Subjective Cognitive Decline Participants Research Articles

Physical Activity Component of the Greek Interventional Geriatric Study to Prevent Cognitive Impairment and Disability (GINGER): Protocol Development and Feasibility Study

Background/Objectives: Individuals with subjective cognitive decline (SCD) have an increased risk of developing dementia, while non-pharmacological multicomponent lifestyle interventions are recommended for prevention/management. The Greek Interventional Geriatric Initiative to Prevent Cognitive Impairment and Disability (GINGER) is such a multicomponent approach, encompassing simultaneous interventions (cognitive training, depression and sleep management, etc.). Exercise/Physical activity (PA) is suggested as one such intervention. This study (i) presents the exercise protocol developed for GINGER and (ii) explores its feasibility (acceptability, applicability, adherence, users’ satisfaction and reliability). Methods: Exercise/PA protocol development, targeting SCD individuals aged > 55 years, utilized relevant guidelines/literature followed by focus group involving exercise specialists. Data were synthesized through consensus to design optimal exercise interventions prescribed on participant’s physical capacity (heart rate, exertion, etc.), comprising 6-month combined aerobic, strengthening, balance and dual-task exercises, delivered 3 times/weekly in two group-based supervised sessions (in-person and online) and one home-based session. Physical outcomes include balance, aerobic capacity [2-Minute Walk Test (2 MWT), IPAQ-7], strength [Hand Grip Strength (HGS), Sit-to-Stand], fear of falling. Eligibility for entering intervention is low IPAQ-7, 2 MWT or HGS scoring. Feasibility was explored with adherence (exercise diaries and Exercise Adherence Rating Scale) and satisfaction (Patient Satisfaction Questionnaire) Results: Intervention was easily delivered with good reliability across testers’ assessments on 13 SCD participants (ICCs = 0.62–0.99), and improved physical outcomes, whereas users’ adherence and satisfaction scored highly. Conclusions: The exercise protocol for SCD was feasible, acceptable, applicable, reliable, demonstrating adherence and satisfaction, while improving physical parameters. It is thus integrated in the GINGER study, where multiple simultaneous interventions will take place to prevent/enhance cognitive function.

CSF neurogranin levels as a biomarker in Alzheimer’s disease and frontotemporal lobar degeneration: a cross-sectional analysis

BackgroundThere is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer’s disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum.MethodsParticipants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism.ResultsNg levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p < .001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p = .029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p = .034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p = .001) and AD-dementia (F[1, 100] = 20.90, p < .001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p = .491) or FTLD-dementia (F[1, 62]= 2.27, p = .051). The main effect of diagnosis across the diagnostic subgroups on Aβ1−42/Ng ratio was significant too (F[4, 263]=, p < .001). We found a non-significant association between Ng levels and memory scores overall (β=-0.25, p = .154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (β=-0.32, p = .358).ConclusionsIn this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aβ1−42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits.

Two-Year Longitudinal Outcomes of Subjective Cognitive Decline in Hispanics Compared to Non-hispanic Whites.

Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW). Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance. Hispanics were at increased risk of progression to MCI (OR: 6.10, 95% CI 1.09-34.20, P = .040). Hispanic participants endorsed more depressive symptoms at baseline (P = .048) that worsened more longitudinally (OR: 3.16, 95% CI 1.18-8.51, P = .023). Hispanic participants had increased SCD complaints on the Brief Cognitive Rating Scale (BCRS) (β = .40 SE: .17, P = .023), and in specific BCRS domains: concentration (β = .13, SE: .07, P = .047), past memory (β = .13, SE: .06, P = .039) and functional abilities (β = .10, SE: .05, P = .037). In objective cognitive performance, Hispanic ethnicity associated with decline in MMSE (β = -.27, SE: .13, P = .039), MoCA (β = -.80 SE: .34, P = .032), Trails A (β = 2.75, SE: .89, P = .002), Trails B (β = 9.18, SE: 2.71, P = .001) and Guild Paragraph Recall Delayed (β = -.80 SE: .28, P = .005). Conclusions: Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group.

Diffusion imaging markers of accelerated aging of the lower cingulum in subjective cognitive decline.

Alzheimer's Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.

Predicting progression of cognitive decline to dementia using dyadic patterns of subjective reporting: evidence from the CompAS longitudinal study.

To analyze the validity of self and informant reports, depressive symptomatology, and some sociodemographic variables to predict the risk of cognitive decline at different follow-up times. A total of 337 participants over 50 years of age included in the CompAS and classified as Cognitively Unimpaired (CU), Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) groups were assessed at baseline and three follow-ups. A short version of the QAM was administered to assess the severity of subjective cognitive complaints (SCCs), and the GDS-15 was used to evaluate the depressive symptoms. At each follow-up assessment, participants were reclassified according to the stability, regression or progression of their conditions. Logistic regression analysis was used to predict which CU, SCD and MCI participants would remain stable, regress or progress at a 3rd follow-up by using self- and informant-reported complaints, depressive symptomatology, age and education at baseline and 2nd follow-ups as the predictive variables. Overall, self-reported complaints predicted progression between the asymptomatic and presymptomatic stages. As the objective deterioration increased, i.e., when SCD progressed to MCI or dementia, the SCCs reported by informants proved the best predictors of progression. Depressive symptomatology was also a predictor of progression from CU to SCD and from SCD to MCI. A late increase in self-reported complaints make valid estimates to predict subjective decline at asymptomatic stages. However, an early increase in complaints reported by informants was more accurate in predicting objective decline from asymptomatic stages. Both, early and late decrease in self-reported complaints successfully predict dementia from prodromic stage. Only late decrease in self-reported complaints predict reversion from prodromic and pre-symptomatic stages.

Associations between Informant-Reported Cognitive Complaint and Longitudinal Cognitive Decline in Subjective Cognitive Decline A 7-Year Longitudinal Study.

This study aimed to determine the predictive values of informant-reported memory decline (IMD) among subjective cognitive decline (SCD) older adults from a 7-year community-based cohort study. Ninety SCD participants were included. Demographic data and neuropsychological test scores at both baseline and 7-year follow-up were collected. Differences between SCD with IMD (+IMD) and SCD without IMD (-IMD) were compared. Logistic regression models were used to determine whether baseline IMD could predict diagnostic outcomes at 7-year follow-up. Forty-one percent of SCD adults had IMD. At baseline, the +IMD group showed more depressive symptoms (p = 0.016) than the -IMD group. Furthermore, the Beijing-version Montreal Cognitive Assessment (MoCA), Digit Span Test-Forward, Visual Matching and Reasoning, and Wechsler Adult Intelligence Scale-RC Picture Completion (WAIS-PC) scores in the +IMD group were significantly lower than those in the -IMD group. Fifty-four percent of +IMD participants converted to mild cognitive impairment (MCI) or dementia at follow-up, and 22.6% of the -IMD participants converted to MCI. Follow-up Mini-Mental State Examination, MoCA, and Verbal Fluency Test scores of the +IMD group were significantly lower than those in the -IMD group. The +IMD group was more likely to progress to cognitive impairment at 7-year follow-up (OR = 3.361, p = 0.028). SCD participants with +IMD may have poorer cognition and are more likely to convert to cognitive impairment over time. Our long-term follow-up study confirmed the importance of informants' perceptions of SCD, which can help clinicians identify individuals at risk of cognitive decline.

P153: The CIMA-Q and CompAS cohort studies on factors associated with Alzheimer's disease (AD): Exploring sociodemographic, health and neuropsychological profile of Subjective Cognitive Decline (SCD) participants from two culturally differentiated samples.

Objective:To explore commonalities and differences in the sociodemographic, health, and neuropsychological characteristics of participants with SCD recruited in two culturally differentiated cohort studies, namely CIMA-Q (Canada; Bellevile et al., 2019) and CompAS (Spain; Juncos et al., 2012).Methods:Older adults with subjective cognitive complaints of the CompAS (N=251; 68.92% women; Control: 30.3%; SCD: 25.9%; MCI: 28.7%) and the CIMA-Q (N=179; 71.5% women; Control:16.1%; SCD: 36.8%; MCI:28.6%) were recruited, respectively, from primary care centers and memory clinics, excluding patients with dementia and other neurological or psychiatric disturbances. Cognitive complaints were assessed considering coincident items of the QAM and MFE questionnaires. Cut-off points for the 5%ile were calculated independently in both samples and according to this, participants were classified as SCD or controls (CompAS: N= 141; CIMA-Q: N=161) considering complaints relevance at baseline (Pereiro et al., 2021). Participants underwent neuropsychological assessment. Participants diagnosed as Mild Cognitive Impairment (MCI) were excluded from the analysis. Between cohort-studies and inter-group (control, SCD) differences were tested in the sociodemographic, health and neuropsychological measures considered. The Holm-Bonferroni correction was applied to reduce the probability of type I error (p&lt;.003).Results:Identical cut-off points for 5%ile were obtained in both samples though SCD prevalence was slightly higher in CIMA-Q. For both samples, equivalence between Control and SCD participants in sociodemographic, health, functionality, and neuropsychological measures was observed. Only complaints and depressive symptomatology was significantly higher in SCD participants than in controls in both CompAS and CIMA-Q studies.Participants of the CIMA-Q, Controls and SCD, showed significantly higher age, cognitive reserve proxies, comorbidity, and better attentional performance than the CompAS participants (see Table 1). CompAS participants, Controls and SCD, showed more neuropsychiatric symptomatology than CIMA-Q participants (see Table 1).Conclusions:Control and SCD participants showed equivalence on sociodemographic, health, functional, and neuropsychological measures in both studies. However, significant between-sample differences in the two groups, particularly in SCD participants, were observed in sociodemographic, health, cognitive reserve, behavioral and attentional measures. Identification of these factors are critical to analyze the transcultural validity of cognitive complaints in predicting progression to AD.Table 1Between group (control, SCD) and Between study (CIMA-Q, CompAS) differences in sociodemographic, health, and cognitive measuresCIMA-QCompASBetween-studies differencesBetween-group differencesBetween-group differencesControlSCDSociodemographicsAgeNSNSCIMA-Q&gt;CompAS; F(1,124)=22.78; p&lt;.001CIMA-Q&gt;CompAS; F(1,172)=36.97; p&lt;.001GenderNSNSNSNSSchooling (years)NSNSNSCIMA-Q&gt;CompAS; F(1,172)=20.74; p&lt;.001Prof. qualificationNSNSCIMA-Q&gt;CompAS; χ24=18.18; p=001CIMA-Q&gt;CompAS; χ24=33.95; p&lt;001Cognitive reserve (quartiles)NSNSCIMA-Q&gt;CompAS; χ23=13.57; p=004CIMA-Q&gt;CompAS;χ23==42.56; p&lt;001Memory familiar antecedentsNSNSNSCIMA-Q&gt;CompAS; χ21==15.03; p&lt;001NeuropsychologySubjective complaints*SCD&gt;Control; F(1,119)=147.17, p&lt;.001)SCD&gt;Control; F(1,177)=192.87, p&lt;.001NSNSCharlson Index*SCD&gt;Control; F(1,115)=5.29, p=.023NSCIMA-Q&gt;CompAS; F(1,123)=394.96; p&lt;.001CIMA-Q&gt;CompAS; F(1,168)=335.98; p&lt;.001General cognitionNS (MoCA)NS (CAMCOG-R)----GDS-15*SCD&gt;Control; F(1,119)=8.60, p=.004SCD&gt;Control; F(1,176)=11.97, p&lt;.001NSNSTMT-A (secs.)*NSNSNSNSTMT-B (secs.)*NSNSCompAS&gt;CIMA-Q; F(1,118)=12.56; p&lt;.001CompAS&gt;CIMA-Q; F(1,163)=21.74; p&lt;.001Verbal fluencyNSNSNSNSSemantic fluencyNSNSNSNSBoston testNSNSNSNSNPI-QNSNSCompAS&gt;CIMA-Q; F(1,119)=16.68; p&lt;.001CompAS&gt; CIMA-Q; F(1,162)=24.46; p&lt;.001Immediate recall (RAVL test)NSNSNSNSShort delay (RAVL test)NSNSNSNSLong delay(RAVL test)NSNSNSNSIntrusions (RAVL test)NSNSNSNSIAVD*NSNSNSNSNote: *On these measures, higher scores denote worse cognition or health condition. TMT: Trail Making Test (A and B forms); NPI-Q: Neuropsychiatric Inventory-Questionnaire; RAVL: Rey Auditory Verbal Learning; IAVD: Instrumental Activity of Daily Living.

Predicting progression within the cognitive decline continuum using self‐ and partner‐reported cognitive complaints, and depressive symptomatology in Cognitively Unimpaired (CU) and Subjective Cognitive Decline (SCD) participants: Evidence from the CompAS longitudinal study

AbstractBackgroundSelf‐, informant reports and also depressive symptoms can predict the risk of cognitive decline. Our aim was to study the joint contribution of complaint reporting and depression to progression along the cognitive decline continuum to dementia.MethodA total of 246 participants [Cognitively Unimpaired (CU): n = 144; Subjective Cognitive Decline (SCD): n = 102] over 50 years from the Compostela Aging Study (CompAS) were assessed at baseline and at three follow‐ups (intervals 18‐24 months). A short version of the QAM was administered to assess severity of complaints. At each follow‐up assessment participants were reclassified according to stability or progression. Logistic regressions were performed to predict stable and progressing CU and SCD participants at 3rd follow‐up by using self‐, informant‐ reports, agreement, and depressive symptomatology as predictive variable at baseline, 1st and 2nd follow‐ups s.ResultsFor CU participants, (a) complaints at baseline predicted progression to SCD by the informant‐report, and to MCI by the self‐informant agreement; (b) complaints at 1st follow‐up predicted progression to SCD or MCI by the self‐report; (c) complaints at 2nd follow‐up predicted progression to SCD by the self‐report and the depressive symptomatology. For SCD participants, progression to MCI and/or dementia was only predicted by the informant‐report at 2nd follow‐up.ConclusionsFor CU participants, self‐report was the best predictor of progression to SCD and/or MCI from the 1st follow‐up. Regards SCD participants, only informant´s report was able to predict the progression to MCI and/or dementia by the end of the follow‐up.

Impact of White Matter Hyperintensities on domain‐specific cognition in Southeast Asians

AbstractBackgroundDementia affects 55 million people worldwide, with 60% of the burden in Asia. White Matter Hyperintensities (WMH) is a key marker of small vessel disease, with high prevalence in Asian populations with prodromal and clinical dementia. WMH is described as: Deep White Matter Hyperintensities (DWMH), Periventricular Hyperintensities (PVH) or Fazekas‐Total (DWMH and PVH).However, association between WMH topography and performance in specific cognitive domains remains unexplored. Thus, this study aims to characterise the impact of Fazekas‐Total, DWMH and PVH on different cognitive domains.Method304 participants (mean age 60.6, mean education years 14.2, mean Montreal Cognitive Assessment 25.99, 43.8% males) from Biomarkers and Cognition Study, Singapore (Dementia Research Centre (Singapore)) met the inclusion criteria.Eight domains of cognition were tested: global cognition, learning and memory, language, executive function, complex‐attention, perceptual‐motor, social‐cognition, and processing speed.Normality tests, correlation analysis and stepwise regression (with Benjamini and Hochberg False Discovery Rate correction) were performed to understand association between Fazekas‐Total, DWMH, PVH on domains of cognition tested, accounting for age, education, and gender.Two approaches were used for data analysis: (1) by grouping participants as Mild Cognitive Impairment (MCI), Subjective Cognitive Decline (SCD) and Cognitively Normal (CN) as per the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria and (2) by grouping participants’ WMH as confluent (DWMH ≥2 and PVH ≥3) and non‐confluent.ResultHigher Fazekas‐Total was associated with slower processing speed (p = 0.0255, R = ‐0.039) in prodromal participants (MCI and SCD). Higher PVH was associated with slower processing speed in MCI (p = 0.017, R = ‐0.32) and CN (p = 0.017, R = ‐0.663) participants. Higher PVH was significantly associated with poorer learning and memory (p = 0.045, R = ‐0.043) in SCD participants. Higher DWMH was significantly associated with poorer learning and memory (p = 0.017, R = ‐0.765) in CN participants.ConclusionThese results demonstrate differential association between PVH, DWMH and cognitive domains, thus the location of WMH determines the affected cognitive domains. Therefore, it is worthwhile to assess PVH and DWMH in clinical cognitive outcomes separately and to understand the upstream pathobiology of DWMH and PVH.Furthermore, higher Fazekas‐Total was strongly associated with slower processing speed in prodromal participants and could be a marker of cognitive decline.

Follow-up Comparisons of Two Plasma Biomarkers of Alzheimer's Disease, Neurofilament Light Chain, and Oligomeric Aβ: A Pilot Study.

Recent evidence suggests that blood-based biomarkers might be useful for Alzheimer's disease (AD). Among them, we intend to investigate whether neurofilament light (NfL) and multimer detection system-oligomeric Aβ (MDS-OAβ) values can be useful in screening, predicting, and monitoring disease progression and how the relationship between NfL and MDS-OAβ values changes. Eighty participants with probable AD dementia, 50 with mild cognitive impairment (MCI), and 19 with subjective cognitive decline (SCD) underwent baseline and follow-up evaluations of the Mini-Mental Status Examination (MMSE) and both plasma biomarkers. Baseline MDS-OAß (p = 0.016) and NfL (p = 0.002) plasma concentrations differed significantly among groups, but only NfL correlated with baseline MMSE scores (r = -0.278, p = 0.001). In follow-up, neither correlated with MMSE changes overall. However, in SCD and MCI participants (n = 32), baseline MDS-OAß correlated with follow-up MMSE scores (r = 0.532, p = 0.041). Linear regression revealed a relationship between baseline MDS-OAβ and follow-up MMSE scores. In SCD and MCI participants, plasma NfL changes correlated with MMSE changes (r = 0.564, p = 0.028). This study shows that only in participants with SCD and MCI, not including AD dementia, can MDS-OAß predict the longitudinal cognitive decline measured by follow-up MMSE. Changes of NfL, not MDS-OAß, parallel the changes of MMSE. Further studies with larger samples and longer durations could strengthen these results..

Extended FNAME performance is preserved in subjective cognitive decline but highly affected in amnestic mild cognitive impairment.

The cognitive characterization of Alzheimer's disease risk states, such as amnestic mild cognitive impairment (aMCI) and subjective cognitive decline (SCD), is fundamental for timely diagnosis and interventions. The Face Name Associative Memory Exam (FNAME) is sensitive to early Alzheimer's disease brain changes, and an extended version captures a fuller range of associative memory abilities. We aimed to assess group effects in the extended FNAME in older adults with SCD, aMCI, and older adult controls (CON). Two concurrently created versions of the extended FNAME were used to test three groups of older adults (CON = 35, SCD = 37, aMCI = 31) at two sites (Mexico = 59, Netherlands = 44). Extended FNAME memory abilities were analyzed in five analyses of variance. Group and site were considered as independent variables. For the recall ability, subtest levels were entered as a within-subject variable. The remaining abilities (Face Recognition, Name Recognition, Spontaneous Name Recall, and Face-Name Matching) were analyzed in independent models. In all models, the main effect for group was significant with large effect sizes, driven by a worse performance of aMCI participants. No significant differences were found between SCD and CON. The main effect for site was only significant in Face Recognition. The worse performance of aMCI in the extended FNAME implies an impairment in associative memory abilities beyond recall. The similar performance of CON and SCD might be explained by the recruitment of SCD participants that did not spontaneously seek help for memory decline. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Validation of an Automated Speech Analysis of Cognitive Tasks within a Semiautomated Phone Assessment

Introduction: We studied the accuracy of the automatic speech recognition (ASR) software by comparing ASR scores with manual scores from a verbal learning test (VLT) and a semantic verbal fluency (SVF) task in a semiautomated phone assessment in a memory clinic population. Furthermore, we examined the differentiating value of these tests between participants with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We also investigated whether the automatically calculated speech and linguistic features had an additional value compared to the commonly used total scores in a semiautomated phone assessment. Methods: We included 94 participants from the memory clinic of the Maastricht University Medical Center+ (SCD N = 56 and MCI N = 38). The test leader guided the participant through a semiautomated phone assessment. The VLT and SVF were audio recorded and processed via a mobile application. The recall count and speech and linguistic features were automatically extracted. The diagnostic groups were classified by training machine learning classifiers to differentiate SCD and MCI participants. Results: The intraclass correlation for inter-rater reliability between the manual and the ASR total word count was 0.89 (95% CI 0.09–0.97) for the VLT immediate recall, 0.94 (95% CI 0.68–0.98) for the VLT delayed recall, and 0.93 (95% CI 0.56–0.97) for the SVF. The full model including the total word count and speech and linguistic features had an area under the curve of 0.81 and 0.77 for the VLT immediate and delayed recall, respectively, and 0.61 for the SVF. Conclusion: There was a high agreement between the ASR and manual scores, keeping the broad confidence intervals in mind. The phone-based VLT was able to differentiate between SCD and MCI and can have opportunities for clinical trial screening.

Validation of the ki:e SB‐C a Novel Digital Speech Biomarker for Cognition in a Dutch Memory Clinic Population

AbstractBackgroundProgressive cognitive decline is the cardinal behavioral symptom in most dementia‐causing diseases such as Alzheimer’s disease. Whereas classic neuropsychological tests often have excellent psychometric properties to measure cognitive decline in dementia, there are scenarios in which they are less suitable. Speech‐based digital biomarkers can be deployed remotely and extracted in a highly automated fashion allowing solutions to scale. We present the validation of a novel digital Speech Biomarker for Cognition (SB‐C) in a Dutch memory clinic population containing patients with Mild Cognitive Impairment (MCI) and age‐ as well as education‐matched participants with Subjective Cognitive Decline (SCD).MethodThe ki:e SB‐C is a novel speech‐based cognitive composite score. The presented validation results are based on a sample that was not used when developing the SB‐C. Validation data has been collected from two age‐ and education‐matched groups: Normal Cognition but subjective cognitive decline (SCD; n = 48, 15 F), MCI (n = 48, 18 F). We automatically extract the SB‐C from SVF and AVLT speech recordings using our proprietary speech analysis pipeline including automatic speech recognition and feature extraction. Recordings were collected from a Dutch memory clinic population containing MCI and SCD participants. We performed (1) analytical and (2) clinical validation. For (1) we performed Spearman rank correlation between SB‐C score and anchor score Mini Mental State Examination (MMSE) to show that the algorithm is correctly measuring the concept of interest cognition. For (2) we performed a non‐parametric Kruskal‐Wallis test to compare SB‐C scores of both NC and MCI groups.ResultThe biomarker score SB‐C and MMSE were strongly correlated (r = 0.61, p &lt; 0.001), such that lower MMSE scores are reflected in lower biomarker scores (compare also figure 1). Additionally, there was a very significant group difference for the SB‐C biomarker score between the NC and MCI group (NC &gt; MCI; χ2 = 26.461 (1), p &lt; 0.001).ConclusionThe ki:e SB‐C is a reliable score for cognition, showing convergent validity with the MMSE and separating well between MCI and SCD populations. The availability of valid digital speech biomarkers for cognition has great potential for decentralized clinical trials in dementia aetiologies and beyond.

Associations between the glial marker myo‐inositol measured by 7T MRS and other AD‐relevant measures

AbstractBackgroundMyo‐inositol (MI) is a presumed marker for glial activation which can be quantified by non‐invasive Magnetic Resonance Spectroscopy (MRS) and is suspected to be elevated in early Alzheimer’s disease (AD). In the framework of the NeuroMET2 project, we investigated the relationship between MI and other AD‐relevant measures.MethodsAbsolute concentrations of MI were measured by 7 tesla MRS in the posterior cingulate cortex (PCC)/precuneus of 26 cognitively healthy individuals (HC), 23 patients with subjective cognitive decline (SCD), 23 with mild cognitive impairment (MCI) and 24 with dementia due to suspected AD. Using linear models, MI’s association with memory ability (NeuroMET Memory Metric), volumes of the hippocampus and PCC/precuneus, and seed‐based functional connectivity were investigated. Interaction terms involving the apolipoprotein E (APOE) ε4 allele were analyzed additionally. All models were adjusted to age and education and weighted based on Cramér‐Lao lower bounds.ResultsAbsolute MI concentrations were substantially elevated in AD patients (adjusted mean [95% CI]=8.5 mmol/l [7.8; 9.3]). However, there were no relevant differences between SCD (6.7 mmol/l [6.0; 7.3]) or MCI (7.5 mmol/l [6.8; 8.2]) and participants of the HC group (7.2 mmol/l [6.6, 7.9]). Across the whole cohort, higher levels of MI were associated with lower memory ability (ß [95% CI]=‐0.31 [‐0.44; ‐0.17], std. ß=‐0.40, p&lt;0.001), smaller hippocampus volume (ß=‐59.89 [‐131.40; 11.62], std. ß=‐0.16, p=0.100) and lower seed‐based functional connectivity (ß=‐3948.41 [‐6480.69; ‐1416.13], std. ß=‐0.34, p=0.003). There was no relevant effect between MI and PCC/precuneus volume (ß=83.27 [‐117.89; 284.43], std. ß=0.08, p=0.413). Finally, there was no substantial mediation effect of APOE ε4 carriership on the association between MI and neither memory ability (ß=0.09 [‐0.18; 0.36], std. ß=0.37, p=0.519), hippocampus volume (ß=‐55.60 [‐223.48; 112.29], std. ß=‐0.45, p=0.511), PCC/precuneus volume (ß=‐110.68 [‐546.22; 324.86], std. ß=‐0.32, p=0.614) nor seed‐based functional connectivity (ß=2009.46 [‐4207.40; 8226.32], std. ß=0.55, p=0.520).ConclusionsAcross a cohort with participants ranging from healthy to AD, we showed that glial activation, measured by MI concentration, was associated with key AD‐related processes. The potential of MI as a non‐invasive biomarker for increasing memory impairment in pre‐dementia stages remains to be explored in longitudinal studies.

Assessment of Social Behavior Using a Passive Monitoring App in Cognitively Normal and Cognitively Impaired Older Adults: Observational Study

BackgroundIn people with cognitive impairment, loss of social interactions has a major impact on well-being. Therefore, patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone apps, which measure social behavior passively and objectively.ObjectiveThis study uses the remote monitoring smartphone app Behapp to assess social behavior, and aims to investigate (1) the association between social behavior, demographic characteristics, and neuropsychiatric symptoms in cognitively normal (CN) older adults, and (2) if social behavior is altered in cognitively impaired (CI) participants. In addition, we explored in a subset of individuals the association between Behapp outcomes and neuropsychiatric symptoms.MethodsCN, subjective cognitive decline (SCD), and CI older adults installed the Behapp app on their own Android smartphone for 7 to 42 days. CI participants had a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer-type dementia. The app continuously measured communication events, app use and location. Neuropsychiatric Inventory (NPI) total scores were available for 20 SCD and 22 CI participants. Linear models were used to assess group differences on Behapp outcomes and to assess the association of Behapp outcomes with the NPI.ResultsWe included CN (n=209), SCD (n=55) and CI (n=22) participants. Older cognitively normal participants called less frequently and made less use of apps (P<.05). No sex effects were found. Compared to the CN and SCD groups, CI individuals called less unique contacts (β=–0.7 [SE 0.29], P=.049) and contacted the same contacts relatively more often (β=0.8 [SE 0.25], P=.004). They also made less use of apps (β=–0.83 [SE 0.25], P=.004). Higher total NPI scores were associated with further traveling (β=0.042 [SE 0.015], P=.03).ConclusionsCI individuals show reduced social activity, especially those activities that are related to repeated and unique behavior, as measured by the smartphone app Behapp. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with Behapp. This research shows that the Behapp app is able to objectively and passively measure altered social behavior in a cognitively impaired population.

Effect of acupuncture on gut microbiota in participants with subjective cognitive decline.

A close relationship has recently been described between subjective cognitive decline (SCD) and gut microbiota disorders. Herein, we aim to investigate the effect of electroacupuncture (EA) on gut microbiota in participants with SCD.We conducted a study of 60 participants with SCD. Sixty participants were allocated to either EA group (n = 30) or sham acupuncture group (n = 30). Both groups received 24 sessions of real acupuncture treatment or identical treatment sessions using the placebo needle. Global cognitive change based on a comprehensive neuropsychological test battery was evaluated to detect the clinical efficacy of acupuncture treatment at the baseline and the end of treatment. Faecal microbial analyses were carried out after collecting stools at T0 and T12 weeks. Microbiomes were analyzed by 16S ribosomal RNA gene sequencing. Correlation analyses were performed to investigate the relationships between the changes in gut microbiota and symptom improvement.Age is a particularly important factor leading to the severity of dementia. Compared with sham acupuncture group, the number of Escherichia–Shigella in EA group decreased after treatment. The number of Escherichia–Shigella in EA group decreased after treatment compared with EA group before treatment. Bifidobacterium is positively correlated with clinical efficacy Z-score and Montreal Cognitive Assessment Scale (both P < .005).Acupuncture could improve global cognitive change among SCD participants by regulating the intestinal flora. Dysbiosis was found in the gut microbiome in SCD and partially relieved by acupuncture. Our study suggests that gut microbiota could be a potential therapeutic target and diagnostic biomarker for SCD.

Difference in Amyloid Load Between Single Memory Domain and Multidomain Subjective Cognitive Decline: A Study from the SILCODE.

Subjective cognitive decline (SCD), an at-risk condition of Alzheimer's disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. We aim to explore the difference in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n = 34) and sd-SCD (n = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F = 5.033, p = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F = 12.309, p = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals.

Structural and Functional Abnormalities of Olfactory-Related Regions in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease.

BackgroundOdor identification (OI) dysfunction is an early marker of Alzheimer’s disease (AD), but it remains unclear how olfactory-related regions change from stages of subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to AD dementia.MethodsTwo hundred and sixty-nine individuals were recruited in the present study. The olfactory-related regions were defined as the regions of interest, and the grey matter volume (GMV), low-frequency fluctuation, regional homogeneity (ReHo), and functional connectivity (FC) were compared for exploring the changing pattern of structural and functional abnormalities across AD, MCI, SCD, and normal controls.ResultsFrom the SCD, MCI to AD groups, the reduced GMV, increased low-frequency fluctuation, increased ReHo, and reduced FC of olfactory-related regions became increasingly severe, and only the degree of reduced GMV of hippocampus and caudate nucleus clearly distinguished the 3 groups. SCD participants exhibited reduced GMV (hippocampus, etc.), increased ReHo (caudate nucleus), and reduced FC (hippocampus-hippocampus and hippocampus-parahippocampus) in olfactory-related regions compared with normal controls. Additionally, reduced GMV of the bilateral hippocampus and increased ReHo of the right caudate nucleus were associated with OI dysfunction and global cognitive impairment, and they exhibited partially mediated effects on the relationships between OI and global cognition across all participants.ConclusionStructural and functional abnormalities of olfactory-related regions present early with SCD and deepen with disease severity in the AD spectrum. The hippocampus and caudate nucleus may be the hub joining OI and cognitive function in the AD spectrum.

Despite heightened risk of cognitive decline, no evidence of local atrophy in people with subjective cognitive decline compared to normal controls in ADNI

AbstractBackgroundPeople with subjective cognitive decline (SCD) are at increased risk for developing Alzheimer’s disease (AD). SCD may thus be a very early clinical manifestations of AD. However, identifying which individuals with SCD will develop AD is difficult with current biomarker techniques. To predict whether someone with SCD will progress to AD, it is necessary to determine whether people with SCD display neurodegeneration in brain regions associated with AD.MethodWe included 1769 baseline and follow‐up MRI scans for 447 participants (177 normal controls, NC; 100 SCD; and 170 early mild cognitive impairment, eMCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). All scans were pre‐processed through a previously validated pipeline. Deformation‐based morphometry (DBM) was performed to examine the pattern of volumetric change over time. An atlas‐based approach was also used to examine mean volume differences for regions of interest (ROIs; lateral ventricles, entorhinal cortex, and amygdala from CerebrA atlas (Manera et al., 2020)) estimated by integrating the Jacobian of the deformation field within the ROI. A previously validated MRI analysis method (SNIPE) was used to determine volume and grading of the hippocampus (Coupe et al., 2012). We applied a linear mixed effects model for all analysis (volume ∼Diagnostic Group +Age +Sex +Amyloid Positivity +APOE e4 +Education +1|ID).ResultLongitudinal volume analysis showed slight atrophy in eMCI compared to NC and SCD. ROI analysis revealed that eMCI had smaller volumes than SCD and NC in the amygdala (NC &amp; SCD: p&lt;.001) and entorhinal cortex (NC: p&lt;.001; SCD: p=.01), and larger lateral ventricles (NC &amp; SCD: p=.01). SNIPE volume and grading analysis revealed that eMCI hippocampal volume differed from both NC and SCD (p&lt;.001). SCD and NC did not differ in any of the analyses. With respect to demographics, people with SCD had 2 years more education (p&lt;0.001) than eMCI and NC.ConclusionThe structural differences observed in eMCI may act as an early biomarker for AD. Although SCD participants’ brain volumes significantly differed from eMCI, they did not differ from NC. However, lack of SCD:NC differences may be due to confounds (e.g., greater education in SCD) within the sample.

Subjective cognitive decline is associated with higher anxiety and depression during the COVID‐19‒related confinement

BackgroundSubjective cognitive decline (SCD) is often related to affective symptoms and both predict cognitive decline. We investigated whether SCD status predicted higher anxiety/depression during the Covid19‐related confinement, along with amyloid positivity in cognitively unimpaired older adults.MethodWe included 205 participants from the ALFA+ study (Table 1). During the confinement, anxiety and depression (Hospital Depression and Anxiety scale, HADS), perceived stress (Perceived Stress Scale) and stress resilience (Brief Resilience Scale) were measured. Participants completed HADS, SCD‐Questionnaire, and underwent a [18F]flutemetamol‐PET scan on average 2.4 years before confinement (baseline). We ran linear analyses with (i) cross‐sectional HADS scores during the confinement as well as (ii) change from baseline to confinement (delta scores) as dependent variables. SCD and amyloid status (+/‐, defined with a Centiloid threshold of 12) and their interaction were considered as predictors, and demographics, APOE‐ε4 status, and baseline HADS (for longitudinal analyses) as covariates. In a second step, perceived stress and stress resilience were considered in the models among covariates.ResultTwenty‐seven percent (n=56) of the participants were classified as SCD and 12.7% as amyloid positive. When main effects were tested, both SCD (p=0.03) and amyloid positivity (p=0.003) were associated with higher HADS scores during confinement (Table 2a). Further, a significant SCD*amyloid interaction was observed (p=0.001) such that only SCD participants with an amyloid positive scan showed higher HADS scores (p=0.001). SCD participants showed higher perceived stress than non‐SCD participants (p=.044), but no differences were found in stress resilience (p=0.6). The inclusion of perceived stress and stress resilience as covariates reduced the SCD effect to a trend (p=0.06) but not the effect of amyloid (p=0.003). Longitudinal analyses with delta scores showed similar results for amyloid but not for SCD main effects (Table 2b). The amyloid*SCD interaction was also significant in longitudinal analyses (p=0.002) with amyloid status predicting an increase in HADS scores only in participants with SCD (p=0.003) (Fig. 1).ConclusionHaving SCD and being amyloid positive is synergistically related to increased anxiety/depression during the Covid19‐related confinement. Longitudinal studies are warranted to investigate the impact of higher confinement related anxiety/depression in the clinical prognosis of the SCD population.