A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease

We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, ([“diffusion tensor”] and [“Alzheimer*” or “mild cognitive impairment”]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.     

Diffusion tensor imaging and Tract-Based Spatial Statistics in Alzheimer's disease and mild cognitive impairment

We aimed to explore the changes in fractional anisotropy (FA) in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by analyzing diffusion tensor imaging (DTI) data using the Tract-Based Spatial Statistics (TBSS). DTI data were collected from 17 AD patients, 27 MCI subjects and 19 healthy controls. Voxel-based analysis with TBSS was used to compare FA among the three groups. Additionally, guided by TBSS findings, a region of interest (ROI)-based analysis along the TBSS skeleton was performed on group-level and the accuracy of the method was assessed by the back-projection of ROIs to the native space FA. Neurofiber tracts with decreased FA included: the parahippocampal white matter, cingulum, uncinate fasciculus, inferior and superior longitudinal fasciculus, corpus callosum, fornix, tracts in brain stem, and cerebellar tracts. Quantitative ROI-analysis further demonstrated the significant decrease on FA values in AD patients relative to controls whereas FA values of MCI patients were found in between the controls and AD patients. We conclude that TBSS is a promising method in examining the degeneration of neurofiber tracts in MCI and AD patients.     

Structural MRI changes detectable up to ten years before clinical Alzheimer's disease

Structural brain changes have been described in both mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, less is known about whether structural changes are detectable earlier, in the asymptomatic phase. Using voxel-based morphometry (VBM) and shape analyses of magnetic resonance imaging (MRI) data, we investigated structural brain differences between groups of healthy subjects, stratified by subsequent diagnoses of MCI or AD during a 10-year follow-up. Images taken at baseline, at least 4 years before any cognitive symptoms, showed that subjects with future cognitive impairment (preclinical AD and MCI) had reduced brain volume in medial temporal lobes, posterior cingulate/precuneus, and orbitofrontal cortex, compared with matched subjects who remained cognitively healthy for 10 years (HC). For only those subjects later diagnosed as AD, significantly greater atrophy at baseline was detected in the right medial temporal lobe, which was also confirmed by shape analysis of the right hippocampus in these subjects. Our results demonstrate that structural brain changes occur years before clinical cognitive decline in AD and are localized to regions affected by AD neuropathology.     

Efficacy of ICT-based interventions in improving psychological outcomes among older adults with MCI and dementia: A systematic review and meta-analysis

The purpose of this systematic review and meta-analysis was to investigate empirical evidence about the effectiveness of Information and Communication Technology-based interventions (ICTs) on different psychological outcomes in adults aged over 60 years with Mild Cognitive Impairment (MCI) or dementia. We conducted a systematic search on Pubmed, Web of Science, Scopus, and PsycInfo with publication year between January 2010 up to April 2021. Any pre-post quantitative intervention study with at least one of the following domains examined: quality of life (QoL), psychological well-being, social interaction, engagement, mood, anxiety, stress, loneliness, self-efficacy, or self-esteem was included. The risk of bias and quality of evidence were assessed using tools based on the Cochrane Handbook for Systematic Review of Interventions criteria. Forty-eight studies with a total of 1488 participants met the selection criteria. Because of the high heterogeneity, we ran nine different random effects meta-analyses divided by outcome and type of cognitive decline which indicated that these treatments were ineffective overall, with some exceptions. Only anxiety (small effect size =−0.375 [−0.609; −0.140]) and behavioral symptoms (BS) (medium effect size =−0.585 [−1.019; −0.152]) in people with dementia (PwD) were found to change significantly. Moreover, effect sizes for QoL in dementia and for mood in people with MCI became significant when moderated by type of ICT, living situation, and experimental setting. In particular, Virtual Reality (VR) appeared to be more effective than other devices for both PwD and MCI, and nursing homes were found to be the best setting for administering these treatments. The trim and fill method found no evidence of publication bias in any of the 9 analyses. However, quality of evidence within (RoB 2, RoB 2 Crossover, ROBINS) and across (GRADE assessment) studies was low, thus these findings should be interpreted with caution. In general, ICT-based intervention can be considered a promising approach for improving anxiety and BS in PwD, and for improving QoL in PwD and mood in people with MCI, specifically when VR is used, when participants live in nursing homes, and when interventions are carried out in nursing homes.¹     

Brain perfusion SPECT with an automated quantitative tool can identify prodromal Alzheimer's disease among patients with mild cognitive impairment

Objective

To improve diagnosis of early Alzheimer's disease (AD), i.e., prodromal AD, by an automated quantitative tool combining brain perfusion single-photon emission computed tomography (SPECT) images and memory tests scores in order to be applied in clinical practice.

Patients and methods

In this prospective, longitudinal, multi-centric study, a baseline ^99mTc-ECD perfusion SPECT was performed in 83 patients with memory complaint and mild cognitive impairment (MCI). After a 3-year follow-up, 11 patients progressed to Alzheimer's disease (MCI-AD group), and 72 patients remained stable (MCI-S group), including 1 patient who developed mild vascular cognitive impairment. After comparison between the MCI-S and MCI-AD groups with a voxel-based approach, region masks were extracted from the statistically significant clusters and used alone or in combination with Free and Cued Selective Reminding Test (FCSRT) scores for the subject's categorization using linear discriminant analysis. Results were validated using the leave-one-out cross-validation method.

Results

Right parietal and hippocampal perfusion was significantly (p < 0.05, corrected) decreased in the MCI-AD group as compared to the MCI-S group. The patients’ classification in the MCI group using the mean activity in right and left parietal cortex and hippocampus yielded a sensitivity, specificity, and accuracy of 82%, 90%, and 89%, respectively. Combination of SPECT results and FCSRT free recall scores increased specificity to 93%.

Conclusion

The combination of an automated quantitative tool for brain perfusion SPECT images and memory test scores was able to distinguish, in a group of amnestic MCI, patients at an early stage of AD from patients with stable MCI.     

Increased fMRI responses during encoding in mild cognitive impairment

Structural and functional magnetic resonance imaging (fMRI) was performed on 21 healthy elderly controls, 14 subjects with mild cognitive impairment (MCI) and 15 patients with mild Alzheimer's disease (AD) to investigate changes in fMRI activation in relation to underlying structural atrophy. The fMRI paradigm consisted of associative encoding of novel picture-word pairs. Structural analysis of the brain was performed using voxel-based morphometry (VBM) and hippocampal volumetry. Compared to controls, the MCI subjects exhibited increased fMRI responses in the posterior hippocampal, parahippocampal and fusiform regions, while VBM revealed more atrophy in MCI in the anterior parts of the left hippocampus. Furthermore, the hippocampal volume and parahippocampal activation were negatively correlated in MCI, but not in controls or in AD. We suggest that the increased fMRI activation in MCI in the posterior medial temporal and closely connected fusiform regions is compensatory due to the incipient atrophy in the anterior medial temporal lobe.     

Increased "absence" of telomeres may indicate Alzheimer's disease/dementia status in older individuals with Down syndrome

We have reported previously that telomeres (ends of chromosomes consisting of highly conserved TTAGGG repeats) were shorter in metaphase and interphase preparations in T lymphocytes from short-term whole blood cultures of women with Down syndrome (DS) and dementia compared to age-matched women with DS but without dementia [E.C. Jenkins, M.T. Velinov, L. Ye, H. Gu, S. Li, E.C. Jenkins Jr., S.S. Brooks, D. Pang, D.A. Devenny, W.B. Zigman, N. Schupf, W.P. Silverman, Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia, Neurobiol. Aging 27 (2006) 41-45]. Our previous study was carried out by measuring changes in fluorescence intensity [using an FITC-labeled peptide nucleic acid (PNA) probe (Applied Biosystems; DAKO) and Applied Imaging software], and we now report on a substantially simpler metric, counts of signals at the ends of chromosomes. Nine adults with DS and dementia plus four who are exhibiting declines in cognition analogous to mild cognitive impairment in the general population (MCI-DS) were compared to their pair-matched peers with DS but without dementia or MCI-DS. Results indicated that the number of chromosome ends that failed to exhibit fluorescent signal from the PNA telomere probe was higher for people with dementia or mild cognitive impairment (MCI-DS). Thus, a simple count of chromosome ends for the "presence/absence" of fluorescence may provide a valid biomarker of dementia status. If this is the case, then after additional research for validation to assure high specificity and sensitivity, the test may be used to identify and ultimately guide treatment for people at increased risk for developing mild cognitive impairment and/or dementia.     

Positive psychological constructs and association with reduced risk of mild cognitive impairment and dementia in older adults: A systematic review and meta-analysis

Understanding factors associated with dementia risk is important for informing future interventions aimed at dementia prevention. There is accumulating evidence for the association between depression and risk of dementia, however less is known about the association between positive psychological factors and dementia incidence. This review aims to synthesise evidence regarding the association between positive psychological constructs (PPCs) and later risk of MCI and dementia in adults aged 50 and over. Literature searches were conducted in Medline, PsycINFO, and Scopus until March 2021. Papers reporting on the association between at least one PPC and later risk of MCI or dementia in people aged 50 + without cognitive impairment at baseline were included. Results from the meta-analyses revealed that purpose in life was significantly associated with a reduced risk of dementia (HR = 0.81, 95% CI [0.78, 0.85], p < .001), however results for positive affect were non-significant (HR = 0.94, 95% CI [0.76, 1.15], p = .54). Results for other PPCs are described narratively. Mixed findings for different PPCs highlight the importance of investigating these factors individually. Understanding which factors may play a protective role in their association with risk of mild cognitive impairment and dementia could have important implications for informing dementia prevention interventions.     

Biomarkers of oxidative and nitrosative damage in Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD) is the most common type of dementia in the elderly. Products of oxidative and nitrosative stress (OS and NS, respectively) accumulate with aging, which is the main risk factor for AD. This provides the basis for the involvement of OS and NS in AD pathogenesis. OS and NS occur in biological systems due to the dysregulation of the redox balance, caused by a deficiency of antioxidants and/or the overproduction of free radicals. Free radical attack against lipids, proteins, sugars and nucleic acids leads to the formation of bioproducts whose detection in fluids and tissues represents the currently available method for assessing oxidative/nitrosative damage. Post-mortem and in-vivo studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment (MCI). In addition to their individual role, biomarkers for OS and NS in AD are associated with altered bioenergetics and amyloid-beta (Aβ) metabolism. In this review we discuss the main results obtained in the field of biomarkers of oxidative/nitrosative stress in AD and MCI in humans, in addition to their potential role as a tool for diagnosis, prognosis and treatment efficacy in AD.     

Default-mode network activity distinguishes amnestic type mild cognitive impairment from healthy aging: a combined structural and resting-state functional MRI study

Resting-state functional magnetic resonance imaging (MRI), have revealed coactivation in a distributed network that characterizes the default-mode in the human brain. However, details from resting-state imaging in amnestic type mild cognitive impairment (aMCI) is poorly understand. Regional homogeneity, which characterizes low-frequency blood oxygenation level dependent fluctuation, after statistically controlling for the regional atrophy and age in resting-state, were examined and compared between the two groups. When regional atrophy was controlled, decreased regional homogeneity in posterior cingulate cortex and precuneus still remained significant in aMCI patients. In addition the aMCI subjects displayed several regions of increased homogeneity, typically in right inferior parietal lobule, right fusiform gyrus and bilateral putamen. The impairment of posterior cingulate and precuneus could be an important marker to distinguish aMCI from healthy aging in the resting-state. Moreover, the increased regional homogeneity changes would be consistent with compensation for damage to the medial temporal regions and limbic structures, perhaps by recruitment of alternative regions.     

Sex differences in the prevalence and incidence of mild cognitive impairment: A meta-analysis

ObjectiveMore women have Alzheimer’s disease (AD) than men. Understanding sex differences in mild cognitive impairment (MCI) may further knowledge of AD etiology and prevention. We conducted a meta-analysis to examine sex differences in the prevalence and incidence of MCI, which included amnestic and non-amnestic subtypes.MethodSystematic searches were performed in July 2015 using MEDLINE/PubMed, Scopus, and PsycINFO for population-or community-based studies with MCI data for men and women. Random-effects model were used.ResultsFifty-six studies were included. There were no statistically significant sex differences in prevalence or incidence of amnestic MCI. There was a significantly higher prevalence (p = 0.038), but not incidence, of non-amnestic MCI among women. There were no sex differences in studies that combined both subtypes of MCI.ConclusionThe only statistically significant finding emerging from this study was that women have a higher prevalence of non-amnestic MCI. To better understand sex differences in the preclinical stages of dementia, studies must better characterize the etiology of the cognitive impairment.     

Diagnosing prodromal Alzheimer's disease: role of CSF biochemical markers

Mild cognitive impairment (MCI) is an aetiologically heterogeneous syndrome. A correct prediction of MCI conversion to Alzheimer's disease (AD) represents a primary goal in routine clinical practice. Since the presence of pathological levels in >or=2 cerebrospinal fluid (CSF) biomarkers; amyloid protein (Abeta42), total tau (h-tau) and phospho-tau (p-tau) seems to reliably identifying MCI subjects converting to AD, we report our experience in a routine clinical setting. In the period from January 2001 to June 2003, 273 consecutive patients referred to our Memory Clinic for diagnostic assessment of cognitive impairment. Of them, 180 underwent a complete diagnostic evaluation including CSF dosage of fragment 1-42 of amyloid protein, total tau and phospho-tau (ELISA Method, Innogenetics, Gent, Belgium), after vascular or other secondary causes of dementia could be excluded. At baseline, 38% of the MCI subjects (20/55) showed pathological levels in >or=2 CSF biomarkers. After 1 year, 11 MCI patients converted to dementia, 33 remained stable, 11 showed a further progression of cognitive impairment still not fulfilling the diagnostic criteria for dementia. Of the 11 converters, 10 showed >or=2 pathological values CSF biomarkers and in all of them, p-tau was high. On the contrary, 29 out of 33 stable MCI (88%) showed no or one pathological CSF value. We confirm that pathological levels in >or=2 CSF biomarkers reliably predict MCI conversion to AD and correctly identify the stable form of MCI.     

轻度认知损伤的流行病学研究进展

随着年龄增长 ,老年人多种认知功能逐渐退化。轻度认知损伤 (mildcognitiveimpairment ,MCI)状态指有记忆力主诉 ,并经他人证实 ;记忆障碍比同龄老人和受同等教育者为重 ,但总的认知功能相对完好 ,且日常生活能力正常 ;尚未到阿尔茨海默病(Alzheimer’sdisease ,AD)的程度[1] 。北京老年病医疗研究中心的一项大型调查显示 ,我国 6 5岁以上老年性痴呆患者估计超过 5 0 0万人 ,约占世界总病例数的四分之一。 5 5岁以上人群发病率接近 3% ,6 5岁以上人群发病率超过 5 %。痴呆已成为继心脑血管疾病后 ,威胁我国老年人健康的又一主要病种 (htt…     

Resting state fMRI in Alzheimer's disease: beyond the default mode network

Using resting state (RS) functional magnetic resonance imaging (fMRI), the connectivity patterns of the default mode (DMN), frontoparietal, executive, and salience networks were explored in 13 Alzheimer's disease (AD) patients, 12 amnestic mild cognitive impairment (aMCI) patients, and 13 healthy controls. Compared with controls and aMCI, AD was associated with opposing connectivity effects in the DMN (decreased) and frontal networks (enhanced). The only RS abnormality found in aMCI patients compared with controls was a precuneus connectivity reduction in the DMN. RS fMRI group differences were only partly related to gray matter atrophy. In AD patients, the mean executive network connectivity was positively associated with frontal-executive and language neuropsychological scores. These results suggest that AD is associated with an alteration of large-scale functional brain networks, which extends well beyond the DMN. In AD, the limited resources of the DMN may be paralleled, in an attempt to maintain cognitive efficiency, by an increased prefrontal connectivity. A medial parietal RS fMRI signal change seems to be present since the early phase of AD.     

Cerebral blood flow in mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis

BackgroundReduced cerebral blood flow (CBF) contributes to the pathophysiology of Alzheimer’s disease (AD). However, it is unclear whether there is a spatial-temporal-specific pattern of changed CBF in AD progression.MethodsWe systematically screened literature databases for cross-sectional and longitudinal studies reporting resting CBF or CBF velocity (CBFv) among patients with AD, mild cognitive impairment (MCI), and healthy controls (HCs). Standardised mean differences (SMDs) for CBF and mean differences (MDs) for CBFv were calculated. Quality assessments, meta-analysis, subgroup analysis, and meta-regression were subsequently performed (PROSPERO: CRD42020207548).ResultsOverall, 244 studies comprising 13,644 participants and 60 regions were included. Compared with HCs, AD subjects had decreased resting CBF throughout the brain (SMD range: -1.87 to -0.32), especially within the posterior cingulate and temporal-parietal regions. However, MCI subjects presented decreased CBF in ten regions with modest effects (SMD range: -0.86 to -0.25), especially in the precuneus. We identified the decreased CBF in the temporal, parietal, and hippocampal regions was associated with the lower AD Mini-Mental State Examination scores.ConclusionsOur findings suggest that the spatial-temporal pattern of CBF decreased from the precuneus, posterior cingulate and temporal-parietal regions to broader areas with progression from HC to MCI to AD, supporting the incorporation of CBF into the AD research framework.     

Does loneliness contribute to mild cognitive impairment and dementia? A systematic review and meta-analysis of longitudinal studies

There is growing evidence that loneliness is associated with mild cognitive impairment (MCI) and dementia. However, the extent of this association remains unclear. A systematic review and meta-analysis of longitudinal studies examining this association was conducted. Six electronic databases were searched from inception to November 15^th 2018. A random-effects meta-analysis was performed to obtain pooled estimates and 95% CIs. Studies were also assessed for heterogeneity, methodological quality and publication bias. A total of 4270 hits were retrieved based on the initial search strategy and ten studies met the eligibility criteria involving 37339 individuals (mean age from 64.9 to 83.1 years). Variation between studies was present for the measurement of loneliness as well as for the case ascertainment of MCI and dementia. Loneliness was positively associated with increased risk of dementia (overall RR = 1.26; 95% CI = 1.14, 1.40; n = 8). Due to lack of sufficient data, we could not explore the association between loneliness and risk of MCI through a meta-analysis, but limited evidence suggests a potential effect of loneliness on MCI. A further understanding of the deleterious effects of loneliness on MCI and dementia may assist the design of environmental and psychological interventions to prevent or delay the onset of these neuropsychiatric conditions.     

Cathepsin D gene and the risk of Alzheimer's disease: A population-based study and meta-analysis

Cathepsin D (CTSD) is a gene involved in amyloid precursor protein processing and is considered a candidate for Alzheimer's disease (AD). The aim of the current study was to examine if variation in CTSD increases the risk of AD. We performed a candidate-gene analysis in a population-based cohort study (N = 7983), and estimated the effect of CTSD on the risk of AD. Additionally, a large meta-analysis was performed incorporating our data and previously published data. The T-allele of CTSD rs17571 was associated with an increased risk of AD (p-value 0.007) in the Rotterdam Study. This association was predominantly found in APOE ε4 noncarriers. A meta-analysis of previously published data showed a significantly increased risk of AD in carriers of the T-allele of rs17571 (OR 1.22, 95% CI 1.03-1.44), irrespective of APOE ε4 carrier status. This study adds to the evidence that CTSD increases the risk of AD, although the effect size is moderate.     

The optimal treatment for improving cognitive function in elder people with mild cognitive impairment incorporating Bayesian network meta-analysis and systematic review

It’s widely acknowledged that, as a neurodegenerative aging disease representing an intermediate stage between cognitive intactness and Alzheimer’s disease (AD), Mild cognitive impairment (MCI) poses an excessive burden on patients’ well-being, family members, health-care providers as well as the whole society. This study focuses on three cognitive interventions proposed by Clare and Woods, which are, Cognitive stimulation (CS), Cognitive training (CT) and Cognitive rehabilitation (CR). Our Network meta-analysis (NMA) aims to compar them with one another to determine the optimal cognitive intervention for elderly adults with MCI in improving their cognitive function. We applied extensive strategies to preliminary literature retrieval to identify relevant randomized controlled trials (RCTs) which scrupulously compared any two of the three cognitive interventions with one another or any one of the three with a control group as the placebo or non-active group in treating elder patients with MCI in accordance with Petersen’s criteria. Our NMA of cognitive interventions for patients diagnosed with MCI appraised the relative effectiveness of cognitive interventions across trials simultaneously. Our study attempts to summarize available data to suggest that CS (Mean difference [MD] = 0.95, 95% confidence interval [CI]:0.27, 1.70) and CT (MD = 0.70, [CI]:0.11,1.30) were significantly beneficial to MCI patients for improving their cognition status while CR (MD = 0.59, [CI]:-0.30,1.50) scored lowest. Our study suggested CS was most likely to be the best intervention for improving the cognitive function of MCI patients.     

Proteomics as a reliable approach for discovery of blood-based Alzheimer’s disease biomarkers: A systematic review and meta-analysis

In order to gauge the impact of proteomics in discovery of Alzheimer’s disease (AD) blood-based biomarkers, this study had systematically reviewed articles published between 1984−2019. Articles that fulfilled the inclusion criteria were assessed for risk of bias. A meta-analysis was performed for replicable candidate biomarkers (CB). Of the 1651 articles that were identified, 17 case-control and two cohort studies, as well as three combined case-control and longitudinal designs were shortlisted. A total of 207 AD and mild cognitive impairment (MCI) CB were discovered, with 48 reported in >2 studies. This review highlights six CB, namely alpha-2-macroglobulin (α2M)_ps, pancreatic polypeptide (PP)_ps, apolipoprotein A-1 (ApoA-1)_ps, afamin_p, insulin growth factor binding protein-2 (IGFBP-2)_ps and fibrinogen-γ-chain_p, all of which exhibited consistent pattern of regulation in >three independent cohorts. They are involved in AD pathogenesis via amyloid-beta (Aβ), neurofibrillary tangles, diabetes and cardiovascular diseases (CVD). Meta-analysis indicated that ApoA-1_ps was significantly downregulated in AD (SMD = −1.52, 95% CI: −1.89, −1.16, p < 0.00001), with low inter-study heterogeneity (I² = 0%, p = 0.59). α2M_ps was significantly upregulated in AD (SMD = 0.83, 95% CI: 0.05, 1.62, p = 0.04), with moderate inter-study heterogeneity (I² = 41%, p = 0.19). Both CB are involved in Aβ formation. These findings provide important insights into blood-based AD biomarkers discovery via proteomics.