digital analysis to be adapted to more complex staining procedures commonly used in neuropathological diagnosis. As the efficiency of scanning and digital analysis of histology images increases, we believe that the basis of our semi-automatic approach may better standardize quantification of neuropathological changes and AD diagnosis, ultimately leading to a more comprehensive understanding of neurological disorders and more efficient patient care.

Neuropsychological Test Performance in Cognitively Normal Spanish-speaking Nonagenarians with Little Education.

To find associations of age, sex, and education with neuropsychological test performance in cognitively normal Spanish-speaking Costa Rican nonagenarians with little education; to provide norms; and to compare their performance with similar Puerto Ricans. For 95 Costa Ricans (90-102 years old, 0-6 years of education), multiple regression assessed associations with demographics of performance on six neuropsychological tests. Analyses of covariance compared them with 23 Puerto Ricans (90-99 years old). Younger age and being female-but not education-were associated with better performance on some neuropsychological tests, in particular episodic memory. The Puerto Ricans performed better on learning and memory tasks. In cognitively intact Spanish-speaking nonagenarians with little or no education, education did not affect test performance. Additional studies of the effect of education on cognitive performance are warranted in other samples with extremely low education or old age. National differences in performance highlight the importance of group-specific norms.

Education-corrected CERAD identifies MCI and dementia in Parkinson's disease.

OBJECTIVES: This study examined whether controlling for educational background in the CERAD cognitive screening battery would affect the likelihood of patients with Parkinson's disease to fulfill criteria for mild cognitive impairment (PD-MCI) and dementia (PDD). MATERIALS & METHODS: One-hundred seventeen patients with PD were studied. Cognitive impairment was determined as two subtest scores falling below either the standard cutoff scores or education-corrected cutoff scores. The presence of dementia was determined by clinical interview or Clinical Dementia Rating. Patients were then classified as PD-MCI and PDD according to cognitive test performance and presence/absence of dementia. RESULTS: The number of cognitively impaired patients (PD-MCI or PDD) was significantly higher when education-controlled cutoff scores were used (62.5% vs 38%). Correspondingly, the number of false negatives (demented PD patients performing normally in CERAD) was significantly lower when education-corrected cutoff scores were used (4% vs 10%). CONCLUSIONS: Controlling for education increases the sensitivity of the CERAD for PD-MCI and PDD.

Relationship between hippocampal atrophy and neuropathology markers: a 7T MRI validation study of the EADC-ADNI Harmonized Hippocampal Segmentation Protocol.

OBJECTIVE: The pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP). METHODS: Temporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aß), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aß, and tau burden for each hippocampal subfield were obtained. RESULTS: We found significant correlations between hippocampal volume and Braak and Braak staging (ρ = -0.75, P = .001), tau (ρ = -0.53, P = .034), Aß burden (ρ = -0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield-wise significant associations were found for Aß in Cornu Ammonis (CA)1 (ρ = -0.58, P = .019) and subiculum (ρ = -0.75, P = .001), tau in CA2 (ρ = -0.59, P = .016), and CA3 (ρ = -0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001). CONCLUSIONS: The observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.

The CERAD neuropsychological assessment battery total score detects and predicts Alzheimer disease dementia with high diagnostic accuracy.

OBJECTIVES: To establish the diagnostic accuracy of the Total Score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NP) both for cross-sectional discrimination of Alzheimer disease (AD) dementia and short-term prediction of incident AD dementia. DESIGN: Longitudinal cohort study with two assessments at a 1.5-year interval. SETTING: Primary care sample randomly recruited via medical record registries. PARTICIPANTS: As part of the German Study on Ageing, Cognition, and Dementia (AgeCoDe), a sample of elderly individuals (N = 1,606; mean age: 84 years) was assessed. MEASUREMENTS: Subjects were assessed with the CERAD-NP and followed up for 18 months (97.6% follow-up rate). Logistic regression and receiver-operating-characteristic (ROC) curve analysis were used to compare the diagnostic accuracy of the CERAD-NP Total Score (CTS) with that of single CERAD-NP scores and the Mini-Mental-State-Examination (MMSE) score. RESULTS: ROC curve analysis resulted in excellent (area under the curve [AUC]: 0.97) cross-sectional discrimination between non-AD and AD dementia subjects. Prediction of incident AD dementia with the CTS was also very good (AUC: 0.89), and was significantly better than prediction based on the MMSE. CONCLUSIONS: The cross-sectional results confirm that the CTS is a highly accurate diagnostic tool for detecting AD dementia in elderly primary care patients. In addition, we provide evidence that the CTS is also accurate for the prediction of incident AD dementia. These findings further support the validity of the CTS as an index of overall cognitive functioning for detection and prediction of AD dementia.

Age, gender, and education are associated with cognitive performance in an older Israeli sample with type 2 diabetes.

OBJECTIVE: To evaluate the relationships of age, education, and gender with performance on neuropsychological tests in a cognitively intact, older Israeli sample with type 2 diabetes (T2D). METHODS: We examined 862 participants, 65-84 years old, enrolled in the Israel Diabetes and Cognitive Decline study. Multiple regression assessed associations of performance on 17 neuropsychological tests, including the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, with age, education, and gender. RESULTS: Higher education and younger age were consistently associated with better performance. Women outperformed men on all memory tasks; men outperformed women on two non-verbal measures. These patterns of demographic associations with cognitive performance were very similar to those of US cohorts. CONCLUSIONS: In a cognitively intact, older Israeli sample with T2D, better test performance is associated primarily with higher education, followed by younger age and gender differences. Although T2D is associated with cognitive deficits, it recapitulates the patterns of relationships between cognitive performance and demographic characteristics seen in non-T2D diabetic samples.

Utility of learning ratio scores from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Memory Test in distinguishing patterns of cognitive decline in veterans referred for neuropsychological evaluation.

Background: The Learning Ratio (LR) is a novel learning score that has shown improved utility over other learning metrics in detecting Alzheimer's disease (AD) across multiple memory tasks. However, its utility on the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD WLMT), a widely used list learning measure sensitive to decline in neurodegenerative disease, is unknown. The goal of the current study was to determine the utility of LR on the CERAD WLMT in differentiating between diagnostic (MiNCD vs MaNCD) and etiologic groups (VaD vs AD) in a veteran sample. Methods: Raw learning slope (RLS) and LR scores were examined in 168 veterans diagnosed with major neurocognitive disorder (MaNCD), mild neurocognitive disorder (MiNCD), or normal aging following neuropsychological evaluation. Patients with MaNCD were further classified by suspected etiology (i.e. microvascular disease vs AD). Results: Whereas RLS scores were not significantly different between MiNCD and MaNCD, LR scores were significantly different between all diagnostic groups (p's < .05). Those with AD had lower LR scores and RLS scores compared to those with VaD (p's < .05). LR classification accuracy was acceptable for MiNCD (AUC = .76), excellent for MaNCD (AUC = .86) and VaD (AUC = .81), and outstanding for AD (AUC = .91). Optimal cutoff scores for WLMT LR were derived from Youden's index. Conclusion: Results support the use of LR scores over RLS when interpreting the CERAD WLMT and highlight the clinical utility of LR in differentiating between diagnostic groups and identifying suspected etiology.

The positive effect of spermidine in older adults suffering from dementia after 1 year.

BACKGROUND: A positive effect of the effect of a 3-month oral spermidine intake on memory performance has already been demonstrated. The continuation of this study aimed to examine whether there could be observed an improvement in memory performance after one year. METHOD: 45 residents of the nursing home "Gepflegt Wohnen" in Hart bei Graz, Styria, Austria, were given a daily dose of 3.3 mg spermidine in their diet for one year. RESULTS: The comparison of the MMSE test results at baseline and after one year demonstrated a significant (p < 0.001) difference. The mean improvement is 5 points. CONCLUSION: The new results confirm the already proven positive effect of oral spermidine intake on memory performance.

Delayed primacy recall performance predicts post mortem Alzheimer's disease pathology from unimpaired ante mortem cognitive baseline.

We propose a novel method to assess delayed primacy in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test. We then examine whether this measure predicts post mortem Alzheimer's disease (AD) neuropathology in individuals who were clinically unimpaired at baseline. A total of 1096 individuals were selected from the Rush Alzheimer's Disease Center database registry. All participants were clinically unimpaired at baseline, and had subsequently undergone brain autopsy. Average age at baseline was 78.8 (6.92). A Bayesian regression analysis was carried out with global pathology as an outcome; demographic, clinical, and apolipoprotein E (APOE) data as covariates; and cognitive predictors, including delayed primacy. Global AD pathology was best predicted by delayed primacy. Secondary analyses showed that delayed primacy was mostly associated with neuritic plaques, whereas total delayed recall was associated with neurofibrillary tangles. Sex differential associations were observed. We conclude that CERAD-derived delayed primacy is a useful metric for early detection and diagnosis of AD in unimpaired individuals. Highlights: We propose a novel method to analyse serial position in the CERAD memory test.We analyse data from 1096 individuals who were cognitively unimpaired at baseline.Delayed primacy predicts post mortem pathology better than traditional metrics.

Late-Life Blood Pressure and Cerebral Amyloid Angiopathy: Findings from the U.S. National Alzheimer's Coordinating Center Uniform Dataset.

High blood pressure (BP) and cerebral amyloid angiopathy (CAA) are two common risk factors for intracranial hemorrhage, potentially leading to cognitive impairment. Less is known about the relationship between BP and CAA, the examination of which was the objective of this study. We analyzed data from 2510 participants in the National Alzheimer's Coordinating Center (NACC) who had information on longitudinal BP measurements before death and on CAA from autopsy. Using the average of four systolic BPs (SBPs) prior to death, SBP was categorized into three groups: <120 mmHg (n = 435), 120-139 mmHg (n = 1335), and ≥140 mmHg (n = 740). CAA was diagnosed using immunohistochemistry in 1580 participants and categorized as mild (n = 759), moderate (n = 529), or severe (n = 292). When adjusted for age at death, sex, APOE genotype, Braak, CERAD, antihypertensive medication use, and microinfarcts, the odds ratios (95% CIs) for CAA associated with SBPs of 120-139 and ≥140 mmHg were 0.91 (0.74-1.12) and 1.00 (0.80-1.26), respectively. Findings from predictor effect plots show no variation in the probability of CAA between the three SBP categories. Microbleeds had no association with CAA, but among those with SBP ≥ 130 mmHg, the proportion of those with microbleeds was numerically greater in those with more severe CAA (p for trend, 0.084). In conclusion, we found no evidence of an association between SBP and CAA. Future studies need to develop non-invasive laboratory tests to diagnose CAA and prospectively examine this association and its implication on the pathophysiology and outcome of Alzheimer's disease.

miR-129-5p as a biomarker for pathology and cognitive decline in Alzheimer's disease.

BACKGROUND: Alzheimer's dementia (AD) pathogenesis involves complex mechanisms, including microRNA (miRNA) dysregulation. Integrative network and machine learning analysis of miRNA can provide insights into AD pathology and prognostic/diagnostic biomarkers. METHODS: We performed co-expression network analysis to identify network modules associated with AD, its neuropathology markers, and cognition using brain tissue miRNA profiles from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) (N = 702) as a discovery dataset. We performed association analysis of hub miRNAs with AD, its neuropathology markers, and cognition. After selecting target genes of the hub miRNAs, we performed association analysis of the hub miRNAs with their target genes and then performed pathway-based enrichment analysis. For replication, we performed a consensus miRNA co-expression network analysis using the ROS/MAP dataset and an independent dataset (N = 16) from the Gene Expression Omnibus (GEO). Furthermore, we performed a machine learning approach to assess the performance of hub miRNAs for AD classification. RESULTS: Network analysis identified a glucose metabolism pathway-enriched module (M3) as significantly associated with AD and cognition. Five hub miRNAs (miR-129-5p, miR-433, miR-1260, miR-200a, and miR-221) of M3 had significant associations with AD clinical and/or pathologic traits, with miR129-5p by far the strongest across all phenotypes. Gene-set enrichment analysis of target genes associated with their corresponding hub miRNAs identified significantly enriched biological pathways including ErbB, AMPK, MAPK, and mTOR signaling pathways. Consensus network analysis identified two AD-associated consensus network modules and two hub miRNAs (miR-129-5p and miR-221). Machine learning analysis showed that the AD classification performance (area under the curve (AUC) = 0.807) of age, sex, and APOE ε4 carrier status was significantly improved by 6.3% with inclusion of five AD-associated hub miRNAs. CONCLUSIONS: Integrative network and machine learning analysis identified miRNA signatures, especially miR-129-5p, as associated with AD, its neuropathology markers, and cognition, enhancing our understanding of AD pathogenesis and leading to better performance of AD classification as potential diagnostic/prognostic biomarkers.