Onset Of Mild Cognitive Impairment Research Articles

Trajectories of Occupational Cognitive Demands and Risk of Mild Cognitive Impairment and Dementia in Later Life: The HUNT4 70+ Study.

The cognitive reserve hypothesis posits that cognitively stimulating work delays the onset of mild cognitive impairment (MCI) and dementia. However, the effect of occupational cognitive demands across midlife on the risk of these conditions is unclear. Using a cohort study design, we evaluated the association between registry-based trajectories of occupational cognitive demands from ages 30-65 years and clinically diagnosed MCI and dementia in participants in the HUNT4 70+ Study (2017-19). Group-based trajectory modeling identified trajectories of occupational cognitive demands, measured by the routine task intensity (RTI) index (lower RTI indicates more cognitively demanding occupation) from the Occupational Information Network. Multinomial regression was implemented to estimate the relative risk ratios (RRRs) of MCI and dementia, after adjusting for age, sex, education, income, baseline hypertension, obesity, diabetes, psychiatric impairment, hearing impairment, loneliness, smoking status, and physical inactivity assessed at HUNT1-2 in 1984-1986 and 1995-1997. To handle missing data, we used inverse probability weighting to account for nonparticipation in cognitive testing and multiple imputation. Based on longitudinal RTI scores for 305 unique occupations, 4 RTI trajectory groups were identified (n = 7,003, 49.8% women, age range 69-104 years): low RTI (n = 1,431, 20.4%), intermediate-low RTI (n = 1,578, 22.5%), intermediate-high RTI (n = 2,601, 37.1%), and high RTI (n = 1,393, 19.9%). Participants in the high RTI group had a higher risk of MCI (RRR 1.74, 95% CI 1.41-2.14) and dementia (RRR 1.37, 95% CI 1.01-1.86), after adjusting for age, sex, and education compared with participants in the low RTI group. In a sensitivity analysis, controlling for income and baseline health-related factors, the point estimates were not appreciably changed (RRR 1.66, 95% CI 1.35-2.06 for MCI, and RRR 1.31, 95% CI 0.96-1.78 for dementia). People with a history of cognitively stimulating occupations during their 30s, 40s, 50s, and 60s had a lower risk of MCI and dementia older than 70 years, highlighting the importance of occupational cognitive stimulation during midlife for maintaining cognitive function in old age. Further research is required to pinpoint the specific occupational cognitive demands that are most advantageous for maintaining later-life cognitive function.

A non-linear relationship between blood pressure and mild cognitive impairment in elderly individuals: A cohort study based on the Chinese longitudinal healthy longevity survey (CLHLS).

Hypertension is an established risk factor for mild cognitive impairment (MCI) in elderly individuals. Nevertheless, the impact of different levels of blood pressure on the progression of MCI remains uncertain. This study aims to investigate the non-linear relationship between blood pressure and MCI in the elderly and detect the critical blood pressure threshold, thus, improving blood pressure management for individuals at high risk of MCI. Data was obtained from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) cohort. We chose normal cognitive elderly individuals who entered the cohort in 2014 for a 5-year follow-up to observe the progression of MCI. Subsequently, we utilized the Cox regression model to identify risk factors for MCI and conducted a Cox-based restricted cubic spline regression (RCS) model to examine the non-linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) with MCI, determining the critical blood pressure threshold for MCI progression. In the elderly population, female (HR = 1.489, 95% CI: 1.017-2.180), lacking of exercise in the past (HR = 1.714, 95% CI: 1.108-2.653), preferring animal fats (HR = 2.340, 95% CI: 1.348-4.061), increased age (HR = 1.061, 95% CI: 1.038-1.084), increased SBP (HR = 1.036, 95% CI: 1.024-1.048), and increased DBP (HR = 1.056, 95% CI: 1.031-1.081) were associated with MCI progression. After adjusting factors such as gender, exercise, preferred types of fats, and age, both SBP (P non-linear < 0.001) and DBP (P non-linear < 0.001) in elderly individuals exhibited a non-linear association with MCI. The risk of MCI rose when SBP exceeded 135mmHg and DBP was in the range of 80-88mmHg. However, when DBP exceeded 88mmHg, there was a declining trend in MCI progression, although the HR remained above 1. The identified critical blood pressure management threshold for MCI was 135/80mmHg. In this study, we discovered that risk factors affecting the progression of MCI in elderly individuals comprise gender (female), preferring to use animal fat, lack of exercise in the past, increased age, increased SBP, and increased DBP. Additionally, a non-linear relationship between blood pressure levels and MCI progression was confirmed, with the critical blood pressure management threshold for MCI onset falling within the prehypertensive range.

Empowerment-based cognitive behavioural therapy for insomnia in persons with mild cognitive impairment: A sequential explanatory mixed-method pilot study.

Insomnia is an emerging risk factor for the onset of mild cognitive impairment (MCI) and its progression to dementia. Impaired cognition and neuropsychiatric symptoms create challenges for persons with MCI to participate actively in non-pharmacological interventions. This study examined the feasibility and preliminary effects of empowerment-based cognitive-behavioural therapy for insomnia (CBT-I) on sleep, cognitive function, and health-related quality of life (HRQoL) in persons with MCI and sleep problems. Sixty participants were randomly allocated to the intervention or control group to receive empowerment-based CBT-I or usual care, respectively. The 12 week intervention comprised all core CBT-I techniques delivered through a group and individualised face-to-face approach. An empowerment approach with interactive teaching methods, goal setting, and action planning was used to deliver the intervention. Outcome measures included subjective and objective sleep quality and pattern, and a battery of neuropsychological tests and the 12-item Short Form Survey were administered 3 months (T1) and 6 months post-randomisation (T2). This intervention is feasible and highly acceptable for persons with MCI. The intervention group showed significant improvements in subjective and objective sleep-related outcomes compared with the control group. Moreover, the intervention group showed greater improvements in global cognition, processing speed, attention, and mental flexibility than the control group at T1 and/or T2. No significant between-group differences were observed in memory or HRQoL scores. The qualitative data converged with the quantitative data. In conclusion, empowerment-based CBT-I was well received by persons with MCI and had potential positive effects on improving sleep and cognition in this cohort.

Alterations in hippocampus-centered morphological features and function of the progression from normal cognition to mild cognitive impairment

Mild cognitive impairment (MCI) is a significant precursor to dementia, highlighting the critical need for early identification of individuals at high risk of MCI to prevent cognitive decline. The study aimed to investigate the changes in brain structure and function before the onset of MCI. This study enrolled 19 older adults with progressive normal cognition (pNC) to MCI and 19 older adults with stable normal cognition (sNC). The gray matter (GM) volume and functional connectivity (FC) were estimated via magnetic resonance imaging during their normal cognition state 3 years prior. Additionally, spatial associations between FC maps and neurochemical profiles were examined using JuSpace. Compared to the sNC group, the pNC group showed decreased volume in the left hippocampus and left amygdala. The significantly positive correlation was observed between the GM volume of the left hippocampus and the MMSE scores after 3 years in pNC group. Besides, it showed that the pNC group had increased FC between the left hippocampus and the anterior-posterior cingulate gyrus, which was significantly correlated with the spatial distribution of dopamine D2 and noradrenaline transporter. Taken together, the study identified the abnormal brain characteristics before the onset of MCI, which might provide insight into clinical research.

Life-Course Socioeconomic Position and Mild Cognitive Impairment in Midlife: Evidence from the 1958 British Birth Cohort

BackgroundDementia has been the leading cause of death in the UK since 2015. Increasing evidence supports an association between socioeconomic position (SEP) and dementia onset in later life. However, limited studies have examined how life-course SEP influences the development of mild cognitive impairment (MCI), an intermediate state potentially preceding dementia. Therefore, the present study aims to examine the relationship between life-course SEP and MCI amongst adults aged 50 years in Great Britain.MethodsWe employed data from the National Child Development Study (NCDS), also known as the 1958 British Birth Cohort, to determine the associations between SEP and MCI in 6590 participants. We categorised life-course measures of SEP as stable high/low or moving upward/downward over the life course. We assessed MCI at age 50 using one standard deviation below the averaged combined scores from all cognitive tests available. We then used binary logistic regression to estimate the longitudinal associations between life-course SEP and MCI.ResultsRelative to those of a high SEP across the life course, participants who moved upward, downward, or remained at a low SEP were significantly associated with 25% (95% CI 1.02–1.54, p = 0.035), 70% (95% CI 1.27–2.27, p < 0.001), and 85% (95% CI 1.50–2.29, p < 0.001), respectively, higher odds of MCI, independent of all selected covariates.ConclusionsLower life-course SEP was associated with significantly higher odds of MCI onset in middle life within the NCDS cohort. Public health policies targeting cognitive impairment should encompass a life-course approach to reduce socioeconomic inequalities.

OCCUPATIONAL COGNITIVE DEMANDS AND RISK OF MILD COGNITIVE IMPAIRMENT AND DEMENTIA: THE HUNT STUDY

Abstract The cognitive reserve hypothesis posits that cognitively stimulating work may delay onset of mild cognitive impairment (MCI) and dementia. However, the impact of work histories across midlife on the risk of these conditions is unclear. We evaluated trajectories of work-related cognitive demands from ages 33-65y and their association with later clinical MCI/dementia. The HUNT4 70+ Study was used (N= 7003 participants, 49.8% women, 2017-19). Group-based-trajectory-modeling was used to identify trajectories of work-related cognitive demands, measured by routine task intensity (RTI) index (Lower RTI indicates less routine-oriented work) from online Occupational Information Network (O*NET). Multinomial regression was used to estimate the relative risk ratios (RRR) of MCI/dementia after adjusting for covariates age, sex and education, income, hypertension, obesity, diabetes, psychiatric impairment, hearing impairment, feeling of loneliness, smoking status, and physical inactivity. Four trajectories were identified; low RTI (20.4%), intermediate-low RTI (22.7%), intermediate-high RTI (36.9%), and high RTI (20.1%). Participants in the high RTI group had higher risk of MCI (RRR 1.74, 95% CI: 1.41,2.14) and dementia (RRR 1.37, 95% CI: 1.01, 1.86) after adjusting for age, sex, and education compared to participants in the low RTI group. When accounting for potential mediators, the increased risk remained for MCI but was no longer significant for dementia, indicating these mediators may account for part of the observed relationship. Our results highlight the importance of cognitive stimulation in the workplace for maintaining cognitive function. This should be taken into account, together with other known risk factors to help prevent cognitive decline in older adults.

Atrophy of Brodmann Area 36 differentiates age‐related subjective memory decline from cognitively normal older adults and is associated with NPTX2

AbstractBackgroundAdvancing age is associated with changes in cognitive functions, particularly memory, although there are significant individual differences between subjects. While some older adults experience minimal cognitive decline, others exhibit more pronounced deterioration that can progress to Alzheimer’s disease dementia (AD). Some older individuals report subjective memory complaints (SMC) despite normal scores on objective memory assessments. Longitudinal studies suggest that SMC may be predictive of AD dementia and precedes the onset of mild cognitive impairment (MCI) by around 15 years. However, given large individual differences and biases towards reporting complaints, objective measures are needed to identify those individuals who are on a trajectory of decline relevant to AD.MethodIn the current study cognitively normal older adults, older adults with SMC, and patients with MCI were recruited from the ADRC and the community to complete neuropsychological assessment, an MRI scan and a lumbar puncture to assess what measures are associated with self‐reported SMC. Structural MRI scans were analyzed using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Cerebrospinal fluid (CSF) was analyzed using standard methods to obtain fluid biomarkers associated with AD.ResultConsistent with previous reports, entorhinal cortex volume significantly differed between cognitively normal older adults and patients with MCI. However, entorhinal cortex volume did not differentiate between controls and SMC subjects. Instead, volume of Brodmann area (BA) 36 was significantly different between control participants and SMC subjects as well as between controls and patients with MCI. Furthermore, volume of the right BA35 and BA36 was moderately correlated with neuronal pentraxin‐2 (NPTX2), a marker of synaptic integrity that is reduced in AD. Volume of the right BA36 was additionally correlated with measures of cognition including the Mini‐Mental Status Exam and objective measures of memory function.ConclusionTogether these findings show that particularly atrophy of BA36 may provide an objective measure differentiating between cognitively normal older adults and those with SMC, and in identifying the early stages of AD prior to a diagnosis of aMCI.

Sense of Purpose in Life Predicts Reduced Risk for and Delayed Onset of Mild Cognitive Impairment: A Multistate Survival Model

AbstractBackgroundWith no known cure for Alzheimer’s disease and related dementias, delaying the onset of cognitive decline represents a key target for future dementia research. Sense of purpose has been shown to be associated with high cognitive functioning, more supportive social ties, and greater intellectual activity, and may be valuable for mitigating cognitive impairment both before and following its onset.MethodLongitudinal data from the Health and Retirement Study (HRS, n = 10,542) and the Rush Memory and Aging Project (MAP, n = 10.48) were used to examine associations between sense of purpose and prospective transitions across normal cognition, mild cognitive impairment (MCI), dementia, and death over up to 12 and 19 years, respectively. Multistate survival modeling examined the impact of sense of purpose on risk for each transition, adjusting for age, sex, education, apolipoprotein‐E allele, and depressive symptoms. Multinomial regression was used to estimate life expectancy in each cognitive state.ResultMore purposeful older adults were found to have lower prospective risk of developing MCI in the HRS (HR = 0.93, 95% CI: 0.90, 0.97) and MAP (HR = 0.82, 95% CI: 0.69, 0.98) and had increased likelihood of improvement in cognitive functioning following MCI classification. In both samples, those higher in sense of purpose were found to have significantly longer overall life expectancy and life expectancy free of cognitive impairment (without MCI or dementia).ConclusionOlder adults higher in sense of purpose appear to live longer lives, with these differences in life expectancy attributable to increases in years lived without cognitive impairment. Replication of findings across longitudinal studies with disparate samples and measurement procedures provides robust support that having a strong sense of purpose in life contributes to cognitive reserve and resilience. Interventions aiming to promote older adult sense of purpose could extend the cognitive healthspan—the period in which individuals live in a cognitively healthy state free of impairment.

Associations among depressive symptoms, hippocampal volume and cognition in community‐dwelling older Latinos

AbstractBackgroundLatinos are the fastest growing subpopulation of older adults in the U.S. and have a higher risk for dementia than non‐Latino Whites. Depressive symptoms are prevalent among US Latinos. However, these symptoms often go undiagnosed and are undertreated. Depressive symptoms may be early manifestations of Alzheimer’s Disease (AD) before the onset of mild cognitive impairment and dementia. It’s unclear whether depressive symptoms in the presence of incipient neurodegeneration are associated with cognitive function in older Latino adults. Here, we examined the associations among depressive symptoms, cognition and hippocampal volume in older Latinos.MethodA total of 65 Spanish‐speaking Latinos enrolled in the Boston Latino Aging Study (BLAST) and the Harvard Aging Brain Study (HABS) were included. Depressive symptoms were assessed with the 30‐item‐Geriatric Depression Scale (GDS) and cognition with the Preclinical Alzheimer’s Cognitive Composite (PACC5), which includes the Mini‐Mental State Examination (MMSE), Digit Symbol Coding, Free and Cued Selective Reminding Test, Category Fluency (animals) and Logical Memory Delayed Recall (NEUROPSI Stories for BLAST participants). A subset of 34 participants also underwent a structural brain MRI on a 3T scanner. Spearman correlations were used to determine cross‐sectional associations among depressive symptoms, hippocampal volume, and cognition. Models were adjusted for age and education.ResultsParticipants had a mean age of 66 +/‐ 7.2 years, a mean education of 12.9 +/‐ 5.1 years, and 74% were female. They had a mean MMSE score of 26.7 +/‐ 2.8, a mean GDS score of 6.1 +/‐ 5.5 and a mean adjusted hippocampal volume of 7836.5 +/ = 630.9 mm3. Correlation analyses revealed that higher depressive symptoms were associated with lower years of education (r = ‐0.39, p&lt;0.001), worse performance on cognitive measures (r = ‐0.33, p = 0.009) and smaller hippocampal volume (r = ‐0.61, p = &lt;0.001).ConclusionsPreliminary results of this ongoing biomarker study suggest that depressive symptoms in older Latinos are associated with markers of neurodegeneration (i.e., hippocampal volume) and worse cognition. Future work will focus on investigating predictors of long‐term emotional and cognitive functioning in Spanish‐speaking, older Latino populations.

Association of the cognitive reserve with the age of onset of mild cognitive impairment and dementia in patients with or Alzheimer’s disease. Antioquia, Colombia.

AbstractBackgroundThe cognitive reserve (CR) has been associated with the extension/compensation of the mental functioning of individuals affected by a neurodegenerative disease in the early stages of the disease. Most of the analyses evaluating CR are in high‐income countries, while there is a lack of capturing the variability related to low‐middle‐income environments such as Colombia. Objective: to analyze the relationship between CR and the age of onset of MCI and/or dementia by Alzheimer’s disease (AD) in patients from Antioquia‐Colombia.MethodA retrospective cohort study of 194 individuals. Clinical and socioeconomic characteristics were described using absolute and relative frequencies, followed by a mixed principal component analysis to represent the CR. A Varimax rotation was used for its interpretation, generating Z scores for the CR and the resulting dimensions. CR was categorized according to the median as high or low. This categorization aims to assess differences in the onset time of MCI and dementia by AD for the survival analysis and Cox regression with multiple imputation models (m = 30). We also examined all data to estimate the raw effect and adjusted for age, sex, and area.Resultsfrom 194 patients, 151 informed the age of onset of MCI, and 165 were later diagnosed with dementia by AD. There were differences between 5 and 9 years in the median age of onset of MCI and dementia by AD, with a later onset for patients with high CR. The CR hazard ratios (HR) were 1.05 and 0.97 for MCI and dementia, respectively. The ratio for the total score tended to be null after adjustment with confounding variables. However, its dimensions remained significant. Specifically, the HRs for an academic position, growing environment, and family status increased the speed of onset of the outcomes for MCI: 1.43, 1.06, and 1,72 and dementia: 1.40, 1.12, and 1.68.Conclusionthe onset times of the MCI and dementia were five years later in subjects with higher CR. Thus, a high academic position, a protective growth environment, and a family status that favors social relationships were associated with the reduction in clinical symptoms of AD since the early stages.

Brain pathological mechanism of weight loss preceding incident mild cognitive impairment

AbstractBackgroundWeight loss in late life is associated with a higher risk of dementia and higher mortality. However, the temporal and etiological associations between weight loss and mild cognitive impairment (MCI) remain unclear.MethodWe examined 709 Alzheimer’s Disease Neuroimaging Initiative participants to investigate body mass index (BMI) trajectories preceding the progression from normal cognition to MCI (N‐t‐M progression), and to explore the association between brain pathology and BMI trajectories preceding incident MCI.ResultDuring N‐t‐M progression, participants developed multiple brain pathologies, and amyloid β (Aβ) accumulation in the frontotemporal region at baseline was associated with decreased BMI (Figure 1, false discovery rate‐corrected p&lt;0.05). For pathological changes, participants had increased accumulation of Aβ and tau, accelerated hypometabolism, and decreased gray matter volume in the brain during N‐t‐M progression. More importantly, accelerated hypometabolism (p&lt;0.001) and gray matter atrophy (p = 0.011) were associated with a rapid decline in BMI during N‐t‐M progression.ConclusionThese findings highlight the importance of regular monitoring of weight changes in older adults as faster BMI decline and lower BMI may be the result of brain pathology and associated with rapid progression of pathology, and provide a theoretical basis for strategies to minimize weight loss to prevent or delay MCI onset.

23 The Utility of Global versus Domain-specific Neuropsychological Test Score Dispersion as Markers of Cognitive Decline

Objective:Higher baseline dispersion (intra-individual variability) across neuropsychological test scores at a single time-point has been associated with more rapid cognitive decline, onset of Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD), faster rates of hippocampal and entorhinal atrophy, and increased AD neuropathology. Comparison between predictions made from test score dispersion within a cognitive domain versus global, cross-domain dispersion is understudied. Global dispersion may be influenced by ability-and test-specific characteristics. This study examined the performance of global versus domain-specific dispersion metrics to identify which is most predictive of cognitive decline over time.Participants and Methods:Data for baseline and five follow-up visits of 308 participants with normal cognition (Mage=73.90, SD=8.12) were selected from the National Alzheimer’s Coordinating Center (NACC) Dataset. Participants were required to have no focal neurological deficits, or history of depression, stroke, or heart attack. Diagnoses and progression to MCI and/or dementia were determined at each visit through consensus conferences. Raw neuropsychological scores were standardized using NACC norms. Global baseline dispersion was defined as the intraindividual standard deviation (ISD) across the 10 scores in the NACC battery. Domain-specific dispersions were calculated by constructing composites and ISD was computed across tests sampling their respective domains (executive functioning/attention/processing speed [EFAS], language, and memory; see Table 1 for details on these tests). Higher values on each of these metrics reflect greater dispersion. Multinomial logistic regression model fit statistics and parameter estimates were compared across four different models (global, EFAS, Language, and Memory dispersion) covarying for age, years of education, sex, race, ethnicity, and ApoE4 status. Models were compared using the Likelihood Ratio Test (LRT) and the Akaike Information Criteria (AIC) of Models statistics.Results:Of the 308 participants, 70 (22.7%) progressed to MCI, and 82 (26.6%) progressed to dementia. Tables 1 and 2 show the results of the logistic regressions for the four models. All models fit the data well, with statistically significant predictions of conversion. Model 1 (global dispersion) showed a better fit than domain-specific models of dispersion per LRT and AIC values. Consistent with the results from mean differences between groups, parameter estimates showed that only global dispersion and EFAS dispersion significantly predicted conversion to dementia (when included with other covariates in models), with higher dispersion reflecting a greater risk of conversion.Conclusions:In this sample, baseline global and EFAS dispersion measures significantly predicted conversion to dementia. Although global dispersion was a stronger predictor of dementia progression, findings suggest that executive functioning performance may be driving this relationship. A single index of global variability, from the calculation of standard deviation across test scores, may be supplementary for clinicians when distinguishing individuals at risk for dementia progression. None of the models were predictive of conversion to MCI. Further research is required to examine cognitive variability differences among patients who progress to MCI and patient-specific factors that may relate to test score dispersion and its utility in predicting the progression of symptoms.

Taking it to the extreme: The search for determinants of cognitive vulnerability and resilience in children with autosomal dominant Alzheimer’s disease

Abstract:Presenilin-1 (PSEN1) mutations predispose individuals to develop autosomal-dominant Alzheimer's disease (ADAD) in middle adulthood. While the pathogenesis of ADAD may be different from late-onset sporadic AD (e.g., differences in disease etiology, age of disease onset, etc), these conditions share many characteristics, including similar abnormalities in amyloid and tau biomarkers, brain structure and brain activity, and clinical features (Quiroz et al., 2010, Quiroz et al., 2011, Quiroz et al. 2018). Biomarker investigations of families with ADAD have already shed light on the trajectory of some AD-related brain changes, especially prior to the onset of clinical symptoms.We have been studying a Colombian kindred with a genetic form of AD caused by a single genetic mutation in the PSEN1 (E280A), which serves as a unique model for preclinical AD. Because of a well-defined age at clinical onset, and near 100% penetrance, this kindred provides important information about the time course and relationships between physiological mechanisms and cognitive changes, and in so doing, it has yielded new insights about presymptomatic AD that will enhance future prevention trials for AD, including primary prevention trials.The well-characterized clinical trajectory of these PSEN1 E280A mutation carriers allow us to examine brain function in children, more than three decades before the average age of onset of mild cognitive impairment (MCI) and dementia in this cohort (45 years for MCI, 50 years for dementia). This is giving us the unique opportunity to characterize the cognitive and behavioral profiles of children genetically determined to develop dementia in their forties, and is helping us improve our understanding of the impact of ADAD mutations in early life cognitive and brain functioning, as well as its potential impact on learning, academic performance and educational attainment. We previously studied 20 PSEN1 E280A carriers and 20 non-carriers aged 9 to 17 years from the Colombian ADAD cohort and showed that mutation-carrying children were distinguished from non-carriers by plasma biomarker findings consistent with Aß1-42 overproduction, as well as by increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (Quiroz et al 2015). More recently, we used the WISC-IV, a measure of general intellectual abilities to examine cognitive abilities in these children. We reported in 265 children with the E280A mutation and 1089 non-carriers that they did not differ on any of the WISC-IV indices. Surprisingly, male carriers performed slightly worse than female carriers on working memory (mean difference = -4.97; P = .001) (Fox-Fuller et al., 2021). Some of our ongoing work includes comprehensive examinations of social, educational and developmental histories along with functional brain networks, as markers of synaptic dysfunction in individuals with ADAD, as this is particularly relevant to understanding the impact of PSEN1 mutations on the developing brain and subsequent neurodegenerative changes seen later in life, without the confounds of aging and age-related comorbidities that often exist in late-onset sporadic AD.Disclosures: Financial: Dr. Quiroz receives a consulting fee from Biogen. Non-Financial: Dr. Quiroz is a Hispanic Neuropsychological Society Member-At-Large and serves as the INS Teleneuropsychology Special Interest Group Chair

Cerebrospinal Fluid Alzheimer's Disease Biomarker Patterns of Change Prior to the Onset of Mild Cognitive Impairment.

Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein E (APOE) status. Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using the fully automated Lumipulse assays. Among participants who progressed to MCI, Aβ42/Aβ40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aβ 42/Aβ40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181, p-tau181/(Aβ 42/Aβ40), and t-tau/(Aβ 42/Aβ 40). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181, t-tau/(Aβ 42/Aβ 40), and p-tau181/(Aβ 42/Aβ 40). These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD.

Exploring the Impact of Age of Onset of Mild Cognitive Impairment on the Profile of Cognitive and Psychiatric Symptoms.

The present study aims to explore the differences in the manifestation of cognitive decline and psychiatric symptoms across the different ages of MCI onset: early onset (EOMCI: <65 years old), middle onset (MOMCI: 65-75 years old), and late onset (LOMCI: >75 years old). It was hypothesized that individuals with EOMCI will preserve their cognitive functions to a greater extent as compared to individuals with LOMCI, even after adjusting the cognitive performance for age and education through the use of published Greek norms. The level of cognitive decline concerning MOMCI was evaluated for extracting more precise conclusions regarding the impact of the age of onset on the patterns of MCI symptomatology. The analyses of data were conducted in a Greek population of individuals with MCI, who were consecutive visitors of the Outpatient Memory Clinic of Nestor Alzheimer's Centre in Athens, Greece. The sample consisted of 297 participants who fulfilled the following inclusion criteria: MCI diagnosis based on Petersen's criteria, Greek mother language, and absence of a psychiatric history or chronic and incurable organic disease. The overall results support the presence of a cognitive advantage of the EOMCI group compared to the LOMCI group. In the MOMCI group, cognitive performance displayed a tendency to remain intermediate compared to the other two groups. Nonetheless, significant differences were observed when this group was compared with the LOMCI group. The current findings indicate that the age of onset should be taken under consideration in the neuropsychological assessment of individuals with MCI. The specific parameters could have implications in terms of prognosis as well as the design and implementation of tailored interventions.

Dimensions of cognitive reserve and their predictive power of cognitive performance and decline in the elderly

BackgroundThe relative importance of different components of cognitive reserve (CR), as well as their differences by gender, are poorly established.ObjectiveTo explore several dimensions of CR, their differences by gender, and their effects on cognitive performance and trajectory in a cohort of older people without relevant psychiatric, neurologic, or systemic conditions.MethodsTwenty-one variables related to the education, occupation, social activities, and life habits of 1,093 home-dwelling and cognitively healthy individuals, between 68 and 86 years old, were explored using factorial analyses to delineate several dimensions of CR. These dimensions were contrasted with baseline cognitive performance, follow-up over 5 years of participants' cognitive trajectory, conversion to mild cognitive impairment (MCI), and brain volumes using regression and growth curve models, controlling for gender, age, marital status, number of medications, trait anxiety, depression, and ApoE genotype.ResultsFive highly intercorrelated dimensions of CR were identified, with some differences in their structure and effects based on gender. Three of them, education/occupation, midlife cognitive activities, and leisure activities, were significantly associated with late-life cognitive performance, accounting for more than 20% of its variance. The education/occupation had positive effect on the rate of cognitive decline during the 5-year follow up in individuals with final diagnosis of MCI but showed a reduced risk for MCI in men. None of these dimensions showed significant relationships with gray or white matter volumes.ConclusionProxy markers of CR can be represented by five interrelated dimensions. Education/occupation, midlife cognitive activities, and leisure activities are associated with better cognitive performance in old age and provide a buffer against cognitive impairment. Education/occupation may delay the clinical onset of MCI and is also associated with the rate of change in cognitive performance.

A Deep Neural Network for Working Memory Load Prediction from EEG Ensemble Empirical Mode Decomposition

Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD) are frequently associated with working memory (WM) dysfunction, which is also observed in various neural psychiatric disorders, including depression, schizophrenia, and ADHD. Early detection of WM dysfunction is essential to predict the onset of MCI and AD. Artificial Intelligence (AI)-based algorithms are increasingly used to identify biomarkers for detecting subtle changes in loaded WM. This paper presents an approach using electroencephalograms (EEG), time-frequency signal processing, and a Deep Neural Network (DNN) to predict WM load in normal and MCI-diagnosed subjects. EEG signals were recorded using an EEG cap during working memory tasks, including block tapping and N-back visuospatial interfaces. The data were bandpass-filtered, and independent components analysis was used to select the best electrode channels. The Ensemble Empirical Mode Decomposition (EEMD) algorithm was then applied to the EEG signals to obtain the time-frequency Intrinsic Mode Functions (IMFs). The EEMD and DNN methods perform better than traditional machine learning methods as well as Convolutional Neural Networks (CNN) for the prediction of WM load. Prediction accuracies were consistently higher for both normal and MCI subjects, averaging 97.62%. The average Kappa score for normal subjects was 94.98% and 92.49% for subjects with MCI. Subjects with MCI showed higher values for beta and alpha oscillations in the frontal region than normal subjects. The average power spectral density of the IMFs showed that the IMFs (p = 0.0469 for normal subjects and p = 0.0145 for subjects with MCI) are robust and reliable features for WM load prediction.

NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment.

This study examined whether cerebrospinal fluid (CSF) baseline levels of the synaptic protein NPTX2 predict time to onset of symptoms of mild cognitive impairment (MCI), both alone and when accounting for traditional CSF Alzheimer's disease (AD) biomarker levels. Longitudinal NPTX2 levels were also examined. CSF was collected longitudinally from 269 cognitively normal BIOCARD Study participants (mean baseline age = 57.7 years; mean follow-up = 16.3 years; n = 77 progressed to MCI/dementia). NPTX2 levels were measured from 3 correlated peptides using quantitative parallel reaction monitoring mass spectrometry. Levels of Aβ42 /Aβ40 , p-tau181 , and t-tau were measured from the same CSF specimens using Lumipulse automated electrochemiluminescence assays. In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR] = 0.76, SE = 0.09, p = 0.023). This association was significant for progression within 7 years (p = 0.036) and after 7 years from baseline (p = 0.001). Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (p < 0.01), and NPTX2 did not interact with the CSF AD biomarkers or APOE-ε4 genetic status. In linear mixed effects models, higher baseline p-tau181 and t-tau levels were associated with higher baseline levels of NPTX2 (both p < 0.001) and greater rates of NPTX2 declines over time. NPTX2 may be a valuable prognostic biomarker during preclinical AD that provides additive and independent prediction of MCI onset among individuals who are cognitively normal. We hypothesize that NPTX2-mediated circuit homeostasis confers resilience during the early phase of AD. ANN NEUROL 2023;94:620-631.

Glutamine Supplementation Preserves Glutamatergic Neuronal Activity in the Infralimbic Cortex, Which Delays the Onset of Mild Cognitive Impairment in 3×Tg-AD Female Mice.

It was recently found that glutamine (Gln) supplementation activates glutamatergic neurotransmission and prevents chronic-stress-induced mild cognitive impairment (MCI). In this study, we evaluated the effects of Gln on glutamatergic activity in the medial prefrontal cortex and the onset of cognitive impairment in a triple-transgenic Alzheimer's disease mouse model (3×Tg-AD). Female 3×Tg-AD mice were fed a normal diet (3×Tg) or a Gln-supplemented diet (3×Tg+Gln) from 2 to 6 months of age. Glutamatergic neuronal activity was analyzed at 6 months, and cognitive function was examined at 2, 4, and 6 months. 3×Tg mice exhibited a decrease in glutamatergic neurotransmission in the infralimbic cortex, but 3×Tg+Gln mice did not. The 3×Tg group showed MCI at 6 months of age, but the 3×Tg+Gln group did not. The expressions of amyloid peptide, inducible nitric oxide synthase, and IBA-1 were not elevated in the infralimbic cortex in the 3×Tg+Gln group. Therefore, a Gln-supplemented diet could delay the onset of MCI even in a mouse model predisposed to cognitive impairment and dementia through genetic modification.

Variations in rest‐activity cycle length and peak timing during Alzheimer’s progression

AbstractBackgroundRest‐activity rhythm is commonly used to assess the circadian regulation and its changes with aging and Alzheimer’s disease (AD). Traditional rhythmicity analyses such as Cosinor analysis assume a rhythm of a constant waveform while ignoring the variations in the length and peak timing between different cycles/days. We introduced a novel rhythmicity analysis based on the uniform phase empirical mode decomposition (UPMEMD) that can provide detailed information of each individual cycle in rest‐activity rhythm. We tested whether variations in rest‐activity cycles change during aging and at different stages of AD.MethodParticipants were 1,065 older adults (baseline age = 80.9±7.3[SD], 807 females) from the Rush Memory and Aging Project. Actigraphy (∼10‐day) was performed annually for up to 13 years. For each recording, the UPMEMD was used to extract the rhythm of ∼24‐h; the length and peak timing were obtained from each cycle; and standard deviations (SD) of cycle lengths and peak timings were computed for each participant. Linear mixed effects models were performed to quantify the within‐subject changes over time in SD of cycle lengths, and separately, SD of peak timings, with adjustments of age, sex, and education years. Change points at diagnoses of mild cognitive impairment (MCI) and Alzheimer’s dementia were considered in the mixed models to examine whether the rates of changes were altered after the diagnoses.ResultSD of cycle length increased by 0.04 hours/year when participants were cognitively intact (95%CI: 0.02‐0.05, p&lt;0.001); the rate increased by an additional 0.04 hours/year after the onset of MCI (95%CI: 0.02‐0.06, p&lt;0.001) and increased further by 0.18 hours/year (95%CI: 0.12‐0.24, p&lt;0.001) after the onset of AD. Moreover, SD of peak timing increased by 0.04 hours/year when the participants were cognitively intact (95%CI: 0.02‐0.05, p&lt;0.001); the rate was accelerated by 0.06 hours/year after the onset of MCI (95%CI: 0.03‐0.08, p&lt;0.001) and further accelerated by 0.26 hours/year (95%CI: 0.20‐0.32, p&lt;0.001) after the onset of AD.ConclusionInterdaily variability in rest‐activity rhythm increased with aging, and the ageing‐related circadian disturbance was accelerated as AD progressed. The markers of rest‐activity rhythm based on proposed rhythmicity analysis may facilitate identification of AD and monitoring of its progression.