scholarly journals Association between plasma exosome neurogranin and brain structure in patients with Alzheimer’s disease: a protocol study

BMJ Open ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. e036990 ◽  
Author(s):  
MengFei He ◽  
Li Sun ◽  
Wenhui Cao ◽  
Changhao Yin ◽  
Wenqiang Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Rating Scale ◽  
Early Stage ◽  
Verbal Learning ◽  
Blood Collection ◽  
Clinical Dementia Rating ◽  
Protocol Study ◽  
Medical University

IntroductionNeurogranin is known to be significantly elevated in patients with Alzheimer’s disease (AD) and may be an effective clinical predictor of cognitive decline and neurodegeneration. Amnestic mild cognitive impairment (aMCI) is an intermediate disease state between normal cognitive ageing and dementia, the latter of which can easily revert to AD. There remains significant uncertainty regarding the conversion of aMCI to AD, and therefore, elucidating such progression is paramount to the field of cognitive neuroscience. In this protocol study, we therefore aim to investigate the changes in plasma neurogranin in the early stage of AD and the mechanism thereof regarding the cognitive progression towards AD.Methods and analysisIn this study, patients with aMCI and AD patients (n=70 each) will be recruited at the memory clinic of the Department of Neurology of Hongqi Hospital affiliated with the Mudanjiang Medical University of China. Healthy older controls (n=70) will also be recruited from the community. All subjects will undergo neuroimaging and neuropsychological evaluations in addition to blood collection at the first year and the third year. We hope to identify a new biomarker of cognitive decline associated with AD and characterise its behaviour throughout the progression of aMCI to AD. This work will reveal novel targets for the therapeutic prevention, diagnosis and treatment of AD. The primary outcome measures will be (1) neuropsychological evaluation, including Mini-Mental State Examination, Montreal Cognitive Assessment, Clinical Dementia Rating scale, Shape Trail Test-A&B, Auditory Verbal Learning Test-HuaShan version; (2) microstructural alterations and hippocampal features from MRI scans; and (3) neurogranin levels in the neuronal-derived exosomes from peripheral blood samples.Ethics and disseminationThe ethics committee of the Hongqi Hospital affiliated with the Mudanjiang Medical University of China has approved this study protocol. The results will be published in peer-reviewed journals and presented at national or international scientific conferences.Trial registration numberChiCTR2000029055.

scholarly journals Predictors of rapid cognitive decline in Alzheimer's disease: results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing

2011 ◽  
Vol 24 (2) ◽  
pp. 197-204 ◽  
Author(s):  
Alessandro Sona ◽  
Ping Zhang ◽  
David Ames ◽  
Ashley I. Bush ◽  
Nicola T. Lautenschlager ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Rating Scale ◽  
Cognitive Status ◽  
Imaging Biomarkers ◽  
Clinical Dementia Rating ◽  
Factors Associated ◽  
Biological Variables ◽  
Rapid Cognitive Decline

ABSTRACTBackground: The AIBL study, which commenced in November 2006, is a two-center prospective study of a cohort of 1112 volunteers aged 60+. The cohort includes 211 patients meeting NINCDS-ADRDA criteria for Alzheimer's disease (AD) (180 probable and 31 possible). We aimed to identify factors associated with rapid cognitive decline over 18 months in this cohort of AD patients.Methods: We defined rapid cognitive decline as a drop of 6 points or more on the Mini-Mental State Examination (MMSE) between baseline and 18-month follow-up. Analyses were also conducted with a threshold of 4, 5, 7 and 8 points, as well as with and without subjects who had died or were too severely affected to be interviewed at 18 months and after, both including and excluding subjects whose AD diagnosis was “possible” AD. We sought correlations between rapid cognitive decline and demographic, clinical and biological variables.Results: Of the 211 AD patients recruited at baseline, we had available data for 156 (73.9%) patients at 18 months. Fifty-one patients were considered rapid cognitive decliners (32.7%). A higher Clinical Dementia Rating scale (CDR) and higher CDR “sum of boxes” score at baseline were the major predictors of rapid cognitive decline in this population. Furthermore, using logistic regression model analysis, patients treated with a cholinesterase inhibitor (CheI) had a higher risk of being rapid cognitive decliners, as did males and those of younger age.Conclusions: Almost one third of patients satisfying established research criteria for AD experienced rapid cognitive decline. Worse baseline functional and cognitive status and treatment with a CheI were the major factors associated with rapid cognitive decline over 18 months in this population.

scholarly journals Association of peripheral blood DNA methylation level with Alzheimer’s disease progression

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Qingqin S. Li ◽  
Aparna Vasanthakumar ◽  
Justin W. Davis ◽  
Kenneth B. Idler ◽  
Kwangsik Nho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Cognitive Decline ◽  
Peripheral Blood ◽  
Rating Scale ◽  
Association Studies ◽  
Clinical Dementia Rating ◽  
Cpg Sites ◽  
Cognition And Learning

Abstract Background Identifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Results The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10−8 [Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACCtrailsB, mPACCdigit, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10−24), which was associated with both the slope of CDR-SB and the MCI conversion status. Conclusion Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression.

scholarly journals Mild Behavioral Impairment and Subjective Cognitive Decline predict Mild Cognitive Impairment

2020 ◽  
Author(s):  
Zahinoor Ismail ◽  
Alexander McGirr ◽  
Sascha Gill ◽  
Sophie Hu ◽  
Nils D. Forkert ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Early Stage ◽  
Subjective Cognitive Decline ◽  
Clinical Dementia Rating ◽  
Behavioral Impairment ◽  
Prevention Studies ◽  
Scalable Methods

AbstractObjectiveBetter methods for detecting preclinical neuropathological change are required for prevention of dementia. Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) can represent neurobehavioral and neurocognitive axes of early stage neurodegenerative processes, which are represented in Stage 2 of the NIA-AA Alzheimer’s disease research framework. Both MBI and SCD may offer an opportunity for premorbid detection. We test the hypothesis that MBI and SCD confer additive risk for incident cognitive decline.MethodsParticipants were cognitively normal older adults followed up approximately annually at Alzheimer’s Disease Centers. Logistic regression was used to determine the relationship between baseline classification (MBI+, SCD+, neither (MBI-SCD-), or both (MBI+SCD+)) and cognitive decline, defined by Clinical Dementia Rating (CDR) total score, at 3 years.ResultsOf 2769 participants (mean age=76; 63% females), 1536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3-years, 349 individuals (12.6%) developed cognitive decline to CDR>0. Compared to SCD-MBI-, we observed an ordinal progression in risk, with ORs [95% CI] as follows: 3.61 [2.42-5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57-6.34] for MBI+SCD-, (20.7% progression) and 8.15 [5.71-11.64] for MBI+SCD+ (30.9% progression).ConclusionMBI in older adults alone or in combination with SCD is associated with a higher risk of incident cognitive decline at 3 years. The highest rate of progression to MCI is observed in those with both MBI and SCD. Used in conjunction, MBI and SCD could be simple and scalable methods to identify patients at high risk for cognitive decline for prevention studies.

scholarly journals Efficacy and Limitations of rCBF-SPECT in the Diagnosis of Alzheimer’s Disease With Amyloid-PET

2019 ◽  
Vol 34 (5) ◽  
pp. 314-321
Author(s):  
Miwako Takahashi ◽  
Tomoko Tada ◽  
Tomomi Nakamura ◽  
Keitaro Koyama ◽  
Toshimitsu Momose
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rating Scale ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Amyloid Pet ◽  
Clinical Dementia Rating ◽  
Positron Emission ◽  
Rcbf Spect

This study aimed to assess efficacy and limitations of regional cerebral blood flow imaging using single-photon emission computed tomography (rCBF-SPECT) in the diagnosis of Alzheimer’s disease (AD) with amyloid-positron emission tomography (amyloid-PET). Thirteen patients, who underwent both rCBF-SPECT and amyloid-PET after clinical diagnosis of AD or mild cognitive impairment, were retrospectively identified. The rCBF-SPECTs were classified into 4 grades, from typical AD pattern to no AD pattern of hypoperfusion; amyloid-beta (Aβ) positivity was assessed by amyloid-PET. Four patients were categorized into a typical AD pattern on rCBF-SPECT, and all were Aβ+. The other 9 patients did not exhibit a typical AD pattern; however, 4 were Aβ+. The Mini-Mental State Examination score and Clinical Dementia Rating scale were not significantly different between Aβ+ and Aβ– patients. A typical AD pattern on rCBF-SPECT can reflect Aβ+; however, if not, rCBF-SPECT has a limitation to predict amyloid pathology.

The Differential Cognitive Deficits Between Patients with Early Stage Alzheimer's Disease and Patients with Early Stage Vascular Dementia

2017 ◽  
Vol 41 (S1) ◽  
pp. S175-S175 ◽  
Author(s):  
J.H. Park ◽  
K. Kyung Min ◽  
J. Byoung Sun
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Cognitive Deficits ◽  
Processing Speed ◽  
Comprehensive Evaluation ◽  
Early Stage ◽  
Word List ◽  
Clinical Dementia Rating ◽  
Korean Version

BackgroundThe study aims to examine whether cognitive deficits are different between patients with early stage Alzheimer's disease (AD) and patients with early stage vascular dementia (VaD) using the Korean version of the CERAD neuropsychological battery (CERAD-K-N).MethodsPatients with early stage dementia, global Clinical Dementia Rating (CDR) 0.5 or 1 were consecutively recruited among first visitors to a dementia clinic, 257 AD patients and 90 VaD patients completed the protocol of the Korean version of the CERAD clinical assessment battery. CERAD-K-N was administered for the comprehensive evaluation of the neuropsychological function.ResultsOf the total 347 participants, 257 (69.1%) were AD group (CDR 0.5 = 66.9%) and 90 (21.9%) were VaD group (CDR 0.5 = 40.0%). Patients with very mild AD showed poorer performances in Boston naming test (BNT) (P = 0.028), word list memory test (P < 0.001), word list recall test (P < 0.001) and word list recognition test (WLRcT) (P = 0.006) than very mild VaD after adjustment of T score of MMSE-KC. However, the performance of trail making A (TMA) was more impaired in VaD group than in AD group. The performance of WLRcT (P < 0.001) was the worst among neuropsychological tests within AD group, whereas TMA was performed worst within VaD group.ConclusionsPatients with early-stage AD have more cognitive deficits on memory and language while patients with early-stage VaD show worse cognitive function on attention/processing speed. In addition, as the first cognitive deficit, memory dysfunction comes in AD and deficit in attention/processing speed in VaD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Associations of Blood Pressure with Functional and Cognitive Changes in Patients with Alzheimer's Disease

2016 ◽  
Vol 41 (5-6) ◽  
pp. 314-323 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Blood Pressure ◽  
Alzheimer's Disease ◽  
Rating Scale ◽  
Late Onset ◽  
Angiotensin Receptor Blockers ◽  
Channel Blockers ◽  
Clinical Dementia Rating ◽  
Cognitive Changes ◽  
Converting Enzyme Inhibitors

Background: Midlife hypertension followed by late life hypotension resulting from neurodegeneration increases amyloidogenesis and tauopathy. Methods: Consecutive outpatients with late-onset Alzheimer's disease (AD) at various stages and their respective caregivers were assessed for score variations in 1 year of tests assessing caregiver burden, functionality and cognition according to blood pressure (BP) variations and APOE haplotypes, while also taking into account differential effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, diuretics, or no antihypertensive medication on score changes. The diagnosis and treatment of arterial hypertension followed the JNC 7 report. Results: Variations in systolic BP (-11.76 ± 17.1 mm Hg), diastolic BP (-4.92 ± 10.3 mm Hg) and pulse pressure (-6.84 ± 12.6 mm Hg) were significant after 1 year (n = 191; ρ < 0.01). For APOE4+ carriers, rises in systolic or diastolic BP improved Clinical Dementia Rating Scale Sum of Boxes scores (ρ < 0.04), with marginally significant improvements in Mini-Mental State Examination scores resulting from risen systolic (ρ = 0.069) or diastolic BP (ρ = 0.079), and in basic independence only regarding risen diastolic BP (ρ = 0.055). APOE4- carriers resisted any functional or cognitive effects of BP variations. No differences were found regarding any antihypertensive class for variations in BP or any test scores, regardless of APOE haplotypes. Conclusions: Targeting mild BP elevations brings better functional and cognitive results for APOE4+ carriers with AD.

scholarly journals Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

2021 ◽  
Author(s):  
Atul Kumar ◽  
Maryam Shoai ◽  
Sebastian Palmqvist ◽  
Erik Stomrud ◽  
John Hardy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Genome Wide Association Study ◽  
Early Stage ◽  
Cognitive Change ◽  
Preclinical Ad ◽  
Genome Wide ◽  
A Genome ◽  
Polygenic Scores

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

scholarly journals A Strategy for Identifying the Risk of Developing Alzheimer's Disease From Healthy Controls: Distance to Novelty Detection Boundary

2020 ◽  
Author(s):  
Jiangbing Mao ◽  
Qinyong Ye ◽  
Hongqing Yang ◽  
Magda Bucholc ◽  
Shuo Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Early Stage ◽  
Novelty Detection ◽  
Imaging Biomarkers ◽  
Support Vector ◽  
Support Vector Data Description ◽  
Healthy Controls

Abstract Background:Machine learning (ML) techniques are expected to tackle the problem of the high prevalence of Alzheimer’s disease (AD) we are facing worldwide. However, few studies of novelty detection (ND), a typical ML technique for safety-critical systems especially in healthcare, were engaged for identifying the risk of developing cognitive impairment from healthy controls (HC) population.Materials and Methods: Two independent datasets were used for this study, including the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) and the Fujian Medical University Union Hospital (FMUUH), China datasets. Multiple feature selection methods were applied to identify the most relevant features for predicting the severity of AD. Four easily interpretable ND algorithms, including k nearest neighbor, Mixture of Gaussian (MoG), KMEANS, and support vector data description were used to construct predictive models. The models were visualized by drawing their decision boundaries tightly surrounding the HC data. A distance to boundary (DtB) strategy was proposed to differentiate individuals with mild cognitive impairment (MCI) and AD from HC. Results: The best overall MCI&AD detection performance in both AIBL and FMUUH was obtained on the cognitive and functional assessments (CFA) modality only using MoG-based ND with AUC of 0.8757 and 0.9443, respectively. The highest sensitivity of MCI was presented by using a combination of CFA and brain imaging modality. The DTB value reflects the risk of developing cognitive impairment for HC and the dementia severity of MCI/AD.Conclusions: Our findings suggest that applying some non-invasive and cost-effective features can significantly detect cognitive decline in an early stage. The visualized decision boundary and the proposed DtB strategy illustrated the severity of cognitive decline of potential MCI&AD patients in an early stage. The results would help inform future guidelines for developing a clinical decision-making support system aiming at an early diagnosis and prognosis of MCI&AD.

scholarly journals Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

2020 ◽  
Vol 78 (3) ◽  
pp. 989-1010
Author(s):  
Gary E. Gibson ◽  
José A. Luchsinger ◽  
Rosanna Cirio ◽  
Huanlian Chen ◽  
Jessica Franchino-Elder ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Placebo Group ◽  
Cognitive Decline ◽  
Controlled Trial ◽  
Amyloid Β ◽  
Cognitive Outcomes ◽  
Disease Assessment ◽  
Clinical Dementia Rating ◽  
Positron Emission

Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

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