Cognitive Impairment Participants Research Articles

Comparison of homocysteine, vitamin B12 and folic acid between rural and urban ageing Indians and its association with mild cognitive impairment and cardiovascular risk factors: a cross-sectional analysis.

The relationship between blood levels of homocysteine (HCY), vitamin B12, folic acid and cognitive impairment is inconclusive. Since HCY is an independent risk factor for cardiovascular diseases, understanding its association with Framingham risk score (FRS) may provide insight into the shared underlying mechanism between cardiovascular disease and cognitive impairment. Cross-sectional analyses utilized baseline data from two ongoing longitudinal studies: the Tata Longitudinal Study of Ageing (n = 923), an urban cohort, and Srinivaspura Ageing, NeuroSenescence and COGnition (n = 4239), a rural cohort. The study compared the HCY, vitamin B12 and folic acid levels across cohorts and normal versus mild cognitive impairment (MCI) participants. The association between HCY and cognitive status was established using regression models. Three models were analysed: model 1-unadjusted; model 2-adjusted for age, gender, smoking, alcohol consumption, diet, hypertension, cardiac illness, diabetes; and model 3-adjusted for variables in model 2 plus vitamin B12 and folic acid. Correlation was calculated between HCY and FRS. The urban cohort exhibited a significantly higher level of HCY [median (IQR) (17.70 (10.2) versus 14.70 (9.7); P < 0.001)], vitamin B12 (251 (231) versus 219 (138); P < 0.001) and folic acid (8.21 (8) versus 5.48 (4); P < 0.001) levels compared to rural cohort. HCY, vitamin B12 and folic acid levels did not differ significantly between normal and MCI participants in the urban cohort. In the rural cohort, among the age-gender matched MCI-normal, participants with normal cognition had higher levels of vitamin B12 (≥60 years) [227 (152) versus 217 (175); P = 0.03] and folic acid (<60 years) [5.91 (4) versus 5.40 (4); P = 0.04] compared to MCI. There was no association between HCY and cognitive status in both the cohorts, but there was a significant positive relationship between vitamin B12 deficiency and Clinical Dementia Rating-Sum of the Boxes (CDR-SOB), as well as folic acid deficiency and CDR-SOB in rural and urban cohorts, respectively, within a specific age group. A significant correlation was observed between FRS and HCY in the rural cohort (r = 0.17, P < 0.001), but not in the urban cohort. This study revealed significant differences in HCY, vitamin B12 and folic acid levels between the cohorts. In the rural cohort, participants with MCI had lower vitamin B12 and folic acid levels in a certain age group. Association between HCY and cognitive status was insignificant in both the cohorts. A small significant correlation between FRS and HCY was seen in the rural cohort.

Examining a Preclinical Alzheimer's Cognitive Composite for Telehealth Administration for Reliability Between In-Person and Remote Cognitive Testing with Neuroimaging Biomarkers.

The preclinical Alzheimer's cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers. We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-β. We examined 648 participants' neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer's Disease Research Center's Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants. There was a significant positive relationship between tPACCin-person and PACC5-RAVLT (Overall group: r2 = 0.94, N = 648), and tPACCin-person and tPACCremote (validation subgroup: ICC = 0.82, n = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-β deposition. There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer's disease.

Performance Differences of a Touch-Based Serial Reaction Time Task in Healthy Older Participants and Older Participants With Cognitive Impairment on a Tablet: Experimental Study.

Digital neuropsychological tools for diagnosing neurodegenerative diseases in the older population are becoming more relevant and widely adopted because of their diagnostic capabilities. In this context, explicit memory is mainly examined. The assessment of implicit memory occurs to a lesser extent. A common measure for this assessment is the serial reaction time task (SRTT). This study aims to develop and empirically test a digital tablet-based SRTT in older participants with cognitive impairment (CoI) and healthy control (HC) participants. On the basis of the parameters of response accuracy, reaction time, and learning curve, we measure implicit learning and compare the HC and CoI groups. A total of 45 individuals (n=27, 60% HCs and n=18, 40% participants with CoI-diagnosed by an interdisciplinary team) completed a tablet-based SRTT. They were presented with 4 blocks of stimuli in sequence and a fifth block that consisted of stimuli appearing in random order. Statistical and machine learning modeling approaches were used to investigate how healthy individuals and individuals with CoI differed in their task performance and implicit learning. Linear mixed-effects models showed that individuals with CoI had significantly higher error rates (b=-3.64, SE 0.86; z=-4.25; P<.001); higher reaction times (F1,41=22.32; P<.001); and lower implicit learning, measured via the response increase between sequence blocks and the random block (β=-0.34; SE 0.12; t=-2.81; P=.007). Furthermore, machine learning models based on these findings were able to reliably and accurately predict whether an individual was in the HC or CoI group, with an average prediction accuracy of 77.13% (95% CI 74.67%-81.33%). Our results showed that the HC and CoI groups differed substantially in their performance in the SRTT. This highlights the promising potential of implicit learning paradigms in the detection of CoI. The short testing paradigm based on these results is easy to use in clinical practice.

Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer's Disease: A Longitudinal Study.

Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

APOEε4 Carriers Exhibit Objective Cognitive Deficits: A Cross-Sectional Study in a Single Center Trial.

To explore the association between the apolipoprotein E (APOE) genotype and objectively assessed cognitive function. In this cross-sectional study, 537 participants underwent a neuropsychological assessment for cognitive function and blood testing for APOE genotype. Based on cognitive test results, participants were stratified into two cohorts: Cognitively Unimpaired participants (CU) and Cognitively Impaired participants (CI). The CI group was further divided into Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). Furthermore, we conducted age stratification, categorizing participants into three age groups: age 1: <65 years, age 2: 65-75 years, and age 3: >75 years. We assessed the disparities in cognitive function associated with ε4 carrier status across different age brackets. Plasma amyloid-β levels were measured in a cohort of 294 participants to investigate potential interactions involving ε4 carrier status, diagnosis, sex, or plasma markers. The APOE genotypic distribution among the 537 participants was characterized as follows: ε2/ε2 (5 participants), ε2/ε3 (67), ε2/ε4 (13), ε3/ε3 (330), ε3/ε4 (113), and ε4/ε4 (9). Allele frequencies were: ε3 at 78.21%, ε4 at 13.41%, and ε2 at 8.38%. Notably, the ε4 carrier frequency was markedly elevated in the AD group at 81.8% when compared to MCI at 32.8% and CU at 21.3% (p < 0.05). Within the Cognitively Unimpaired (CU) cohort, the sole discernible contrast between ε4+ and ε4- emerged in STT-B (p < 0.05). Within the CI group, ε4 carriers showed statistically poorer scores as compared to non-ε4 carriers in several cognitive tests (p < 0.05). Age stratification result revealed that, among ε4 carriers, cognitive function scores within the age 3 group were significantly inferior to those of age 1 and age 2 groups (p < 0.05). Plasma amyloid-β detection was applied to the 294 participants. We tested plasma amyloid-β (Aβ42) and plasma amyloid-β (Aβ40) levels and calculated the Aβ42/Aβ40 ratio. We found that among female ε4 carriers, both Aβ42 and the Aβ42/Aβ40 ratio were notably lower than their male counterparts (p < 0.05). The ε3/ε3 was the most prevalent among participants, succeeded by ε3/ε4 and ε2/ε3. The least prevalent were ε2/ε4, ε4/ε4, and ε2/ε2 genotypes. The ε3 was predominant, followed by the ε4 and ε2. Individuals with the ε4 allele exhibited significant cognitive impairment, with an especially high prevalence in AD group at 81.8%. The study unveils a pronounced correlation between the ε4 allele and cognitive deficits, implying its potential role in the advancement and severity of cognitive disorders, notably Alzheimer's disease. Cognitive function declines with age in individuals carrying the ε4, and women are more affected by ε4.

APOE ε4 is associated with decreased synaptic density in cognitively impaired participants.

We aimed to investigate the effect of apolipoprotein E4 (APOE) ε4 on synaptic density in cognitively impaired (CI) participants. One hundred ten CI participants underwent amyloid positron emission tomography (PET) with 18F-florbetapir and synaptic density PET with 18F-SynVesT-1. We evaluated the influence of APOE ε4allele on synaptic density and investigated the effects of ε4 genotype on the associations of synaptic density with Alzheimer's disease (AD) biomarkers. The mediation effects of AD biomarkers on ε4-associated synaptic density loss were analyzed. Compared with non-carriers, APOE ε4 allele carriers exhibited significant synaptic loss in the medial temporal lobe. Amyloid beta (Aβ) and tau pathology mediated the effects of APOE ε4 on synaptic density to different extents. The associations between synaptic density and tau pathology were regulated by the APOE ε4 genotype. The APOE ε4 allele was associated with decreased synaptic density in CI individuals and may be driven by AD biomarkers.

A novel method for PET connectomics guided by fibre-tracking MRI: Application to Alzheimer's disease.

This study introduces a novel brain connectome matrix, track-weighted PET connectivity(twPC) matrix, which combines positron emission tomography (PET) and diffusion magnetic resonance imaging data to compute a PET-weighted connectome at the individual subject level. The new method is applied to characterise connectivity changes in the Alzheimer's disease (AD) continuum. The proposed twPC samples PET tracer uptake guided by the underlying white matter fibre-tracking streamline point-to-point connectivity calculated from diffusion MRI (dMRI). Using tau-PET, dMRI and T1-weighted MRI from the Alzheimer's Disease Neuroimaging Initiative database, structural connectivity (SC) and twPC matrices were computed and analysed using the network-based statistic (NBS) technique to examine topological alterations in early mild cognitive impairment (MCI), late MCI and AD participants. Correlation analysis was also performed to explore the coupling between SC and twPC. The NBS analysis revealed progressive topological alterations in both SC and twPC as cognitive decline progressed along the continuum. Compared to healthy controls, networks with decreased SC were identified in late MCI and AD, and networks with increased twPC were identified in early MCI, late MCI and AD. The altered network topologies were mostly different between twPC and SC, although with several common edges largely involving the bilateral hippocampus, fusiform gyrus and entorhinal cortex. Negative correlations were observed between twPC and SC across all subject groups, although displaying an overall reduction in the strength of anti-correlation with disease progression. twPC provides a new means for analysing subject-specific PET and MRI-derived information within a hybrid connectome using established network analysis methods, providing valuable insights into the relationship between structural connections and molecular distributions. PRACTITIONER POINTS: New method is proposed to compute patient-specific PET connectome guided by MRI fibre-tracking. Track-weighted PET connectivity (twPC) matrix allows to leverage PET and structural connectivity information. twPC was applied to dementia, to characterise the PET nework abnormalities in Alzheimer's disease and mild cognitive impairment.

Association of adherence to the Chinese version of the MIND diet with reduced cognitive decline in older Chinese individuals: Analysis of the Chinese Longitudinal Healthy Longevity Survey.

Current evidence suggests that the Mediterranean-Dietary Approaches to Stop Hypertension (DASH) diet intervention for Neurodegenerative Delay (MIND) is associated with a reduced risk of cognitive impairment among North American and Oceanian populations. However, there has been limited exploration of whether this association extends to the Asian population. This study aimed to assess the correlation between the Chinese version of the MIND (cMIND) diet and cognitive impairment in older Chinese individuals. We utilized data from the 2008 wave of the Chinese Longitudinal Healthy Longevity Survey. Participants aged ≥65 years with normal cognitive function at baseline were enrolled. The cMIND diet score (cMINDDS) was calculated by assessing dietary patterns based on survey responses. The Chinese version of the Mini-Mental State Examination (MMSE) was employed to diagnose cognitive impairment in participants. We stratified the analysis by cMINDDS and conducted additional sensitivity analyses. The cohort consisted of 6411 participants. Over a 3-year follow-up, 1165 (18.6%) individuals who initially had normal cognitive function developed cognitive impairment. A linear association was observed between cMINDDS and cognitive impairment. The increased cMINDDS was associated with a reduced risk of cognitive impairment (quartile 1 vs. quartile 4: the adjusted odds ratio [OR] = 0.77, 95% confidence interval [CI]: [0.60, 0.97], p trend = 0.023). Regarding food composition, higher consumption of fresh fruits and nuts was associated with a decreased risk of cognitive impairment (OR = 0.77, 95% CI: [0.66, 0.89] and OR = 0.70, 95% CI [0.58, 0.86], respectively). Adherence to the cMIND diet was associated with lower risks of cognitive impairment in older Chinese individuals. The cMIND diet, based on the MIND dietary pattern, could serve as a preventive measure against cognitive impairment.

Interleukin‐3 is associated with soluble TREM2 and mediates amyloid and tau pathology in Alzheimer’s disease

AbstractBackgroundDysfunction of glial cell communication is involved in Alzheimer’s disease (AD) pathogenesis. Recent studies reported that interleukin‐3 (IL‐3) participated in astrocyte‐microglia crosstalk and restricted pathological progression in AD mice. However, how IL‐3 relates to microglial activity and AD pathology in humans remains unclear.MethodWe included 311 participants with cerebrospinal fluid (CSF) IL‐3, sTREM2 (microglial biomarker), and AD biomarkers (Aβ42, p‐tau, and t‐tau) from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We compared IL‐3 levels in different stages of AD and assessed the associations between IL‐3 with sTREM2 and AD biomarkers at baseline and with longitudinal cognitive change. Mediation models were used to explore the potential mechanism of how IL‐3 affects sTREM2 and AD pathology.ResultCSF IL‐3 levels decreased with increasing Aβ pathology and increased with increasing tau pathology, especially in cognitive impairment participants (Figure 1). CSF IL‐3 was significantly associated with CSF sTREM2 and CSF AD biomarkers (Figure 2). Mediation analysis showed that IL‐3 and sTREM2 mediated the effects of CSF Aβ on CSF tau pathology (βp‐tau = 0.053, βt‐tau = 0.055, all p &lt; 0.001) (Figure 3).ConclusionOur findings suggest that IL‐3 is associated with the microglia biomarker and that they respond strongly to amyloid and tau pathologies. Hence, IL‐3 could be a key marker for clinical trial design. We encourage future studies on enhancing IL‐3 levels as a therapeutic intervention to slow the development of AD pathology.

Developing Topics.

Alzheimer's disease (AD) is highly related to brain amyloid and tau deposition. PET images evaluate these patterns of amyloid and tau proteinopathy noninvasively. Tau PET is less familiar than amyloid PET to clinicians and researchers, it may occur inter- and intra-observer variability to determine abnormalities in visual rating. We purposed to find optimal thresholds of tau PET, compared with visual assessment, and suggest the most appropriate standard of tau PET assessment using the assist of automated quantitative analysis of PET. 101 participants were enrolled in tau (18F-flortaucipir), amyloid (18F-flutemetamol) PET, and a three-dimension T1-weighted MR image study. Each regional SUVR was calculated using SCALE PET version 1.2 (Neurophet Inc., Seoul, Republic of Korea.). Each regions-of-interest (ROI)-mean SUVR of reference region (whole cerebellum (CW) and cerebellar gray matter (CG)) and quantitative Tau PET positivity was compared with visual rating results of a nuclear medicine physician. We compared accuracy of tau PET positivity driven from 1) total Braak ROI, 2) a priori ROI, and 3) whole cerebral cortical mean SUVR above 1.65 (CW, CG) or 1.30 (CG). The highest accuracy was observed 0.832 with above 1.65 mean SUVR in a priori ROI using CG reference region. False negative (FN), where participants classified as negative with mean SUVR when visually positive (FN), was 26.7%. These FN participants were mostly identified as borderline patients who were categorized to Braak III/IV (3) or V/VI (24) in visual rating. All the participants classified as tau positive in the quantitative method were amyloid positive while 54.1% were in the tau negative group. Also, the patient group composed of AD and mild cognitive impairment (MCI) participants was 96.3% in positive, behalf 55.4% in negative group. Both visual rating and quantitative classification showed a significant difference between negative and positive groups (p <0.001). Visual assessment may provide more sensitive outcome than quantitative estimation, i.e., mean SUVR. Our quantitative methods of tau PET showed high accuracy with visual assessment in the regions of early Braak stage, i.e., Braak I/II/III/IV. In the future, there needed to develop more sensitive cutoff values or quantitative methods for tauopathy deposition observation.

Trajectories of plasma biomarkers of Alzheimer’s disease and neurodegeneration in the general population

AbstractBackgroundPlasma biomarkers of Alzheimer’s disease (AD) and neurodegeneration have demonstrated diagnostic utility and associations with AD pathology. Our objective was to map the average trajectories over age of plasma biomarkers and more established biomarkers including cognition, amyloid PET, and hippocampal volume.MethodWe included 1731 cognitively unimpaired (CU) and 226 mild cognitive impairment (MCI) participants from the Mayo Clinic Study of Aging (mean age of 70.3 years; 46.3% female; 14.8 years of mean education) with one or more measurements of amyloid‐PET, MRI with hippocampal volume measurements adjusted for head size (HVa), and plasma biomarkers (Aβ42/40 ratio, p‐tau181, GFAP, and NfL measured using Quanterix Simoa assays). A global cognitive z‐score was created by averaging the z‐scores of memory, language, executive function, and visuospatial domains. Smoothing spline curves were calculated for the values of each variable over age and placed on the same plot. Since each variable has a different scale, the smoothed curves were centered at the predicted value at age 50 and scaled so that a value of 1 would be one standard deviation of the fitted values from ages 50‐80.ResultAt age 50, GFAP and NfL start to increase, and Aβ42/40 was observed to decrease. At age 55, amyloid‐PET and p‐tau181 had a smooth and upward‐curving increase. After age 70, the average values of p‐tau181 increased at a higher rate. Average cognition started declining after 55 years. HVa began to decline after age 60 and then showed a steeper decline at age 72.ConclusionThis study demonstrates that predicted values of plasma GFAP, NfL, and Aβ42/40 across participants begin to change at younger ages than cognitive decline or increases observed in amyloid PET. The changes observed during middle age in GFAP and NfL likely reflect non‐AD pathologies and aging processes, while Aβ42/40 may be a leading indicator of future cerebral amyloidosis. Predicted plasma neurodegenerative biomarkers (GFAP and NfL) begin to change at younger ages than a traditional biomarker of neurodegeneration (HVa). Predicted ptau181 increases were observed in tandem with amyloid PET likely reflecting current amyloid status.

Clinical Manifestations.

Apathy is defined as the lack of motivation and has been found to be associated with incident dementia in western populations (Dalen, 2018). Little is known about the impact of apathy in Asians. Apathy is a prevalent behavioural symptom of pre dementia and current literature shows that apathy increases the risk of dementia (Bock, 2020). Apathy is also linked to an increased risk of frailty(Ayers, 2018) and found to impair executive function and processing speed(Lohner, 2017). We aim to evaluate the association of apathy with cognitive function, frailty and lifestyle factors in a pre-dementia community population in Singapore. We recruited 534 participants from the community who completed a detailed neuropsychological assessment. Apathy was measured using the mild behavioural impairment checklist (MBI-C). To test for the association of apathy with the different variables, we performed a multiple generalized linear model controlling for covariates age, sex and education. The study population included 186 participants with subjective cognitive decline and 348 mild cognitive impairment participants from Dementia Research Centre (Singapore). Mean age of the cohort was 62.55, SD = 9.55, mean education years was 13.97, SD = 3.45 and majority were women (57.1%). The prevalence of apathy among our cohort was 23.5%. Compared to participants without apathy, those with apathy had poorer cognitive scores in processing speed (test of coding) (β = -4.60, p<0.001), executive function (colour trails 2) (β = 9.71, p = 0.020), episodic memory on the RAVLT Delayed (β = -0.738, p = 0.026), RCFT Delayed (β = -1.941, p = 0.009) and FCSRT delayed (β = -0.616, p = 0.030). Participants with apathy were also more frail (β = 0.316, p<0.001) on the Fried Phenotype frailty assessment test and had poorer quality of life (β = -12.49, p<0.001), had lower levels of physical activity (β = 0.163, p = 0.017), and had poorer sleep (β = 2.25, p<0.001). Apathy is associated with worse cognitive performance, higher frailty, lower physical performance and poorer sleep in an Asian pre-dementia community cohort. Screening for apathy and appropriate early intervention could reduce incidence of dementia and frailty.

Understanding the Episodic Memory and Executive Functioning Axis Impairment in MCI Patients: A Multicenter Study in Comparison with CSF Biomarkers.

This study aimed to explore the association between a verbal learning task that evaluates the potential mutual dependency between memory and executive functions (i.e., the Test of Memory Strategies, TMS) and cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarkers. A sample of 47 mild cognitive impairment (MCI) participants from Poland and Spain were classified according to the Erlangen Score Diagnostic Algorithm (ESA) into CSF- (n = 16) and CSF+ (n = 31) groups. Correlation analyses between TMS word-list conditions and CSF biomarkers were conducted. Additionally, an analysis of covariance was performed to define the effect on ESA classification in the sample, using as a covariable the country of origin of the participants. Significant associations between the TMS-3 condition and Aβ42, t-tau, and p-tau were observed for the whole sample. In addition, the CSF- participants obtained higher cognitive performance in TMS-3 compared to the CSF+ group. This outcome persisted if the groups were based on Aβ42 scores, but not t-tau or p-tau values. These findings could indicate that poor performance on verbal learning tests may be affected by executive dysfunctions. Therefore, future intervention plans focused on training executive functions would be of interest to improve the ability of MCI patients to encode and organize information.

Prevalence and localization of nocturnal epileptiform discharges in mild cognitive impairment.

Recent evidence shows that identifying and treating epileptiform abnormalities in patients with Alzheimer's disease could represent a potential avenue to improve clinical outcome. Specifically, animal and human studies have revealed that in the early phase of Alzheimer's disease, there is an increased risk of seizures. It has also been demonstrated that the administration of anti-seizure medications can slow the functional progression of the disease only in patients with EEG signs of cortical hyperexcitability. In addition, although it is not known at what disease stage hyperexcitability emerges, there remains no consensus regarding the imaging and diagnostic methods best able to detect interictal events to further distinguish different phenotypes of Alzheimer's disease. In this exploratory work, we studied 13 subjects with amnestic mild cognitive impairment and 20 healthy controls using overnight high-density EEG with 256 channels. All participants also underwent MRI and neuropsychological assessment. Electronic source reconstruction was also used to better select and localize spikes. We found spikes in six of 13 (46%) amnestic mild cognitive impairment compared with two of 20 (10%) healthy control participants (P = 0.035), representing a spike prevalence similar to that detected in previous studies of patients with early-stage Alzheimer's disease. The interictal events were low-amplitude temporal spikes more prevalent during non-rapid eye movement sleep. No statistically significant differences were found in cognitive performance between amnestic mild cognitive impairment patients with and without spikes, but a trend in immediate and delayed memory was observed. Moreover, no imaging findings of cortical and subcortical atrophy were found between amnestic mild cognitive impairment participants with and without epileptiform spikes. In summary, our exploratory study shows that patients with amnestic mild cognitive impairment reveal EEG signs of hyperexcitability early in the disease course, while no other significant differences in neuropsychological or imaging features were observed among the subgroups. If confirmed with longitudinal data, these exploratory findings could represent one of the first signatures of a preclinical epileptiform phenotype of amnestic mild cognitive impairment and its progression.

Verbal memory depends on structural hippocampal subfield volume.

To investigate correlates in hippocampal subfield volume and verbal and visual memory function in patients with temporal lobe epilepsy (TLE), mild amnestic cognitive impairment (MCI) and heathy participants (HP). 50 right-handed participants were included in this study; 11 patients with temporal lobe epilepsy (TLE), 18 patients with mild amnestic cognitive impairment (MCI) and 21 healthy participants (HP). Verbal memory performance was evaluated via the verbal memory test (VLMT) and visual memory performance via the diagnosticum for cerebral damage (DCM). Hippocampal subfield volumes of T1-weighted Magnetic Resonance Imaging (MRI) scans were computed with FreeSurfer version 7.1. Stepwise correlation analyses were performed between the left hippocampal subfield volumes and learning, free recall, consolidation and recognition performance scores of the VLMT as well as between right hippocampal subfield volumes and visual memory performance. The volume of the left subicular complex was highly correlated to learning performance (β = 0.284; p = 0.042) and free recall performance in the VLMT (β = 0.434; p = 0.001). The volume of the left CA3 subfield showed a significant correlation to the consolidation performance in the VLMT (β = 0.378; p = 0.006) and recognition performance in the VLMT (β = 0.290; p = 0.037). There was no significant correlation identified between the right hippocampal subfields and the visual memory performance. The results of this study show verbal memory correlates with hippocampal subfields and support the role of left subiculum and left CA2/CA3 in verbal memory performance.

A metabolism-functional connectome sparse coupling method to reveal imaging markers for Alzheimer's disease based on simultaneous PET/MRI scans.

Abnormal glucose metabolism and hemodynamic changes in the brain are closely related to cognitive function, providing complementary information from distinct biochemical and physiological processes. However, it remains unclear how to effectively integrate these two modalities across distinct brain regions. In this study, we developed a connectome-based sparse coupling method for hybrid PET/MRI imaging, which could effectively extract imaging markers of Alzheimer's disease (AD) in the early stage. The FDG-PET and resting-state fMRI data of 56 healthy controls (HC), 54 subjective cognitive decline (SCD), and 27 cognitive impairment (CI) participants due to AD were obtained from SILCODE project (NCT03370744). For each participant, the metabolic connectome (MC) was constructed by Kullback-Leibler divergence similarity estimation, and the functional connectome (FC) was constructed by Pearson correlation. Subsequently, we measured the coupling strength between MC and FC at various sparse levels, assessed its stability, and explored the abnormal coupling strength along the AD continuum. Results showed that the sparse MC-FC coupling index was stable in each brain network and consistent across subjects. It was more normally distributed than other traditional indexes and captured more SCD-related brain areas, especially in the limbic and default mode networks. Compared to other traditional indices, this index demonstrated best classification performance. The AUC values reached 0.748 (SCD/HC) and 0.992 (CI/HC). Notably, we found a significant correlation between abnormal coupling strength and neuropsychological scales (p < .05). This study provides a clinically relevant tool for hybrid PET/MRI imaging, allowing for exploring imaging markers in early stage of AD and better understanding the pathophysiology along the AD continuum.

Head-to-Head Comparison of Two Plasma Phospho-tau Assays in Predicting Conversion of Mild Cognitive Impairment to Dementia.

Among blood biomarkers, phospho-tau181 (pTau181) is one of the most efficient in detecting Alzheimer disease across its continuum. However, transition from research to routine clinical use will require confirmation of clinical performance in prospective cohorts and evaluation of cofounding factors. Here we tested the Lumipulse assay for plasma pTau181 in mild cognitive impairment (MCI) participants from the Baltazar prospective cohort. We compared the performance of this assay to the corresponding Simoa assay for the prediction of conversion to dementia. We also evaluated the association with various routine blood parameters indicative of comorbidities. Lumipulse and Simoa gave similar results overall, with hazard ratios for conversion to dementia of 3.48 (95% CI, 2.23-5.45) and 3.70 (95%CI, 2.39-5.87), respectively. However, the 2 tests differ somewhat in terms of the patients identified, suggesting that their use may be complementary. When combined with age, sex, and apolipoprotein E (APOE)ε4 status, areas under the curves for conversion detection were 0.736 (95% CI, 0.682-0.791) for Lumipulse and 0.733 (95% CI, 0.679-0.788) for Simoa. Plasma pTau181 was independently associated with renal dysfunction (assessed by creatinine and glomerular filtration) for both assays. Cardiovascular factors (adiponectin and cholesterol), nutritional, and inflammatory markers (total protein content, C-reactive protein) also impacted plasma pTau181 concentration, although more so with the Simoa than with the Lumipulse assay. Plasma pTau181 measured using the fully automated Lumipulse assay performs as well as the Simoa assay for detecting conversion to dementia of MCI patients within 3 years and Lumipulse is less affected by comorbidities. This study suggests a pathway to routine noninvasive in vitro diagnosis-approved testing to contribute to the management of Alzheimer disease. NCT01315639.

Optimal Weighting of Preclinical Alzheimer's Cognitive Composite (PACC) Scales to Improve their Performance as Outcome Measures for Alzheimer's Disease Clinical Trials.

Cognitive composite scales constructed by combining existing neuropsychometric tests are seeing wide application as endpoints for clinical trials and cohort studies of Alzheimer's disease (AD) predementia conditions. Preclinical Alzheimer's Cognitive Composite (PACC) scales are composite scores calculated as the sum of the component test scores weighted by the reciprocal of their standard deviations at the baseline visit. Reciprocal standard deviation is an arbitrary weighting in this context, and may be an inefficient utilization of the data contained in the component measures. Mathematically derived optimal composite weighting is a promising alternative. Sample size projections using standard power calculation formulas were used to describe the relative performance of component measures and their composites when used as endpoints for clinical trials. Power calculations were informed by (n=1,333) amnestic mild cognitive impaired participants in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. A composite constructed using PACC reciprocal standard deviation weighting was both less sensitive to change than one of its component measures and less sensitive to change than its optimally weighted counterpart. In standard sample size calculations informed by NACC data, a clinical trial using the PACC weighting would require 38% more subjects than a composite calculated using optimal weighting. These findings illustrate how reciprocal standard deviation weighting can result in inefficient cognitive composites, and underscore the importance of component weights to the performance of composite scales. In the future, optimal weighting parameters informed by accumulating clinical trial data may improve the efficiency of clinical trials in AD.

Exploratory Assessment of Proteomic Network Changes in Cerebrospinal Fluid of Mild Cognitive Impairment Patients: A Pilot Study.

(1) Background: Despite the existence of well-established, CSF-based biomarkers such as amyloid-β and phosphorylated-tau, the pathways involved in the pathophysiology of Alzheimer's disease (AD) remain an active area of research. (2) Methods: We measured 3072 proteins in CSF samples of AD-biomarker positive mild cognitive impairment (MCI) participants (n = 38) and controls (n = 48), using the Explore panel of the Olink proximity extension assay (PEA). We performed group comparisons, association studies with diagnosis, age, and APOE ε4 status, overrepresentation analysis (ORA), and gene set enrichment analysis (GSEA) to determine differentially expressed proteins and dysregulated pathways. (3) Results: GSEA results demonstrated an enrichment of granulocyte-related and chemotactic pathways (core enrichment proteins: ITGB2, ITGAM, ICAM1, SELL, SELP, C5, IL1A). Moreover, some of the well-replicated, differentially expressed proteins in CSF included: ITGAM, ITGB2, C1QA, TREM2, GFAP, NEFL, MMP-10, and a novel tau-related marker, SCRN1. (4) Conclusion: Our results highlight the upregulation of neuroinflammatory pathways, especially chemotactic and granulocyte recruitment in CSF of early AD patients.

Cognitive, clinical and genetic characterization of dementia in Cali, Colombia: A pilot study in a diverse population

AbstractBackgroundThe aging population and the prevalence of dementia are rapidly growing in Latin America. People with dementia are underdiagnosed and not well characterized in this region. The scenario is complicated by limited options for culturally proper testing and Latinos' socio‐biological and phenotypic diversity, which affect dementia presentation. In Cali, frontotemporal dementia (FTD) is misdiagnosed as a psychiatric disorder in &gt;70% of cases. Delay in the accurate diagnosis and misdiagnosis of dementia affects genetic counseling, treatment, prognosis, and caregiver burden. Furthermore, most of the discovery efforts in genetics are based on data from populations of European ancestry. This bias in representation can exacerbate existing disease and healthcare disparities. Innovative technology for neuropsychological assessment could help make an early and accurate diagnosis. Genetic analysis is novel in this region, and the proposed work lays the basis for the genomic studies we advocate for.MethodWe will evaluate the accuracy of the TabCAT cognitive tests for the identification of cognitive impairment in participants previously diagnosed with FTD (N = 20), AD (N = 20), and healthy controls (N = 40). We also will assess the NPI. In addition, we will collect family history information for neurodegenerative diseases, genome sequencing of the sample.ResultWe hypothesize that the TabCAT evaluation will show sensitivity and specificity &gt;.80 for detecting cognitive impairment, exceeding the accuracy of standard cognitive screenings, such as the Montreal Cognitive Assessment (MoCA). The assessment will be similarly accurate for detecting cognitive impairment in AD and bvFTD, each separately compared to controls. For participants with bvFTD, the NPI will improve the classification of bvFTD from controls and AD, above and beyond the cognitive tests. We hypothesize that 10‐20% of the participants will have a family history of dementia and be identified with genetic risk for neurodegenerative diseases.ConclusionThis pilot lays the groundwork to establish a new site for ReDLat, a consortium of multiple partners to expand dementia research in Latin America and the Caribbean. Assessing this underrepresented population, we will contribute to an accurate characterization of dementia in Colombia, which will improve dementia diagnosis and reduce health inequities in this region.