Cognitive Research Articles

Signs of consciousness in AI: Can GPT-3 tell how smart it really is?

The emergence of artificial intelligence (AI) is transforming how humans live and interact, raising both excitement and concerns—particularly about the potential for AI consciousness. For example, Google engineer Blake Lemoine suggested that the AI chatbot LaMDA might become sentient. At that time, GPT-3 was one of the most powerful publicly available language models, capable of simulating human reasoning to a certain extent. The notion of GPT-3 having some degree of consciousness could be linked to its ability to produce human-like responses, hinting at a basic level of understanding. To explore this further, we administered both objective and self-assessment tests of cognitive (CI) and emotional intelligence (EI) to GPT-3. Results showed that GPT-3 outperformed average humans on CI tests requiring the use and demonstration of acquired knowledge. However, its logical reasoning and EI capacities matched those of an average human. GPT-3’s self-assessments of CI and EI didn’t always align with its objective performance, with variations comparable to different human subsamples (e.g., high performers, males). A further discussion considered whether these results signal emerging subjectivity and self-awareness in AI. Future research should examine various language models to identify emergent properties of AI. The goal is not to discover machine consciousness itself, but to identify signs of its development, occurring independently of training and fine-tuning processes. If AI is to be further developed and widely deployed in human interactions, creating empathic AI that mimics human behavior is essential. The rapid advancement toward superintelligence requires continuous monitoring of AI’s human-like capabilities, particularly in general-purpose models, to ensure safety and alignment with human values.

Cognitive reserve as residual variance in cognitive performance: Latent dimensionality, correlates, and dementia prediction.

Cognitive reserve (CR) is typically operationalized as episodic memory residualized on brain health indices. The dimensionality of more generalized models of CR has rarely been examined. In a sample of N = 113 dementia-free older adults (ages 62-86 years at MRI scan; 58.4% women), the domain-specific representation of general cognition (COG) before vs. after residualization on brain indices (brain volume loss, cerebral blood flow, white matter hyperintensities) was compared (i.e., COG vs. CR). COG and CR were assessed by 15 tasks spanning five domains: processing speed, verbal memory, visuospatial memory, fluid reasoning, and vocabulary. Measurement invariance and item-construct representation were tested in a series of structural factor analyses. COG and CR were then examined in relation to 22 risk and protective factors and dementia status at time of death. Item-factor loadings differed such that CR more strongly emphasized fluid reasoning. More years of education, higher occupational class, more hobbies/interests, and fewer difficulties with personal mobility similarly predicted better COG and CR. Only the sub-domain of visuospatial memory (both before and after residualization) was associated with conversion to dementia by end-of-life (r = -.30; p = .01). Results provide tentative support for the role of fluid reasoning (intelligence) as a potential compensatory factor for age- and/or neuropathology-related reductions in processing speed and memory. Intellectually stimulating work, efforts to preserve personal mobility, and a diversity of hobbies and interests may attenuate age- and/or pathology-related reductions in cognitive functioning prior to dementia onset.

The added value of the cognition, dining, gastrointestinal problems, sleep and tiredness bolt-on dimensions to the EQ-5D-5L in patients with coeliac disease.

Multiple studies suggest that the EQ-5D may overestimate health-related quality of life (HRQoL) in patients with coeliac disease (CD). We aimed to develop and psychometrically test potentially relevant bolt-on dimensions to improve the measurement performance of the EQ-5D-5L in CD patients. The development and selection of bolt-ons were informed by a literature review on HRQoL in CD, expert and patient input. A cross-sectional online survey was conducted amongst 312 adult CD patients. Respondents completed the EQ-5D-5L, two condition-specific bolt-ons newly-developed for the present study [dining (DI) and gastrointestinal problems (GI)] and three existing bolt-ons [cognition (CO), sleep (SL) and tiredness (TI)]. The following psychometric properties were tested: ceiling, informativity, convergent and known-group validity, and dimensionality (confirmatory factor analysis). Adding the TI, SL, GI, DI and CO individual bolt-ons reduced the ceiling of the EQ-5D-5L (39%) to 17%, 23%, 24%, 26% and 37%, respectively. GI excelled with strong convergent validity with the Gastrointestinal Symptom Rating Scale total score (rs=0.71) and improved the discriminatory power for all known-groups. GI was the only bolt-on loading on a different factor from the five core dimensions, whereas the other four bolt-ons loaded onto the same 'psychosocial health' factor as the EQ-5D-5L anxiety/depression dimension. The DI, GI, SL and TI bolt-ons, especially the GI, enhance the validity of EQ-5D-5L in patients with CD, suggesting their value in capturing important HRQoL aspects potentially missed by the five core dimensions. These bolt-ons can be used in sensitivity analyses supporting health technology assessments and subsequent resource allocation decisions.

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from EMIF-AD MBD and ADNI. For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these groups. Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Cerebrospinal Fluid Proteomics Identifies Potential Biomarkers for Early-Onset Alzheimer’s Disease

Background: Early-onset Alzheimer’s disease (EOAD) exhibits a notable degree of heterogeneity as compared to late-onset Alzheimer’s disease (LOAD). The proteins and pathways contributing to the pathophysiology of EOAD still need to be completed and elucidated. Objective: Using correlation network analysis and machine learning to analyze cerebrospinal fluid (CSF) proteomics data to identify potential biomarkers and pathways associated with EOAD. Methods: We employed mass spectrometry to conduct CSF proteomic analysis using the data-independent acquisition method in a Chinese cohort of 139 CSF samples, including 40 individuals with normal cognition (CN), 61 patients with EOAD, and 38 patients with LOAD. Correlation network analysis of differentially expressed proteins was performed to identify EOAD-associated pathways. Machine learning assisted in identifying crucial proteins differentiating EOAD. We validated the results in an Western cohort and examined the proteins expression by enzyme-linked immunosorbent assay (ELISA) in additional 9 EOAD, 9 LOAD, and 9 CN samples from our cohort. Results: We quantified 2,168 CSF proteins. Following adjustment for age and sex, EOAD exhibited a significantly greater number of differentially expressed proteins than LOAD compared to CN. Additionally, our data indicates that EOAD may exhibit more pronounced synaptic dysfunction than LOAD. Three potential biomarkers for EOAD were identified: SH3BGRL3, LRP8, and LY6 H, of which SH3BGRL3 also accurately classified EOAD in the Western cohort. LY6 H reduction was confirmed via ELISA, which was consistent with our proteomic results Conclusions: This study provides a comprehensive profile of the CSF proteome in EOAD and identifies three potential EOAD biomarker proteins.

Identifying and understanding cognitive profiles in multiple sclerosis: a role for visuospatial memory functioning

BackgroundThe heterogeneous nature of cognitive impairment in people with multiple sclerosis (PwMS) hampers understanding of the underlying mechanisms and developing patient-tailored interventions. We aim to identify and classify cognitive profiles in PwMS, comparing these to cognitive status (preserved versus impaired).MethodsWe included 1213 PwMS (72% female, age 45.4 ± 10.7 years, 83% relapsing–remitting MS). Cognitive test scores were converted to Z-scores compared to healthy controls for the functions: attention, inhibition, information processing speed (IPS), verbal fluency and verbal/visuospatial memory. Concerning cognitive status, impaired cognition (CI) was defined as performing at Z ≤ − 1.5 SD on ≥ 2 functions. Cognitive profiles were constructed using latent profile analysis on all cognitive functions. Cognitive profiles or status was classified using gradient boosting decision trees, providing the importance of each feature (demographics, clinical, cognitive and psychological functioning) for the overall classification.ResultsSix profiles were identified, showing variations in overall performance and specific deficits (attention, inhibition, IPS, verbal fluency, verbal memory and visuospatial memory). Across the profiles, IPS was the most impaired function (%CI most preserved profile, Profile 1 = 22.4%; %CI most impaired profile, Profile 6 = 76.6%). Cognitive impairment varied from 11.8% in Profile 1 to 95.3% in Profile 6. Of all cognitive functions, visuospatial memory was most important in classifying profiles and IPS the least (area under the curve (AUC) = 0.910). For cognitive status, IPS was the most important classifier (AUC = 0.997).ConclusionsThis study demonstrated that cognitive heterogeneity in MS reflects a continuum of cognitive severity, distinguishable by distinct cognitive profiles, primarily explained by variations in visuospatial memory functioning.

Polygenic Variation Underlying Educational Attainment and Attention-Deficit/Hyperactivity Disorder Indexes Behavior Ratings of Executive Functions in Child Psychiatry Outpatients

Objective: We leveraged common genetic variation underlying ADHD, educational attainment (EA) and cognition (COG) to understand the nature of the Behavior Rating Inventory for Executive Functions (BRIEF) and its relationship to academic functioning. Method: Participants were 991 youth, ages 7 to 17, consecutively referred for neuropsychiatric evaluation. Polygenic scores (PGS) for ADHD, EA, and COG were related to the BRIEF using regression analyses. Structural equation models were used to examine the associations between the PGS, BRIEF and academic outcomes (math, reading, and special education services [EDPLAN]). Results: After modeling the PGS together, only the EA and ADHD PGS significantly associated with the BRIEF. The BRIEF partially mediated the relationships between EA PGS with math and EDPLAN and fully mediated the relationship between ADHD PGS and EDPLAN. Conclusion: Genetic data extend evidence that the BRIEF measures a construct relevant to educational success that differs from what is indexed by cognitive testing.

The Impact of Online Learning during the COVID-19 Pandemic on Language Learning Strategies, Proficiency, and Enjoyment among Thai EFL Students

Amidst the COVID-19 pandemic, individuals worldwide found themselves compelled to adapt to unforeseen circumstances. An integral part of this adjustment was the transformation of conventional instructional methods, shifting from traditional classroom-based learning to the realm of online education. In this new educational landscape, online learning has emerged as the only avenue for both educators and learners to sustain their academic journeys. The objective of this study was to examine potential changes in the application of language learning strategies (LLSs) in the context of online English learning amidst the COVID-19 pandemic. The study also aimed to explore whether these variations were influenced by individuals’ levels of language proficiency and their level of enjoyment of learning English. If any variations were identified, the study aimed to analyze the specific patterns that emerged. The study included 205 students who were enrolled in a public university in northeastern Thailand. Data collection involved administering both the LLS questionnaire and the enjoyment of the English learning questionnaire. Quantitative data analysis involved the use of descriptive statistics, ANOVA, and Chi-square tests. The study revealed significant variations in the frequency of overall strategy utilization based on two variables: language proficiency and individual enjoyment with the process of learning English. While there were no significant variations in overall strategy usage based on language proficiency, notable differences were observed based on their level of enjoyment of learning English. In terms of distinct categories, significant differences were observed in the utilization of LLS within the metacognitive (MET) and affective (AFF) categories, especially concerning language proficiency. Moreover, substantial variances were evident across all six categories—memory (MEM), cognitive (COG), compensation (COM), MET, AFF, and social (SOC)—in the level of satisfaction derived from the process of learning English.

PREVALENCE OF METABOLIC COMORBIDITIES AMONG COGNITIVELY NORMAL AND IMPAIRED WHITE AND AFRICAN AMERICANS

Abstract Assessing comorbidities associated with a MCI diagnosis is crucial for diagnostic accuracy and for understanding the role of comorbidities in cognitive decline. In this study of amnestic (aMCI) and non-amnestic (naMCI) MCI participants and persons with normal cognition (CN), we compared the prevalence of three primary comorbidities: Hypertension (HTN), Hyperlipidemia (HLD), and Diabetes Mellitus (DM) across African American and White populations using Chi-squares. Participant data (N = 9,342, 17% African American) were available through the National Alzheimer’s Coordinating Center and included: CN (n = 5,963; MOCA mean=27), aMCI (2,694; MOCA=22), and naMCI (685; MOCA=24) with diagnosis and data per their first Uniform Data Set (Version 3) visit. Significant differences in the distribution of HTN, HLD, and DM were found among the diagnostic groups for the total cohort and racial groups, separately; however, diagnostic differences across races were not always consistent. The relative rates of DM and HLD across the diagnostic groups for both races were generally similar, though higher percentages were seen in African Americans (25% of African Americans, 10% of Whites). As for HTN (52% of African Americans, 39% of Whites), however, the distributions differ across the diagnostic groups and race (%yes for diagnosis; White Americans: CN 35%, aMCI 47%, naMCI 44%; African Americans: CN 66%, aMCI 70%, naMCI 79%, p< 0.001). These findings highlight the importance of considering the contributions of both race and diagnosis when evaluating the role of comorbid factors and metabolic disorders in NC and MCI groups, in particular when considering blood pressure-related measures.

Clinical Manifestations.

The Hachinski ischemic score (HIS) scale is used to exclude as much as possible, individuals with dominant cerebrovascular pathology from those with dominant AD pathology. White matter hyperintensities (WMH) are the gold-standard for evaluating cerebrovascular pathology and linked to worsening cognitive impairment. HIS ≤ 4 are used to minimize non-AD pathology in ADNI participants. Here we sought to understand whether HIS scores for hypertension (HMHYPERT) in ADNI3 were associated with greater WMH burden (and hence cerebrovascular pathology) even within individuals with HIS ≤ 4. We compared HMHYPERT scores between individuals with normal cognition (CN) and with mild cognitive impairment (MCI), and participants and correlated with percent WMH burden. A total of 263 subjects screened for ADNI3 (92 MCI [38 F], age = 73 ± 6; 146 CN [94 F], age = 74 ± 7) who had HIS scores and FLAIR MRI acquisitions within a year of each other. 25 All AD participants were excluded. WMH burden was calculated by segmenting them using the Lesion Segmentation Toolbox and normalizing their volume by total intracranial volume. We used the HMHYPERT as a vascular risk factor, excluding those with any focal neurological symptoms. For analysis, we dichotomized participants into those with HMHYPERT = 0 and HMHYPERT>0. To examine whether a non-zero HMHYPERT score corresponds to greater WMH burden, we examined the prevalence of WMH in between these 2 groups and within the MCI and CN groups. Although not significant, HMHYPERT scores were higher in MCI. (Fig. 1A, MCI = 0.48±0.50, CN = 0.39±0.49). We found a greater proportion of MCI subjects had HMHYPERT>0 than CN subjects (Fig. 1B, HMHYPERT = 0: CN = 61.0% and MCI = 52.2%; HMHYPERT > 0: CN = 40.0% and MCI = 48.1%). WMH burden was greater in MCI (0.33±0.53) than CN (0.20±0.32) (Fig. 2A). MCI participants with HMHYPERT>0 had the highest WMH burden followed by MCI participants with HMHYPERT = 0, CN with HMHYPERT >0, and CN with HMHYPERT = 0 had the lowest WMH burden. (Fig. 2B). Cerebrovascular pathology increases significantly with diagnosis, but its severity increases further with findings of hypertension even when total HIS ≤ 4.

Executive function performance depends on hypertension in individuals with sub‐threshold total Hachinski score

AbstractBackgroundThe Hachinski Ischemia Scale (HIS) differentiates AD and vascular dementia and is used to include individuals with minimal vascular risk factors in ADNI i.e., HIS ≤ 4. HIS score includes history of hypertension (HMHYPERT), a known risk for mild cognitive impairment (MCI) and vascular dementia. Cerebrovascular disease affects performance on tasks involving executive function, such as, planning and processing speed more than memory. Here, we determined if HMHYPERT scores influences executive functioning in all ADNI3 participants with normal cognition (CN) and MCI even with minimal vascular risks.MethodWe included a total of 272 participants (102 MCI, age = 74± 8 [42F, 50 HMHYPERT>0], MoCA = 23 ±3 and 170 CN, age = 73 ±6, [109F, 62 HMHYPERT>0], MoCA = 26 ±3), who underwent HIS, Trails Making Test B, Clock Drawing and Copy scores for executive function, and The Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory Test (LOGMEM) scores for memory performance within 12 months. We converted both memory tests into z‐scores and created a composite memory score. Similarly, we created a composite executive function score. To determine if HMHYPERT was associated particularly with executive function, we ran the linear regression analyses twice for the two composite cognitive scores. The following model was used: Composite score ∼ Normalized Age + Sex + Cognitive status * HMHYPERT.Result Executive function: Fig. 1 A shows scores for Trails B, Clock Draw and Clock Copy. The regression analysis showed that executive function was associated with only sex and HYMHYPERT (p<0.05).Memory function Fig. 1 B shows scores for Logical Memory and RAVLT tests in CN and MCI. As expected, MCI groups demonstrate the lowest averages compared to CN groups. As expected, regression analysis showed that memory performance was strongly determined by diagnostic status (p<0.001). Age was significantly associated with memory performance (p<0.05). HMHYPERT was only marginally significantly associated with memory performance (p = 0.08).ConclusionUsing HMHYPERT score as a measure of vascular risk, we observed notable differences in executive function. Although HIS scores ≤ 4 minimize vascular pathology in ADNI3, cognitive performance is still associated with these scores.

Associations between 5‐lipoxygenase activating protein (FLAP) genetic variation rs9551963 and Alzheimer’s disease phenotypes

AbstractBackgroundLeukotrienes are inflammatory mediators, synthesized by 5‐lipoxygenase and its activating protein (FLAP), and their activity may play a role in Alzheimer’s disease (AD). In AD mouse models, inhibition of FLAP improved memory and reduced amyloid (Aβ) deposition. Single nucleotide polymorphisms (SNPs) of ALOX5AP, which encodes FLAP, have been implicated in ischemic stroke in humans. However, there is limited research on the relationship between ALOX5AP and AD. This longitudinal study investigated associations between the ALOX5AP SNP rs9551963 A/C and various AD phenotypes.MethodParticipants from the Alzheimer’s Disease Neuroimaging Initiative (phases GO, 2, and 3) diagnosed with AD, mild cognitive impairment (MCI), or clinically normal cognition (CN) were categorized as minor allele carriers (AC, CC) or non‐carriers (AA) of rs9551963. Mini Mental State Exam (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) % forgetting were selected to assess cognition. Cerebrospinal fluid biomarkers and MRI brain volumetric data were also considered. Interactions between rs9551963 genotype and time (baseline, month 24, and month 48) were measured in mixed models. All models controlled for age, sex, and APOE e4 status; education and baseline intracranial volume were additional controls in cognitive and volumetric analyses respectively.ResultMinor allele carriers in the AD‐MCI Aβ‐positive group had worse decline on the MMSE (F1,297 = 5.33, p = 0.022, n = 521), and smaller volumes of whole brain (F1,146 = 7.13, p = 0.008, n = 408) and hippocampus (F1,132 = 6.38, p = 0.013, n = 377) over time that were not seen in other subgroups. In the AD subgroup, Aβ‐positive carriers had greater increases in RAVLT % forgetting scores (F1,135.5 = 6.19, p = 0.014, n = 158) and greater whole brain volume loss (F1,27.6 = 5.67, p = 0.024, n = 132), over time. These associations were not seen in Aβ‐negative participants.ConclusionMinor allele carriers of the ALOX5AP SNP rs9551963 who were Aβ‐positive showed greater loss of cognitive status and memory, and more hippocampal and whole brain atrophy, over time. These findings suggest a possible effect of leukotriene synthesis in the progression of AD.

5 Large-Scale Network Connectivity and Cognitive Function after Exercise Training in Older Adults

Objective:Despite growing evidence regarding the association between exercise training (ET) and functional brain connectivity, little is known about the effects of ET on within- and between-network functional connectivity (FC) of core brain networks. We investigated the effects of ET on within- and between-network functional connectivity of the default mode network (DMN), frontoparietal network (FPN), and salience network (SAL) in older adults with intact cognition (CN) and older adults diagnosed with mild cognitive impairment (MCI). We further examined whether the ET-induced changes in FC were associated with changes in cognitive performance.Participants and Methods:33 older adults (78.0±7.0 years; 16 MCI and 17 CN) participated in the present study. Before and after a 12-week walking ET intervention, participants underwent cardiorespiratory fitness tests, the Controlled Oral Word Association Test (COWAT), the Rey Auditory Verbal Learning test (RAVLT), a narrative memory test (logical memory; LM), and a resting-state fMRI scan. We examined the within- and between-network connectivity of the DMN, FPN, and SAL before and after ET. We also used linear regression to examine associations between ET-related changes in the within- and between-network connectivity and cognitive function.Results:There were significant improvements in VO2peak, COWAT, RAVLT, and LM after ET across participants. Significant increases in within-network connectivity of the DMN and SAL were observed in response to ET across participants. FC between the DMN-FPN, DMN-SAL, and FPN-SAL were also increased after ET. Moreover, greater SAL within connectivity and FPN-SAL between connectivity were associated with enhanced LM immediate recall performance after ET. There were no significant interactions between Time (before vs after ET) and Group (CN vs MCI) for network connectivity or cognitive function.Conclusions:Our findings suggest that increased within- and between-network connectivity following 12-weeks of walking exercise may subserve improvements in memory performance in older individuals with intact cognition and in those diagnosed with MCI.

Empathy deficits, callous-unemotional traits and structural underpinnings in autism spectrum disorder and conduct disorder youth.

Distinct empathy deficits are often described in patients with conduct disorder (CD) and autism spectrum disorder (ASD) yet their neural underpinnings and the influence of comorbid Callous-Unemotional (CU) traits are unclear. This study compares the cognitive (CE) and affective empathy (AE) abilities of youth with CD and ASD, their potential neuroanatomical correlates, and the influence of CU traits on empathy. Adolescents and parents/caregivers completed empathy questionnaires (N = 148 adolescents, mean age = 15.16 years) and T1 weighted images were obtained from a subsample (N = 130). Group differences in empathy and the influence of CU traits were investigated using Bayesian analyses and Voxel-Based Morphometry with Threshold-Free Cluster Enhancement focusing on regions involved in AE (insula, amygdala, inferior frontal gyrus and cingulate cortex) and CE processes (ventromedial prefrontal cortex, temporoparietal junction, superior temporal gyrus, and precuneus). The ASD group showed lower parent-reported AE and CE scores and lower self-reported CE scores while the CD group showed lower parent-reported CE scores than controls. When accounting for the influence of CU traits no AE deficits in ASD and CE deficits in CD were found, but CE deficits in ASD remained. Across all participants, CU traits were negatively associated with gray matter volumes in anterior cingulate which extends into the mid cingulate, ventromedial prefrontal cortex, and precuneus. Thus, although co-occurring CU traits have been linked to global empathy deficits in reports and underlying brain structures, its influence on empathy aspects might be disorder-specific. Investigating the subdimensions of empathy may therefore help to identify disorder-specific empathy deficits.

Odor Discrimination as a Marker of Early Alzheimer's Disease.

Olfactory dysfunction is an early symptom of Alzheimer's disease (AD). However, olfactory tests are rarely performed in clinical practice because their diagnostic efficacy in detecting early AD is unclear. To investigate odor discrimination in patients with early AD and the efficacy of olfactory discrimination tests in differentiating these patients from subjects with normal cognition (CN). Thirty patients each with mild dementia due to AD (MD-AD) and mild cognitive impairment due to AD (MCI-AD) and 30 older subjects with CN were enrolled. All participants underwent cognitive examinations (CDR, MMSE, ADAS-Cog 13, and verbal fluency) and odor discrimination tests (Sniffin' Sticks test, Burghart®, Germany). The MD-AD group achieved significantly worse scores on the olfactory discrimination test than the MCI-AD group, and the MCI-AD group achieved significantly worse results than the CN group (p < 0.05). A cut-off score of≤10 had a diagnostic accuracy of 94.44% (95% CI, 87.51-98.17%) in differentiating patients with MCI-AD/MD-AD from subjects with CN and of 91.67% (95% CI, 81.61-97.24%) in differentiating those with MCI-AD from subjects with CN. Our multinomial logistic regression model with demographic data and ADAS-Cog 13 scores as predictor variables correctly classified 82.2% of the cases (CN, 93.3%; MC-AD, 70%; MD-AD, 83.3%); on adding the olfactory discrimination score to the model, the percentage increased to 92.2% (CN, 96.7%; MCI-AD, 86.7%; MD-AD, 93.3%). Odor discrimination is impaired in cases of early AD and continues to deteriorate as the disease progresses. The olfactory discrimination test showed good diagnostic efficacy in detecting early AD.

A study on factors associated with age of Alzheimer's disease onset

Objective: To understand the distribution characteristics of age of Alzheimer's disease (AD) onset and influencing factors. Methods: Based on the follow-up data of Alzheimer's Disease Neuroimaging Initiative from 2005 to 2022, participants with normal cognition (CN) or mild cognitive impairment (MCI) at baseline survey, and those with progression to AD during follow-up period were selected as study subjects. Univariate analysis and multiple linear regression analysis were performed to explore the associations of gender, race, number of ApoE ε4 genes carried, family history, years of education and marital status with the age of AD onset. Results: A total of 405 participants, with an average age of (74.0±6.9) years at baseline survey, progressed to AD during follow up period. The age of AD onset was (76.6±7.5) years, and age of onset in men was about 1.9 years later than women. Multiple linear regression analysis showed that for each increase in ApoE ε4 gene number, the age of AD onset was about 0.344 years earlier. The age of AD onset was 4.007 years earlier for those with MCI at baseline survey compared with those with CN. Years of education were not significantly associated with the age of onset of AD (P>0.05). Conclusion: Those who carry ApoE ε4 gene, and have MCI at baseline survey might have earlier age of AD onset.

Arterial stiffness and physical fitness on cognitive function in community-dwelling middle-aged and older adults.

This study examined whether decline in cognitive function is related to arterial stiffness and reduction in physical fitness in middle-aged and older adults. A total of 1554 healthy middle-aged and older adults participated in this study. The trail making test parts-A (TMT-A) and B (TMT-B), brachial-ankle pulse wave velocity (baPWV), grip strength, the 30-s chair stand (CS-30) test, the 6-min walk (6MW) test, the 8-foot up-and-go (8UG) test and gait assessment were performed. Participants were classified into a middle-aged group (40-64years; mean, 50.4 ± 0.2years) or an older group (≥ 65years; mean, 73.1 ± 0.5years), as well as into three cognition (COG) groups (high, moderate, and low) based on median TMT-A and -B scores (high scores on both, either, or neither TMT-A and -B, respectively). The results revealed that baPWV was significantly lower in the high-than in the moderate- and low-COG groups in both middle-aged and older adults (P < 0.05). In addition, except for a few parameters (e.g., 6MW test in middle-aged adults), physical fitness was significantly higher in the high-than in the moderate- and low-COG groups in both middle-aged and older adults (P < 0.05). Multivariate regression analysis revealed that baPWV (P < 0.05) and some physical fitness indicators (grip strength, CS-30, and 8UG) were significantly independently associated with both TMT-A and -B in the middle-aged and older groups (P < 0.05). These results suggest that increased arterial stiffness and reduced physical fitness are associated with impaired cognitive function in middle-aged and older adults.

Evaluating Dementia Neuroanatomic Risk of a Clinical Cohort Using MRI

AbstractBackgroundMRI is a widely used modality to evaluate dementia risk. Here, we extend previous work by estimating the Alzheimer’s disease pattern similarity (AD‐PS) scores for participants of a community‐dwelling older adult cohort to evaluate neuroanatomic risk of AD using MRI.MethodBaseline MRI data were available from 522 participants from the Wake Forest Alzheimer’s Disease Research Center’s (ADRC) Clinical Core with mean age 70.2, 81.2% White and 17.6% African American. Of those, 253 were cognitively impaired (dementia and mild cognitive impairment (MCI)) and 138 underwent [11C]PiB PET (MCI = 48 and dementia = 19). Global PiB SUVR was averaged from a cortical region of interest sensitive to early AD. Participants were classified as amyloid positivity using a previously defined threshold (≥1.21 SUVR). AD‐PS scores were estimated based on GM probability maps according to previously reported machine learning methodology[1]. High‐dimensional classifiers were trained using ADNI MRI data. To generate the AD‐PS scores, MRI data from the ADRC cohort was provided as input to the classifiers.We investigated associations that AD‐PS scores [range 0‐1] had with amyloid positivity and cognitive impairment. All analyses were adjusted for age, sex, race and education. AD‐PS scores discrimination of participants with dementia versus normal cognition (CN) was compared to hippocampal volume and cortical thickness in temporal regions based meta‐ROI which are sensitive to AD.ResultAD‐PS scores were strongly associated with cognitive impairment: OR = 4.1, CI: 95% [2.9‐5.9], p&lt;0.0001. In addition, they were associated with amyloid positivity with OR = 2.8,CI: 95% [1.7‐4.7], p&lt;0.001, N = 138. These amyloid positivity results did not hold in analyses limited to CN participants only(N = 71). Performance when discriminating patients with dementia from CN individuals was highest for AD‐PS score (AUC = 92.2, CI: 95% [86.9‐97.5]), followed by hippocampal volume (AUC = 86.5, CI: 95% [81.1‐91.2]) and cortical thickness in temporal regions based meta‐ROI (AUC = 81.5 CI: 95% [74.4‐88.6], See‐Figure).ConclusionThis work highlights further the generalization performance of our machine learning algorithm. AD‐PS scores, a measure of dementia neuroanatomic risk, strongly discriminated individuals with dementia from CN individuals in the Wake Forest ADRC.

Large-Scale Network Connectivity and Cognitive Function Changes After Exercise Training in Older Adults with Intact Cognition and Mild Cognitive Impairment.

Despite growing evidence regarding the association between exercise training (ET) and functional brain network connectivity, little is known about the effects of ET on large-scale within- and between-network functional connectivity (FC) of core brain networks. We investigated the effects of ET on within- and between-network functional connectivity of the default mode network (DMN), frontoparietal network (FPN), and salience network (SAL) in older adults with intact cognition (CN) and older adults diagnosed with mild cognitive impairment (MCI). The association between ET-induced changes in FC and cognitive performance was examined. 33 older adults (78.0±7.0 years; 16 MCI and 17 CN) participated in this study. Before and after a 12-week walking ET intervention, participants underwent a graded exercise test, Controlled Oral Word Association Test (COWAT), Rey Auditory Verbal Learning Test (RAVLT), a narrative memory test (logical memory; LM), and a resting-state fMRI scan. We examined the within (W) and between (B) network connectivity of the DMN, FPN, and SAL. We used linear regression to examine associations between ET-related changes in network connectivity and cognitive function. There were significant improvements in cardiorespiratory fitness, COWAT, RAVLT, and LM after ET across participants. Significant increases in DMNW and SALW, and DMN-FPNB, DMN-SALB, and FPN-SALB were observed after ET. Greater SALW and FPN-SALB were associated with enhanced LM immediate recall performance after ET in both groups. Increased within- and between-network connectivity following ET may subserve improvements in memory performance in older individuals with intact cognition and with MCI due to Alzheimer's disease.

Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment.

The last few years have seen major advances in blood biomarkers for Alzheimer's Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias. We evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. Two sets of banked plasma samples from the Massachusetts Alzheimer's Disease Research Center's longitudinal cohort study were examined: A longitudinal prognostic sample (n = 85) consisting of individuals with mild cognitive impairment (MCI) and 4 years of follow-up and a cross-sectional sample (n = 238) consisting of individuals with AD, other neurodegenerative diseases (OND), and normal cognition (CN). Participants with MCI who progressed to dementia due to probable AD during follow-up had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors. The best prognostic discrimination was observed with pTau181 (AUC = 0.83, 1.7-fold increase) and GFAP (AUC = 0.83, 1.6-fold increase). Participants with autopsy- and/or biomarker verified AD had higher plasma levels of pTau181, tTau and GFAP compared to CN and OND, while NfL was elevated in AD and further increased in OND. The best diagnostic discrimination was observed with pTau181 (AD vs CN: AUC = 0.90, 2-fold increase; AD vs. OND: AUC = 0.84, 1.5-fold increase) but tTau, NfL, and GFAP also showed good discrimination between AD and CN (AUC = 0.81-0.85; 1.5-2.2 fold increase). These new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP demonstrated diagnostic utility for detection of AD. Moreover, the absolute baseline plasma levels of pTau181 and GFAP reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations.