Decline In Mild Cognitive Impairment Research Articles

Moderation of Amyloid-β Deposition on the Effect of Cholinesterase Inhibitors on Cognition in Mild Cognitive Impairment.

Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer's disease; this Aβ heterogeneity may explain inconsistent results. This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. We examined 118 individuals with amnestic MCI (ages 55-90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI.

Classification of mild cognitive impairment and normal cognition using an automated voice-based testing application

An easy-to-use tool that can detect cognitive decline in mild cognitive impairment (MCI) is required. In this study, we aimed to construct a machine learning model that discriminates between MCI and cognitively normal (CN) individuals using spoken answers to questions and speech features. Participants of ≥50 years of age were recruited from the Silver Human Resource Center. The Japanese Version of the Mini-Mental State Examination (MMSE-J) and Clinical Dementia Rating (CDR) were used to obtain clinical information. We developed a research application that presented neuropsychological tasks via automated voice guidance and collected the participants' spoken answers. The neuropsychological tasks included time orientation, sentence memory tasks (immediate and delayed recall), and digit span memory-updating tasks. Scores and speech features were obtained from spoken answers. Subsequently, a machine learning model was constructed to classify MCI and CN using various classifiers, combining the participants' age, gender, scores, and speech features. We obtained a model using Gaussian Naive Bayes, which classified typical MCI (CDR 0.5, MMSE ≤26) and typical CN (CDR 0 and MMSE ≥29) with an area under the curve (AUC) of 0.866 (accuracy 0.75, sensitivity 0.857, specificity 0.712). We built a machine learning model that can classify MCI and CN using spoken answers to neuropsychological questions. Easy-to-use MCI detection tools could be developed by incorporating this model into smartphone applications and telephone services.

Cortical and subcortical gray matter abnormalities in mild cognitive impairment

Gray matter changes are thought to be closely related to cognitive decline in mild cognitive impairment (MCI) patients. The study aimed to explore cortical and subcortical structural alterations in MCI and their association with cognitive assessment. 24 MCI patients and 22 normal controls (NCs) were included. Voxel-based morphometry (VBM), vertex-based shape analysis and surface-based morphometry (SBM) analysis were applied to explore subcortical nuclei volume, shape and cortical morphology. Correlations between structural changes and cognition were explored using spearman correlation analysis. Support vector machine (SVM) classification evaluated MCI identification accuracy. MCI patients showed significant atrophy in the left thalamus, left hippocampus, left amygdala, right pallidum, right hippocampus, along with inward deformation in the left amygdala. SBM analysis revealed that MCI group exhibited shallower sulci depth in the left hemisphere and increased cortical gyrification index (GI) in the right frontal gyrus. Correlation analysis showed the positive correlation between right hippocampus volume and episodic memory, while negative correlation between the altered GI and memory performance in MCI group. SVM analysis demonstrated superior performance of sulci depth and GI derived from SBM in MCI identification. When combined with cortical and subcortical metrics, SVM achieved a peak accuracy of 89 % in distinguishing MCI from NC. The study reveals significant gray matter structural changes in MCI, suggesting their potential role in underlying functional differences and neural mechanisms behind memory impairment in MCI.

Estimating individual trajectories of structural and cognitive decline in mild cognitive impairment for early prediction of progression to dementia of the Alzheimer’s type

Only a third of individuals with mild cognitive impairment (MCI) progress to dementia of the Alzheimer’s type (DAT). Identifying biomarkers that distinguish individuals with MCI who will progress to DAT (MCI-Converters) from those who will not (MCI-Non-Converters) remains a key challenge in the field. In our study, we evaluate whether the individual rates of loss of volumes of the Hippocampus and entorhinal cortex (EC) with age in the MCI stage can predict progression to DAT. Using data from 758 MCI patients in the Alzheimer’s Disease Neuroimaging Database, we employ Linear Mixed Effects (LME) models to estimate individual trajectories of regional brain volume loss over 12 years on average. Our approach involves three key analyses: (1) mapping age-related volume loss trajectories in MCI-Converters and Non-Converters, (2) using logistic regression to predict progression to DAT based on individual rates of hippocampal and EC volume loss, and (3) examining the relationship between individual estimates of these volumetric changes and cognitive decline across different cognitive functions—episodic memory, visuospatial processing, and executive function. We find that the loss of Hippocampal volume is significantly more rapid in MCI-Converters than Non-Converters, but find no such difference in EC volumes. We also find that the rate of hippocampal volume loss in the MCI stage is a significant predictor of conversion to DAT, while the rate of volume loss in the EC and other additional regions is not. Finally, individual estimates of rates of regional volume loss in both the Hippocampus and EC, and other additional regions, correlate strongly with individual rates of cognitive decline. Across all analyses, we find significant individual variation in the initial volumes and the rates of changes in volume with age in individuals with MCI. This study highlights the importance of personalized approaches in predicting AD progression, offering insights for future research and intervention strategies.

Moderating effect of education on glymphatic function and cognitive performance in mild cognitive impairment.

This research aims to investigate putative mechanisms between glymphatic activity and cognition in mild cognitive impairment (MCI) and analyzes whether the relationship between cognitive reserve (CR) and cognition was mediated by glymphatic activity. 54 MCI patients and 31 NCs were enrolled to evaluate the bilateral diffusivity along the perivascular spaces and to acquire an index for diffusivity along the perivascular space (ALPS-index) on diffusion tensor imaging (DTI). The year of education was used as a proxy for CR. The ALPS-index was compared between two groups and correlation analyses among the ALPS-index, cognitive function, and CR were conducted. Mediation analyses were applied to investigate the correlations among CR, glymphatic activity and cognition. MCI group had a significantly lower right ALPS-index and whole brain ALPS-index, but higher bilateral diffusivity along the y-axis in projection fiber area (Dyproj) than NCs. In MCI group, the left Dyproj was negatively related to cognitive test scores and CR, the whole brain ALPS-index was positively correlated with cognitive test scores and CR. Mediation analysis demonstrated that glymphatic activity partially mediated the correlations between CR and cognitive function. MCI exhibited decreased glymphatic activity compared to NCs. CR has a protective effect against cognitive decline in MCI, and this effect may be partially mediated by changes in glymphatic activity.

A 3D pseudo-continuous arterial spin labeling study of altered cerebral blood flow correlation networks in mild cognitive impairment and Alzheimer's disease.

To investigate the abnormalities of the three-dimensional pseudo-continuous arterial spin labeling (3D PCASL) based cerebral blood flow (CBF) correlation networks in mild cognitive impairment (MCI) and Alzheimer's disease (AD). 3D PCASL images of 53 cognitive normal (CN) subjects, 43 subjects with MCI, and 30 subjects with AD were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Whole-brain CBF maps were calculated using PCASL and proton density-weighted images (PDWI). The 246 regional CBF values, including the cortex and subcortex, were obtained after registering the Brainnetome Atlas to the individual CBF maps. The Pearson correlation coefficient between every two regions across subjects was calculated to construct the CBF correlation network. Then the topologies of CBF networks with regard to global properties (global network efficiency, clustering coefficient, characteristic path length, and small-world properties), hub regions, nodal properties (betweenness centrality, BC), and connections were compared among CN, MCI, and AD. Significant changes in the global and nodal properties were observed in the permutation tests, and connections with significant differences survived after the z-statistic and false discovery rate (FDR) correction. The CBF correlation networks of CN, MCI, and AD all showed small-world properties. Compared with CN, global efficiency decreased significantly in AD. Significant differences in nodal properties and a loss of hub regions are noted in the middle temporal lobe in both MCI and AD. In the frontal lobe, BC is reduced in MCI while it is increased in the occipital lobe in AD. The identified altered hub regions with significant differences in MCI and AD were mainly distributed in the hippocampus and entorhinal cortex. In addition, disrupted hub regions in AD with significantly decreased connections were mainly found in the precuneus/posterior cingulate cortex (PCC) and hippocampus-cortical cortex. Noninvasive 3D PCASL-based CBF correlation networks are capable of showing changes in topological organization in subjects with MCI and AD, and the observed disruption in the topological organization may underlie cognitive decline in MCI and AD.

Long-acting exenatide does not prevent cognitive decline in mild cognitive impairment: a proof-of-concept clinical trial

PurposeAccording to preclinical evidence, GLP-1 receptor may be an actionable target in neurodegenerative disorders, including Alzheimer’s disease (AD). Previous clinical trials of GLP-1 receptor agonists were conducted in patients with early AD, yielding mixed results. The aim was to assess in a proof-of-concept study whether slow-release exenatide, a long-acting GLP-1 agonist, can benefit the cognitive performance of people with mild cognitive impairment (MCI).MethodsThirty-two (16 females) patients were randomized to either slow-release exenatide (n = 17; 2 mg s.c. once a week) or no treatment (n = 15) for 32 weeks. The primary endpoint was the change in ADAS-Cog11 cognitive test score at 32 weeks vs baseline. Secondary endpoints herein reported included additional cognitive tests and plasma readouts of GLP-1 receptor engagement. Statistical analysis was conducted by intention to treat.ResultsNo significant between-group effects of exenatide on ADAS-Cog11 score (p = 0.17) were detected. A gender interaction with treatment was observed (p = 0.04), due to worsening of the ADAS-Cog11 score in women randomized to exenatide (p = 0.018), after correction for age, scholar level, dysglycemia, and ADAS-Cog score baseline value. Fasting plasma glucose (p = 0.02) and body weight (p = 0.03) decreased in patients randomized to exenatide.ConclusionIn patients with MCI, a 32-week trial with slow-release exenatide had no beneficial effect on cognitive performance.Trial registration numberNCT03881371, registered on 21 July, 2016.

The role of olfactory dysfunction in mild cognitive impairment and Alzheimer's disease: A meta-analysis

PurposeThis comprehensive meta-analysis investigates the association between olfactory deficits in mild cognitive impairment (MCI) and Alzheimer's disease (AD). MethodsA thorough search across databases identified articles analyzing olfactory status in MCI or AD patients. Methodological quality assessment followed PRISMA guidelines. Hedges' g effect size statistic computed standard mean differences and 95% confidence intervals. Moderator analysis was conducted. ResultsAmong the included studies (65 for MCI and 61 for AD), odor identification exhibited larger effect sizes compared to odor threshold and discrimination, in both MCI and AD samples. Moderate effect size is found in OI scores in MCI (k = 65, SE = 0.078, CI 95% = [-1.151, -0.844]). Furthermore, compared to MCI, AD had moderate to large heterogeneous effects in olfactory identification (k = 61, g = -2.062, SE = 0.125, CI 95% = [-2.308, -1.816]). Global cognitive status is positively related to olfactory identification impairment in both MCI (k = 57, Z = 2.74, p = 0.006) and AD (k = 53, Z = 5.03, p < 0.0001) samples. ConclusionOlfactory impairments exhibit a notable and substantial presence in MCI. Among these impairments, odor identification experiences the greatest decline in MCI, mirroring the primary sensory deficit observed in AD. Consequently, the incorporation of a straightforward odor identification test is advisable in the evaluation of individuals vulnerable to the onset of AD, offering a practical screening tool for early detection.

Elevated Amyloid-β PET Scan and Cognitive and Functional Decline in Mild Cognitive Impairment and Dementia of Uncertain Etiology.

Elevated amyloid-β (Aβ) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer's disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aβ on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty. We aimed to investigate whether elevated Aβ on PET scan predicts cognitive and functional decline over an 18-month period in those with MCI or dementia of uncertain etiology. In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aβ on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner. Individuals with either MCI or dementia and elevated Aβ (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aβ on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aβ were also reported to have greater functional decline compared to those without elevated Aβ, even though the latter group showed significant care partner-reported functional decline over time. Elevated Aβ on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD.

Depression and Agitation Factors Are Related to Regional Brain Atrophy and Faster Longitudinal Cognitive Decline in Mild Cognitive Impairment.

Neuropsychiatric symptoms (NPS) are a common aspect of Alzheimer's disease (AD). Multiple studies have investigated its brain correlates, but it still remains unclear how they relate with brain atrophy in mild cognitive impairment (MCI). Our objective was to investigate brain volume in MCI patients as a function of NPS. We measured grey matter volume, neuropsychological status and NPS (Neuropsychiatric Inventory, NPI), in a sample of 81 MCI patients (43 females). Participants were divided in groups depending on presence (NPS+) or absence (NPS-) of NPS and on type of NPS. We found lower volume of left temporal pole in patients with depression compared to NPS- (p = 0.012), and in patients with agitation compared to NPS- in the right middle occipital gyrus (p = 0.003). We also found a significant correlation between volume of left temporal pole and MMSE (r(78) = 0.232, p = 0.019). Finally, NPS+ presented lower cross-sectional cognitive level than NPS- (t(79) = 1.79, p = 0.038), and faster cognitive decline (t(48) = -1.74, p = 0.044). Our results support the colocalization of structural damage as a possible mechanism underlying the relationship between MCI and depression and provide novel evidence regarding agitation. Moreover, our longitudinal evidence highlights the relevance of an adequate identification of NPS in MCI patients to identify those at risk of faster cognitive decline.

Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values&gt;0.31) nor p‐tau (p‐values&gt;0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values&gt;0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values&lt;0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082

Longitudinal cortical thinning is associated with cognitive decline in MCI and Alzheimer’s disease in the Korean population

AbstractUndAlzheimer’s disease (AD) is characterized by cognitive dysfunction likely secondary to progressive neurodegeneration in the brain. However, to what extent regional cortical thickness (CT) changes are related to cognitive decline in the Asian population remains unclear.MethodWe measured CT using Freesurfer v6 from T1‐weighted magnetic resonance imaging (MRI) data in 603 Korean participants, including 71 young and 288 old cognitively unimpaired (CU young and CU old), 149 with mild cognitive impairment (MCI), and 92 AD from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). Cognitive function of each participant was quantified by the MMSE. MRI and cognitive data were acquired at baseline (n = 603) and a 2‐year follow‐up visit (n = 380). Linear mixed‐effect models were used to estimate diagnosis group, time, and group‐by‐time interaction effects on CT measurements, with age, sex, and education as covariates. Pearson’s correlations between CT measurements and MMSE total score were computed, corrected for multiple comparisons by false discovery rate (FDR).ResultAt baseline, CU old participants had lower CT values than CU young participants in the inferior parietal cortex and frontal and parietal regions. In comparison with CU old participants, MCI and AD showed widespread lower CT values, more pronounced in the medial temporal lobe (i.e., the entorhinal cortex and parahippocampal gyrus), inferior temporal cortex, medial prefrontal cortex, and medial parietal cortex (i.e., the posterior cingulate cortex and precuneus), with AD lower than MCI in these regions. These regions also showed the most longitudinal atrophy in both AD and MCI over 2 years. AD patients showed faster and more widespread atrophy patterns than MCI and CU old participants. We identified significant (PFDR&lt;0.05) positive linear correlations between cognitive decline and regional CT measurements, particularly in regions showing significant cortical thinning across time.ConclusionIn this study, we replicated the typical cross‐sectional and longitudinal brain atrophy patterns, and relationships with cognitive decline in an Asian cohort. Our findings support the generalizability of atrophy patterns in MCI and AD, suggesting common neurobiological mechanisms underlying AD symptoms across different ethnoracial populations.

Self- versus informant-report of cognitive decline in mild cognitive impairment: Concordance with cognitive and functional performance.

Debate continues regarding the use of self- versus informant-report to diagnose mild cognitive impairment (MCI) with studies reporting patients both overestimating and underestimating their abilities relative to informants. We assessed concordance of self- versus informant-report of cognitive decline with objective cognitive and functional performance in the participants of the preventing Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression randomized controlled trial (PACt-MD). Three hundred six participants with MCI, and their informants, reported on cognitive decline; the participants also completed a comprehensive assessment of objective cognitive and functional performance. Based on the discrepancy between self- versus informant-report of cognitive decline, we grouped participants into categories of underestimators, congruent estimators, and overestimators. Informant- but not self-reported cognitive decline significantly correlated with objective cognitive performance. There were 68 underestimators, 94 congruent estimators, and 144 overestimators. Underestimators had significantly lower objective cognitive performance and functional performance than congruent estimators and overestimators. Cognitive performance significantly predicted functional performance in all three groups, and the relationship between cognitive and functional performance was moderated by the discrepancy between self- and informant-report. We showed a poor concordance among self-report of cognitive decline and both informant-report of cognitive decline and cognitive performance in patients with MCI. Our findings highlight clinical and research value in the assessment and consideration of degree of discrepancy between self- and informant-reports of cognitive decline in MCI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations between Neuropsychiatric Symptoms and Alzheimer's Disease Biomarkers in People with Mild Cognitive Impairment.

Neuropsychiatric symptoms (NPS) are associated with faster decline in mild cognitive impairment (MCI). This study aimed to investigate the association between NPS severity and Alzheimer's disease (AD) biomarkers, i.e., amyloid-β (Aβ), phosphorylated tau protein (p-tau) and hippocampal volume ratio (HR), to characterise in more detail MCI patients with a poor prognosis. A total of 506 individuals with MCI and 99 cognitively unimpaired older adults were selected from the ADNI dataset. The patients were divided into three different groups based on their NPI-Q total scores: no NPS (n = 198), mild NPS (n = 160) and severe NPS (n = 148). Regression models were used to assess the association between the severity of NPS and each biomarker level and positivity status. Cerebrospinal fluid Aβ levels were positively associated with older age and lower MMSE scores, while higher p-tau levels were associated with female sex and lower MMSE scores. Only patients with severe NPS had a lower HR (β = -0.18, p = 0.050), i.e., more pronounced medio-temporal atrophy, than those without NPS. Only HR was associated with the presence of NPS, partially in line with previous evidence showing that severe NPS may be explained primarily by greater grey matter loss. Future longitudinal studies will be needed to ascertain the relevance of this finding.

Characterization of diffusion magnetic resonance imaging revealing relationships between white matter disconnection and behavioral disturbances in mild cognitive impairment: a systematic review.

White matter disconnection is the primary cause of cognition and affection abnormality in mild cognitive impairment (MCI). Adequate understanding of behavioral disturbances, such as cognition and affection abnormality in MCI, can help to intervene and slow down the progression of Alzheimer's disease (AD) promptly. Diffusion MRI is a non-invasive and effective technique for studying white matter microstructure. This review searched the relevant papers published from 2010 to 2022. Sixty-nine studies using diffusion MRI for white matter disconnections associated with behavioral disturbances in MCI were screened. Fibers connected to the hippocampus and temporal lobe were associated with cognition decline in MCI. Fibers connected to the thalamus were associated with both cognition and affection abnormality. This review summarized the correspondence between white matter disconnections and behavioral disturbances such as cognition and affection, which provides a theoretical basis for the future diagnosis and treatment of AD.

Reduced cortical cholinergic innervation correlates with cognitive decline in mild cognitive impairment

AbstractBackgroundDysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. The association of cortical cholinergic denervation with diverse cognitive profiles in dementia, particularly at early stages, has not yet been fully explored. We assessed the relationship of cholinergic denervation in the cortex measured using 18F‐fluoroethoxybenzovesamicol (FEOBV) with cognitive decline at an early stage of dementia.MethodParticipants (8 with mild cognitive impairment (MCI) and 10 cognitively unimpaired (CU) controls, aged 60‐86, 55.6% female, MMSE = 28.7±1.5) underwent neuropsychological assessment and FEOBV PET imaging. The neuropsychological battery of tests included measures of memory, executive function, attention and language. Domain‐specific composite scores were calculated by averaging z‐scores of the related tests or subtasks within a domain. FEOBV images were co‐registered to the concurrent structural MRI and normalised to the supratentorial white matter reference region resulting in a standardized uptake value ratio (SUVR). Voxel‐wise analysis was performed on normalised FEOBV images to investigate associations with clinical diagnosis and domain‐specific cognitive performance. Voxel‐based morphometry was also performed to rule out differences in brain morphology. All analyses were corrected for age, sex and total intracranial volume and adjusted for multiple comparisons.ResultThe MCI group showed significantly lower global FEOBV SUVR in the cortex although only a focal cluster of reductions near the right middle temporal gyrus was found in the voxel‐wise comparisons. When associations with cognitive performance profiles were assessed in the full cohort, regional positive correlations were found between FEOBV SUVR and cognitive scores across different domains (Figure 1), although these did not include memory. For executive functioning, widespread correlation patterns were observed across both cortical and subcortical regions. Moreover, overlapping profiles were identified for all three cognitive domains of executive function, attention and language, which covered the anterior cingulate gyrus, olfactory cortex, calcarine cortex, middle temporal gyrus and caudate nucleus.ConclusionWe have demonstrated that the topographic profile of FEOBV retention correlated with reduced cognitive performance in different domains, suggesting that reduced cortical cholinergic terminal integrity is an important pathological feature of cognitive decline.

Metabolic syndrome biomarkers relate to rate of cognitive decline in MCI and dementia stages of Alzheimer’s disease

BackgroundThe relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate of cognitive decline in mild cognitive impairment (MCI) and dementia stages of Alzheimer’s disease (AD) is unknown. The role of peripheral and cerebrospinal fluid (CSF) levels of Apolipoprotein A1 (ApoA1), a key functional component of HDL, on cognitive decline also remains unclear among them. Here we evaluate baseline plasma TG/HDL-C ratio and CSF and plasma ApoA1 levels and their relation with cognitive decline in the MCI and Dementia stages of AD.Patients and methodsA retrospective longitudinal study (156 participants; 106 MCI, 50 AD dementia) from the Alzheimer’s Disease Neuroimaging Initiative, with an average of 4.0 (SD 2.8) years follow-up. Baseline plasma TG/HDL-C, plasma, and CSF ApoA1 and their relationship to inflammation and blood–brain barrier (BBB) biomarkers and longitudinal cognitive outcomes were evaluated. Multivariable linear mixed effect models were used to assess the effect of baseline analytes with longitudinal changes in Mini-Mental State Exam (MMSE), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Logical Memory delayed recall (LM) score after controlling for well-known covariates.ResultsA total of 156 participants included 98 women, 63%; mean age was 74.9 (SD 7.3) years. At baseline, MCI and dementia groups did not differ significantly in TG/HDL-C (Wilcoxon W statistic = 0.39, p = 0.39) and CSF ApoA1 levels (W = 3642, p = 0.29), but the dementia group had higher plasma ApoA1 than the MCI group (W = 4615, p = 0.01). Higher TG/HDL-C ratio was associated with faster decline in CDR-SB among MCI and dementia groups. Higher plasma ApoA1 was associated with faster decline in MMSE and LM among MCI, while in contrast higher CSF ApoA1 levels related to slower cognitive decline in MMSE among MCI. CSF and plasma ApoA1 also show opposite directional correlations with biomarkers of BBB integrity. CSF but not plasma levels of ApoA1 positively correlated to inflammation analytes in the AGE-RAGE signaling pathway in diabetic complications (KEGG ID:KO04933).ConclusionsBiomarkers of metabolic syndrome relate to rate of cognitive decline among MCI and dementia individuals. Elevated plasma TG/HDL-C ratio and plasma ApoA1 are associated with worse cognitive outcomes in MCI and dementia participants. CSF ApoA1 and plasma ApoA1 likely have different roles in AD progression in MCI stage.

The combination of hyperventilation test and graph theory parameters to characterize EEG changes in mild cognitive impairment (MCI) condition.

Hyperventilation (HV) is a voluntary activity that causes changes in the neuronal firing characteristics noticeable in the electroencephalogram (EEG) signals. HV-related changes have been scribed to modulation of pO2/pCO2 blood contents. Therefore, an HV test is routinely used for highlighting brain abnormalities including those depending to neurobiological mechanisms at the basis of neurodegenerative disorders. The main aim of the present paper is to study the effectiveness of HV test in modifying the functional connectivity from the EEG signals that can be typical of a prodromal state of Alzheimer's disease (AD), the Mild Cognitive Impairment prodromal to Alzheimer condition. MCI subjects and a group of age-matched healthy elderly (Ctrl) were enrolled and subjected to EEG recording during HV, eyes-closed (EC), and eyes-open (EO) conditions. Since the cognitive decline in MCI seems to be a progressive disconnection syndrome, the approach we used in the present study is the graph theory, which allows to describe brain networks with a series of different parameters. Small world (SW), modularity (M), and global efficiency (GE) indexes were computed among the EC, EO, and HV conditions comparing the MCI group to the Ctrl one. All the three graph parameters, computed in the typical EEG frequency bands, showed significant changes among the three conditions, and more interestingly, a significant difference in the GE values between the MCI group and the Ctrl one was obtained, suggesting that the combination of HV test and graph theory parameters should be a powerful tool for the detection of possible cerebral dysfunction and alteration.

PROPOSING THE NEUROGENESIS HYPOTHESIS FOR ALZHEIMER’S DISEASEWITH A CASE STUDY‐ PHASE 2 CLINICAL TRIALS OF NA‐831

AbstractBackgroundIn the hippocampus, new neurons are generated throughout life via a process called adult hippocampal neurogenesis (AHN). In mild cognitive impairment (MCI) and mild to moderate AD (early AD), AHN is reduced suggesting that AHN impairment compromises hippocampal functions. Augmenting AHN could help prevent or slow cognitive decline in MCI and early AD. The neurogenesis hypothesis is supported by the results of a Phase 2 randomized, double‐blind, placebo controlled clinical trial of NA‐831.MethodNA‐831 is a small drug molecule, which activates synaptic AMPA receptors, and increases the expression of brain derived neurotrophic factor (BDNF), which is crucial in synaptic plasticity, learning and memory formation in the hippocampus. NA‐831 restores neurogenesis by increasing the number of DCX+PCNA+ neuroblast cells. The study was conducted in 56 patients with MCI, mild and moderate Alzheimer’s disease, who received 10mg to 30 mg of NA‐831 or placebo orally per day for 24 weeks.ResultNA‐831 provided a significant delay in cognitive decline in MCI as measured by ADAS‐Cog‐13, an average score difference of 3.4 compared to placebo (p = 0.01; ITT) after 24 weeks of treatment. Similarly, NA‐831 delayed cognitive decline in early AD, an average score difference of 4.1 com‐pared to placebo (p = 0.001; ITT). CIBIC‐Plus showed 78% of the study participants receiving NA‐831 improved (p = 0.01; ITT). NA‐831 was well‐tolerated at 30 mg/day for 24 weeks, and no serious adverse events were observed.ConclusionThe Neurogenesis Hypothesis, and details of the Phase 2 clinical trials will be presented and discussed.

Investigating the protective contribution of PLCG2 P522R variant in microglia‐mediated immune pathways in Alzheimer’s Disease

AbstractBackgroundAs the main innate immune cell in central nervous system (CNS), microglia plays an indispensable roles in neuroinflammation and neurodegenerative diseases, such as Alzheimer’s Disease (AD). Large scale population studies have identified an AD‐associated rare coding variant in the Phospholipase C Gamma 2 (PLCG2) locus (rs72824905, P522R, P=5.38x10‐10, odds ratio = 0.68), which potentially offers protection against AD. This variant is associated with lower Aβ1‐42 and pTau181 levels in patients, as well as delays cognitive decline in mild cognitive impairment (MCI) progression. It has been reported that PLCG2 highly expresses in microglia in CNS and mainly involved in immune response, therefore, PLCG2 P522R variant may be a central player in the microglial‐mediated immune pathways during AD pathogenesis.MethodWe generated a PLCG2522R/R knock‐in mouse model carrying this human variant with CRISPR‐mediated gene editing. To explore the protective nature of PLCG2 P522R variant, we generated PLCG2522R/R; 5XFAD mouse model by crossing PLCG2522R/R knock‐in model with the 5XFAD mice, and accessed major AD phenotypes including Aβ load and microgliosis in vivo.ResultOur data showed that PLCG2522R/R;5XFAD mice exhibited attenuated AD pathologies compared with PLCG2522P/P;5XFAD mice, including less burden of Aβ in cortical and hippocampal regions, and less Aβ‐associated microglia clustering around Aβ plaques at early stage of AD.Conclusion PLCG2 P522R variant can protect against AD pathology in PLCG2522R/R;5XFAD mice, which may likely link to its hypermorphic effect in immune pathways, so that PLCG2522R/R microglia potentially have improved phagocytotic function and restrict Aβ accumulation in brain. We believe that investigating the protective role of PLCG2 P522R mutation may help us better understand the neuroinflammation aspect of AD pathogenesis, and provide new strategies to developing clinical therapy in the future.