Decline In Mild Cognitive Impairment Research Articles

Topline Results of EXERT: Can Exercise Slow Cognitive Decline in MCI?

AbstractBackgroundThe EXERT trial (NCT02814526) was a Phase 3, multicenter, randomized single‐blind study that examined the effects of regular exercise on cognition and other measures of brain function in a planned sample of 300 older adults with amnestic mild cognitive impairment (MCI).MethodThe Alzheimer’s Disease Cooperative Study (ADCS) coordinated the trial, in partnership with Wake Forest and the YMCA of the USA. Participants were randomized to moderate intensity aerobic training (AX), or to stretching, balance and range of motion (SBR) for 18 months. In the first 12 months, exercise was supervised 2x/week and completed independently 2x/week. All exercise was unsupervised in Months 13‐18. Outcomes assessments were completed at baseline and every 6 months. The primary endpoint was 12‐month change from baseline on the ADAS‐Cog‐Exec, a validated measure of global cognitive function. In addition, 12‐month changes in the ADAS‐Cog‐Exec and CDR‐SB were compared for EXERT intervention groups relative to other cohorts to estimate effects of intervention versus no intervention (i.e., “Usual Care”).Result296 participants were enrolled, and over 31,000 exercise sessions were completed during the first 12 months. Attendance remained high (AX: 81%; SBR: 87%), and >60% of participants reported continued exercise through the pandemic. Neither the AX group nor the SBR group showed 12‐month declines on the ADAS‐Cog‐Exec and CDR‐SB. There were no significant treatment differences between AX and SBR on these outcomes. In the Usual Care analysis comparing ADNI‐1 and EXERT participants matched on key variables (demographics, baseline cognitive function, APOE4), ADNI‐1 MCI participants showed the expected 12‐month decline on the ADAS‐Cog‐Exec, but the EXERT AX and SBR groups did not (ADNI‐1 vs. AX: p = 0.012; vs. SBR: p = 0.00049).ConclusionGlobal cognitive function did not change over 12 months of follow‐up for MCI participants in EXERT, suggesting that both the AX and SBR interventions may have stalled cognitive decline. EXERT is the longest exercise trial conducted in MCI to date, and greater ‘volume’ of exercise may have provided more protection, regardless of exercise intensity. Both groups received equal amounts of weekly socialization, which may have contributed to this protection. Our results are noteworthy given that trial was conducted during the COVID‐19 pandemic.

Comparative efficacy of lithium and aducanumab for cognitive decline in patients with mild cognitive impairment or Alzheimer's disease: A systematic review and network meta-analysis.

In 2021, the US Food and Drug Administration granted an accelerated approval to aducanumab for patients with mild cognitive impairment (MCI) and mild dementia caused by Alzheimer's disease (AD); however, the cost of aducanumab is high, at approximately $28,000 for one year per person. On the other hand, lithium is much cheaper at $40 a year, and has been reported to be effective for the cognitive decline observed in both patients with MCI and AD. In contrast to acetylcholinesterase inhibitors and N-methyl D-aspartate receptor antagonists, aducanumab and lithium may be disease-modifying drugs. Therefore, we focused on aducanumab and lithium and compared the effects of these drugs on the cognitive decline in MCI and AD patients using a network meta-analysis. PubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov were searched for randomized controlled trials testing lithium or aducanumab for the treatment of cognitive decline in patients with MCI or AD, up to January 31, 2022. A frequentist fixed-effect network meta-analysis was performed to estimate direct and indirect effects. The primary outcome was change scores in cognitive decline measured by Mini-Mental State Examination. This study has been registered with PROSPERO (number CRD42022304807). Network meta-analysis demonstrated that lithium was significantly more effective than aducanumab in the primary outcome. Although there were various limitations in this study, lithium may be a more cost-effective treatment than aducanumab for MCI and AD.

The effects of aerobic exercise and transcranial direct current stimulation on cognitive function in older adults with and without cognitive impairment: A systematic review and meta-analysis.

Aerobic exercise (AE) may slow age-related cognitive decline. However, such cognition-sparing effects are not uniform across cognitive domains and studies. Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation and is also emerging as a potential alternative to pharmaceutical therapies. Like AE, the effectiveness of tDCS is also inconsistent for reducing cognitive impairment in ageing. The unexplored possibility exists that pairing AE and tDCS could produce synergistic effects and reciprocally augment cognition-improving effects in older individuals with and without cognitive impairments. Previous research found such synergistic effects on cognition when cognitive training is paired with tDCS in older individuals with and without mild cognitive impairment (MCI) or dementia. The purpose of this systematic review with meta-analysis was to explore if pairing AE with tDCS could augment singular effects of AE and tDCS on global cognition (GC), working memory (WM) and executive function (EF) in older individuals with or without MCI and dementia. Using a PRISMA-based systematic review, we compiled studies that examined the effects of AE alone, tDCS alone, and AE and tDCS combined on cognitive function in older individuals with and without mild cognitive impairment (MCI) or dementia. Using a PICOS approach, we systematically searched PubMed, Scopus and Web of Science searches up to December 2021, we focused on 'MoCA', 'MMSE', 'Mini-Cog' (measures) and 'cognition', 'cognitive function', 'cognitive', 'cognitive performance', 'executive function', 'executive process', 'attention', 'memory', 'memory performance' (outcome terms). We included only randomized controlled trials (RTC) in humans if available in English full text over the past 20 years, with participants' age over 60. We assessed the methodological quality of the included studies (RTC) by the Physiotherapy Evidence Database (PEDro) scale. Overall, 68 studies were included in the meta-analyses. AE (ES = 0.56 [95% CI: 0.28-0.83], p=0.01) and tDCS (ES = 0.69 [95% CI: 0.12-1.26], p=0.02) improved GC in all three groups of older adults combined (healthy, MCI, demented). In healthy population, AE improved GC (ES = 0.46 [95% CI: 0.22-0.69], p=0.01) and EF (ES = 0.27 [95% CI: 0.05-0.49], p=0.02). AE improved GC in older adults with MCI (ES = 0.76 [95% CI: 0.21-1.32], p=0.01). tDCS improved GC (ES = 0.69 [90% CI: 0.12-1.26], p=0.02), all three cognitive function (GC, WM and EF) combined in older adults with dementia (ES = 1.12 [95% CI: 0.04-2.19], p=0.04) and improved cognitive function in older adults overall (ES = 0.69 [95% CI: 0.20-1,18], p=0.01). Our systematic review with meta-analysis provided evidence that beyond the cardiovascular and fitness benefits of AE, pairing AE with tDCS may have the potential to slow symptom progression of cognitive decline in MCI and dementia. Future studies will examine the hypothesis of this present review that a potentiating effect would incrementally improve cognition with increasing severity of cognitive impairment.

Autonomic function predicts cognitive decline in mild cognitive impairment: Evidence from power spectral analysis of heart rate variability in a longitudinal study.

BackgroundDespite the emerging clinical relevance of heart rate variability (HRV) as a potential biomarker of cognitive decline and as a candidate target for intervention, there is a dearth of research on the prospective relationship between HRV and cognitive change. In particular, no study has addressed this issue in subjects with a diagnosis of cognitive status including cognitive impairment.ObjectiveTo investigate HRV as a predictor of cognitive decline in subjects with normal cognition (NC) or Mild Cognitive Impairment (MCI). Specifically, we tested the literature-based hypothesis that the HRV response to different physical challenges would predict decline in different cognitive domains.MethodsThis longitudinal study represents the approximately 3-year follow-up of a previous cross-sectional study enrolling 80 older outpatients (aged ≥ 65). At baseline, power spectral analysis of HRV was performed on five-minute electrocardiographic recordings at rest and during a sympathetic (active standing) and a parasympathetic (paced breathing) challenge. We focused on normalized HRV measures [normalized low frequency power (LFn) and the low frequency to high frequency power ratio (LF/HF)] and on their dynamic response from rest to challenge (Δ HRV). Extensive neuropsychological testing was used to diagnose cognitive status at baseline and to evaluate cognitive change over the follow-up via annualized changes in cognitive Z-scores. The association between Δ HRV and cognitive change was explored by means of linear regression, unadjusted and adjusted for potential confounders.ResultsIn subjects diagnosed with MCI at baseline a greater response to a sympathetic challenge predicted a greater decline in episodic memory [adjusted model: Δ LFn, standardized regression coefficient (β) = −0.528, p = 0.019; Δ LF/HF, β = −0.643, p = 0.001] whereas a greater response to a parasympathetic challenge predicted a lesser decline in executive functioning (adjusted model: Δ LFn, β = −0.716, p < 0.001; Δ LF/HF, β = −0.935, p < 0.001).ConclusionOur findings provide novel insight into the link between HRV and cognition in MCI. They contribute to a better understanding of the heart-brain connection, but will require replication in larger cohorts.

Elucidation of the mechanism of cognitive decline in mild cognitive impairment using causal discovery

Mild cognitive impairment (MCI) is the stage between the expected cognitive decline of normal aging and the more serious decline of dementia. Since MCI may increase risk of later developing dementia caused by Alzheimer's disease (AD) or other neurological conditions, it is important to detect and treat MCI early in order to prevent dementia. Causal discovery, which can visualize causal relationships (cause and effect) among data, has recently been attracting attention. One of its algorithms, the Linear Non-Gaussian Acyclic Model (LiNGAM), can extract causal relationships among variables from statistical data only, using probability distributions of variables that are generally non-Gaussian. In this study, we used LiNGAM to analyze gene expression data in the hippocampus of healthy subjects and of MCI patients, and also the Mini-Mental State Examination (MMSE) scores, which are used to assess cognitive decline. We found that cell adhesion molecule 4 (CADM4) gene regulates cognitive processes that are measured in terms of MMSE scores. Our results revealed a causal relationship between gene expression changes and MMSE scores, and allowed us to identify the genes responsible for cognitive decline..

Automated Classification of Mild Cognitive Impairment by Machine Learning With Hippocampus-Related White Matter Network.

BackgroundDetection of mild cognitive impairment (MCI) is essential to screen high risk of Alzheimer’s disease (AD). However, subtle changes during MCI make it challenging to classify in machine learning. The previous pathological analysis pointed out that the hippocampus is the critical hub for the white matter (WM) network of MCI. Damage to the white matter pathways around the hippocampus is the main cause of memory decline in MCI. Therefore, it is vital to biologically extract features from the WM network driven by hippocampus-related regions to improve classification performance.MethodsOur study proposes a method for feature extraction of the whole-brain WM network. First, 42 MCI and 54 normal control (NC) subjects were recruited using diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI), and T1-weighted (T1w) imaging. Second, mean diffusivity (MD) and fractional anisotropy (FA) were calculated from DTI, and the whole-brain WM networks were obtained. Third, regions of interest (ROIs) with significant functional connectivity to the hippocampus were selected for feature extraction, and the hippocampus (HIP)-related WM networks were obtained. Furthermore, the rank sum test with Bonferroni correction was used to retain significantly different connectivity between MCI and NC, and significant HIP-related WM networks were obtained. Finally, the classification performances of these three WM networks were compared to select the optimal feature and classifier.Results(1) For the features, the whole-brain WM network, HIP-related WM network, and significant HIP-related WM network are significantly improved in turn. Also, the accuracy of MD networks as features is better than FA. (2) For the classification algorithm, the support vector machine (SVM) classifier with radial basis function, taking the significant HIP-related WM network in MD as a feature, has the optimal classification performance (accuracy = 89.4%, AUC = 0.954). (3) For the pathologic mechanism, the hippocampus and thalamus are crucial hubs of the WM network for MCI.ConclusionFeature extraction from the WM network driven by hippocampus-related regions provides an effective method for the early diagnosis of AD.

Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study.

Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03–2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31–17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.

A Longitudinal Study of Plasma pTau181 in Mild Cognitive Impairment with Lewy Bodies and Alzheimer's Disease.

BackgroundAlzheimer's disease (AD) co‐pathology is common in dementia with Lewy bodies and is associated with increased decline. Plasma pTau181 is a blood‐based biomarker that can detect AD co‐pathology.ObjectivesWe investigated whether pTau181 was associated with cognitive decline in mild cognitive impairment with Lewy bodies (MCI‐LB) and MCI with AD (MCI‐AD).MethodsWe assessed plasma pTau181 using a single‐molecule array (Simoa) immunoassay at baseline and follow‐up in a longitudinal cohort of MCI‐LB, MCI‐AD, and controls.ResultsOne hundred forty‐six subjects (56 probable MCI‐LB, 22 possible MCI‐LB, 44 MCI‐AD, and 24 controls) were reviewed for up to 5.7 years. Probable MCI‐LB had significantly higher pTau181 (22.2% mean increase) compared with controls and significantly lower (24.4% mean decrease) levels compared with MCI‐AD. Receiver operating characteristic analyses of pTau181 in discriminating probable MCI‐LB from controls showed an area under the curve (AUC) of 0.68 (83% specificity, 57% sensitivity); for discriminating MCI‐AD from healthy controls, AUC was 0.8 (83.3% specificity, 72.7% sensitivity). pTau181 concentration was less useful in discriminating between probable MCI‐LB and MCI‐AD: AUC of 0.64 (71.4% specificity, 52.3% sensitivity).There was an association between pTau181 and cognitive decline in MCI‐AD but not in MCI‐LB. In a subset with repeat samples there was a nonsignificant 3% increase per follow‐up year in plasma pTau181. The rate of change in pTau181 was not significantly different in different diagnostic subgroups.ConclusionspTau181 was not associated with an increased decline assessed using either baseline or repeat pTau181. pTau181 partially discriminated probable MCI‐LB from controls and MCI‐AD from controls but was not useful in distinguishing probable MCI‐LB from MCI‐AD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Tai Chi enhances cognitive training effects on delaying cognitive decline in mild cognitive impairment.

Cognitive training and physical exercise have shown positive effects on delaying progression of mild cognitive impairment (MCI) to dementia. We explored the enhancing effect from Tai Chi when it was provided with cognitive training for MCI. In the first 12 months, the cognitive training group (CT) had cognitive training, and the mixed group (MixT) had additional Tai Chi training. In the second 12 months, training was only provided for a subgroup of MixT. In the first 12 months, MixT and CT groups were benefited from training. Compared to the CT group, MixT had additional positive effects with reference to baseline. In addition, Compared to short-time training, prolonged mixed training further delayed decline in global cognition and memory. Functional magnetic resonance imaging showed more increased regional activity in both CT and MixT. Tai Chi enhanced cognitive training effects in MCI.Moreover, Tai Chi and cognitive mixed training showed effects on delaying cognitive decline.

Gamma band functional connectivity reduction in patients with amnestic mild cognitive impairment and epileptiform activity.

There is growing evidence for neuronal hyperexcitability in Alzheimer’s disease. Hyperexcitability is associated with an increase in epileptiform activity and the disruption of inhibitory activity of interneurons. Interneurons fire at a high rate and are frequently associated with high-frequency oscillations in the gamma frequency band (30–150 Hz). It is unclear how hyperexcitability affects the organization of functional brain networks. A sample of 63 amnestic mild cognitive impairment patients underwent a magnetoencephalography resting-state recording with eyes closed. Twenty (31.75%) mild cognitive impairment patients had epileptiform activity. A cluster-based analysis of the magnetoencephalography functional connectivity revealed a region within the right temporal cortex whose global connectivity in the gamma frequency band was significantly reduced in patients with epileptiform activity relative to those without epileptiform activity. A subsequent seed-based analysis showed that this was largely due to weaker gamma band connectivity of this region with ipsilateral frontal and medial regions, and the upper precuneus area. In addition, this reduced functional connectivity was associated with higher grey matter atrophy across several cortical regions in the patients with epileptiform activity. These functional network disruptions and changes in brain physiology and morphology have important clinical implications as they may contribute to cognitive decline in mild cognitive impairment and Alzheimer’s disease.

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer's Disease.

Systemic inflammation is an organism's response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer's disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the "principal culprit" in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

Elucidation of the mechanism of cognitive decline in mild cognitive impairment (MCI) using causal discovery

Elucidation of the mechanism of cognitive decline in mild cognitive impairment (MCI) using causal discovery

Reduced cortical cholinergic innervation measured using [18F]-FEOBV PET imaging correlates with cognitive decline in mild cognitive impairment

Dysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. A validated method to directly quantify cortical cholinergic terminal integrity enables exploration of the involvement of this system in diverse cognitive profiles associated with dementia, particularly at a prodromal stage. In this study, we used the radiotracer [18F]-fluoroethoxybenzovesamicol (FEOBV) as a direct measure of cholinergic terminal integrity and investigated its value for the assessment of cholinergic denervation in the cortex and associated cognitive deficits. Eighteen participants (8 with mild cognitive impairment (MCI) and 10 cognitively unimpaired controls) underwent neuropsychological assessment and brain imaging using FEOBV and [18F]-florbetaben for amyloid-β imaging. The MCI group showed a significant global reduction of FEOBV retention in the cortex and in the parietal and occipital cortices specifically compared to the control group. The global cortical FEOBV retention of all participants positively correlated with the BF, hippocampus and grey matter volumes, but no association was found between the global FEOBV retention and amyloid-β status. Topographic profiles from voxel-wise analysis of FEOBV images revealed significant positive correlations with the cognitive domains associated with the underlying cortical areas. Overlapping profiles of decreased FEOBV were identified in correlation with impairment in executive function, attention and language, which covered the anterior cingulate gyrus, olfactory cortex, calcarine cortex, middle temporal gyrus and caudate nucleus. However, the absence of cortical atrophy in these areas suggested that reduced cholinergic terminal integrity in the cortex is an important factor underlying the observed cognitive decline in early dementia. Our results provide support for the utility and validity of FEOBV PET for quantitative assessment of region-specific cholinergic terminal integrity that could potentially be used for early detection of cholinergic dysfunction in dementia following further validation in larger cohorts.

Neuropsychiatric Profile as a Predictor of Cognitive Decline in Mild Cognitive Impairment

Introduction: Mild cognitive impairment is often associated with affective and other neuropsychiatric symptoms (NPS). This co-occurrence might have a relevant impact on disease progression, from MCI to dementia.Objective: The aim of this study was to explore the trajectories of cognitive decline in an MCI sample from a memory clinic, taking into consideration a perspective of isolated cognitive functions and based on NPS clusters, accounting for the different comorbid symptoms collected at their baseline visit.Methods: A total of 2,137 MCI patients were monitored over a 2.4-year period. Four clusters of NPS (i.e., Irritability, Apathy, Anxiety/Depression and Asymptomatic) were used to run linear mixed models to explore the interaction of cluster with time on cognitive trajectories using a comprehensive neuropsychological battery (NBACE) administered at baseline and at the three subsequent follow-ups.Results: A significant interaction between cluster and time in cognitive decline was found when verbal learning and cued-recall were explored (p = 0.002 for both memory functions). For verbal learning, the Irritability cluster had the largest effect size (0.69), whereas the Asymptomatic cluster showed the smallest effect size (0.22). For cued-recall, the Irritability cluster had the largest effect size among groups (0.64), and Anxiety/Depression had the smallest effect size (0.21).Conclusions: In MCI patients, the Irritability and Apathy NPS clusters shared similar patterns of worsening in memory functioning, which could point to these NPS as risk factors of a faster cognitive decline, acting as early prognostic markers and helping in the diagnostic process.

Identification of plasma protein panels for detection of cognitive decline in MCI and AD by LC‐MS/MS

AbstractBackgroundFor the prevention of dementia, noninvasive screening methods which detect the signs of cognitive decline before clinical symptom occurs are needed. We previously reported blood‐based composite marker for mild cognitive impairment (MCI) and Alzheimer's disease (AD) consisting of apoA1, TTR, and C3. A combination of blood proteins could be a promising biomarker for monitoring the progression of cognitive decline from early stages of the disease. Here, we developed LC‐MS/MS‐based blood test using plasma proteins for MCI and AD to explore accurate and practical screening of the disease.MethodWe constructed a robust and reproducible LC‐MS/MS blood test system equipped with MRM to quantify 45 major plasma proteins with relatively high amounts using isotope‐labeled synthetic peptide. These plasma protein levels from 192 cases (NDC: 58, MCI: 71, AD: 63) were determined. Multinomial regression and ROC analyses were performed to identify the combination of the plasma protein panels that could discriminate NDC vs. MCI and/or AD.ResultWe found eight interpretable protein biomarker candidates in plasma for MCI and AD, which were related to innate immunity, coagulation pathways, lipid metabolism, and nutrition. Some of them are involved in the neurovascular unit injury. The optimal combination of these proteins and the coefficients of the logistic models revealed different clinical potential between male and female. In the model discriminating cognitive impairment from NDC, the AUC values of the ROC analysis were 0.82 and 0.72 for male and female, respectively. Furthermore, we constructed composite scores optimized for male and female using these plasma protein panels, and they had a significant correlation with severity of the cognitive decline determined by clinical manifestation.ConclusionLC‐MS‐based plasma protein panels interpretable for pathophysiology of AD detect signs of cognitive decline and progression of the disease.

Diffusion tensor imaging findings in empirically derived incident MCI subtypes

AbstractBackgroundEarly changes in white matter (WM) measured using diffusion tensor imaging (DTI) are sensitive markers of WM degeneration and predict future cognitive decline in mild cognitive impairment (MCI). We sought to examine whether changes in WM integrity differed among empirically derived subtypes of incident MCI.MethodParticipants included 66 individuals with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) previously identified via cluster analysis as having one of four MCI subtypes: subtle cognitive impairment (SCI; n = 13, mean age 78; 15% women), amnestic (n = 24; mean age 79; 54% women), dysnomic (n = 8; mean age 79; 38% women), and dysexecutive (n = 21; mean age 82; 33% women). All participants completed 3T MRI at the time of the MCI diagnosis. We compared the MCI subtypes to 100 cognitively unimpaired (CU) participants (mean age 77; 49% women). We used tract‐based spatial statistics to examine voxel‐level differences in fractional anisotropy (FA). We also fit a linear regression model to regional FA data from the corpus callosum (CC), the major interhemispheric WM connection, to quantify the relative differences in WM damage.ResultAll MCI subtypes except the subtle cognitive impairment group had widespread decreased FA. Relative to CU, the amnestic cluster showed decreased FA in the CC (genu), cingulum, fornix and uncinate fasciculus (UF); the dysnomic cluster showed decreased FA in the CC (genu, splenium), fornix, UF, anterior thalamic radiation (ATR), and corticospinal tract (CST); and the dysexecutive group showed decreased FA in the CC (genu, body, splenium), cingulum, UF, ATR, CST, and superior longitudinal fasciculus. The dysexecutive cluster had the most severe bilateral involvement among all MCI subtypes. The regional analysis showed that the amnestic, dysnomic, and dysexecutive groups (but not the subtle cognitive impairment group) had significantly lower FA of the CC compared to CU (p&lt;0.001; Figure 1).ConclusionWe found widespread WM degeneration in the commissural and long association fibers in amnestic, dysnomic, and dysexecutive incident MCI subtypes. The extent of CC damage seen in Figure 1. confirmed the voxel‐level results and suggests that interhemispheric WM disconnection is relevant to the development of MCI.

Spatial variation of perfusion MRI reflects cognitive decline in mild cognitive impairment and early dementia

Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer’s dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the view that vascular health contributes to cognitive decline associated with Alzheimer’s disease.

B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment.

Background:Metals, silicon, and homocysteine are linked to Alzheimer’s disease. B vitamin therapy lowers homocysteine and slows brain atrophy and cognitive decline in mild cognitive impairment (MCI).Objective:Examine metals and silicon as predictors of cognition/brain atrophy in MCI, their interaction with homocysteine and cysteine, and how B vitamins affect these relationships.Methods:MCI participants (n = 266, 77.6-year-old, 60.7% female) in VITACOG trial were randomized to receive daily folic acid (0.8 mg)/vitamin B12 (0.5 mg)/vitamin B6 (20 mg) (n = 133) or placebo for two years. At baseline and end-of-study, cranial MRIs were obtained from 168 participants, cognition was analyzed by neuropsychological tests, and serum iron, copper, arsenic, aluminum, and silicon quantified by inductively-coupled plasma mass spectrometry in 196 participants. Data were analyzed by bivariate and multiple regression.Results:Baseline iron, cysteine, and homocysteine were significantly associated with brain atrophy rate. Homocysteine effects on brain atrophy rate were modified by iron and cysteine. At baseline, iron, copper, aluminum, and silicon were significantly associated with one or more domains of cognition: semantic memory, verbal episodic memory, attention/processing speed, and executive function. At end-of-study, baseline iron, copper, aluminum, and silicon predicted cognition in at least one domain: semantic memory, verbal episodic memory, visuospatial episodic memory, attention/processing speed, and global cognition in the placebo but not the B vitamin group.Conclusion:Disparate effects of serum iron, copper, aluminum, silicon, and homocysteine on cognition and brain atrophy in MCI suggest that cognitive impairment is independent of brain atrophy. These factors showed domain-specific associations with cognition, which were abrogated by B vitamin therapy.

Visit-to-visit blood pressure variability in mild cognitive impairment: A possible marker of Alzheimer's disease in the SPRINT study?

Visit-to-visit blood pressure variability in mild cognitive impairment: A possible marker of Alzheimer's disease in the SPRINT study?

Plasma Glutathione Levels Decreased with Cognitive Decline among People with Mild Cognitive Impairment (MCI): A Two-Year Prospective Study.

Glutathione (GSH) is a major endogenous antioxidant. Several studies have shown GSH redox imbalance and altered GSH levels in Alzheimer’s disease (AD) patients. Early detection is crucial for the outcome of AD. However, whether GSH can serve as a biomarker during the very early-phase of AD, such as mild cognitive impairment (MCI), remains unknown. The current prospective study aimed to examine the longitudinal change in plasma GSH concentration and its influence on cognitive decline in MCI. Overall, 49 patients with MCI and 16 healthy individuals were recruited. Plasma GSH levels and cognitive function, measured by the Mini-Mental Status Examination (MMSE) and Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog), were monitored every 6 months. We employed multiple regressions to examine the role of GSH level in cognitive decline in the 2 years period. The MCI patients showed significant decline in plasma GSH levels and cognitive function from baseline to endpoint (month 24). In comparison, the healthy individuals’ GSH concentration and cognitive function did not change significantly. Further, both GSH level at baseline and GSH level change from baseline to endpoint significantly influenced cognitive decline among the MCI patients. To our knowledge, this is the first study to demonstrate that both plasma GSH levels and cognitive function declined 2 years later among the MCI patients in a prospective manner. If replicated by future studies, blood GSH concentration may be regarded as a biomarker for monitoring cognitive change in MCI.