Normal Cognition Research Articles

The association of gait velocity and cognitive performance in a sample of older Chinese Americans: A pilot study

AbstractBackgroundGait velocity and cognition generally decline as individuals age. Studies have indicated that gait velocity can be used as a simple, novel, and relatively culture‐free cognitive assessment tool in older adults, particularly in domains of memory, attention, and executive function. There is limited research in this area with racial/ethnic minority groups. This study examined the association between performance on specific cognitive domains and gait velocity in older Chinese Americans – a growing, yet underrepresented group in US‐based research.Method71 Chinese American older adults (age 73.6 ± 6.9) with normal cognition (n = 27), mild cognitive impairment (n = 32), and early dementia (n = 12) were included in a pilot study at the Alzheimer’s Disease Research Center (ADRC) at Mount Sinai. Participants underwent a standard dementia evaluation in Mandarin/Cantonese, which included a clinical interview, medical exam, and neuropsychological testing. All participants self‐reported as Chinese Americans who were primarily Cantonese‐ or Mandarin‐speaking. Exclusion criteria included: not proficient in Cantonese/Mandarin, mobility impairment, as well as history of psychiatric disorder(s) and cerebrovascular accident. Diagnoses were assigned at a consensus conference. Exploratory factor analysis was conducted to determine cognitive domains encompassing the neuropsychological battery, which included tests of processing speed/attention, executive function, memory, and language/verbal fluency. Gait velocity was measured with a walking speed test measured in seconds. Multiple linear regression was used to examine the association between gait velocity and cognitive performance, while controlling for age, education, depression measured by Geriatric Depression Scale (GDS), and lifestyle/medical factors (e.g., tobacco/alcohol use, hypertension).ResultFactor analysis demonstrated 4 principal neuropsychological factors: non‐contextual memory, contextual memory, processing speed, and language/verbal fluency. The regression model showed that lower scores on a test of non‐contextual memory was associated with slower gait velocity. Higher GDS scores were associated with slower gait velocity.ConclusionConsistent with previous studies with predominately non‐Hispanic White samples, we found an association between gait velocity and non‐contextual memory in older Chinese Americans. In contrast to the literature, no other cognitive domains were significant in this small sample. The finding provides preliminary data to support the use of gait velocity as a novel cognitive assessment in this historically underrepresented group.

Homocysteine, vitamin B12, folic acid levels and its association with Mild Cognitive Impairment in urban and rural dwelling Indians

AbstractBackgroundHomocysteine (Hcy) is a sulfur containing amino acid generated in the metabolism of methionine involving co‐factors such as B vitamins and folic acid. Deficiency of these co‐factors have been associated with increased Hcy levels (Hutto, 1997). Relationship between differing levels of plasma Hcy, vitamin B12, folic acid and cognitive impairment is inconclusive.MethodCross sectional analysis was done using the baseline data from two ongoing longitudinal studies such as Tata Longitudinal Study of Ageing (TLSA, N = 984) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG, N = 4404), an urban and rural cohorts (Sundarakumar et al, 2020) respectively. Hcy, vitamin B12, folic acid levels were compared between the subjects of both cohorts. Comparison of these levels between healthy and MCI (Mild Cognitive Impairment) subjects within and across the cohorts were done. CDR (Clinical Dementia Rating) scale was used to classify subjects having normal cognition and MCI, considering score of 0.5 as MCI. Mann‐Whitney U test was used to compare these levels between the groups.ResultHcy, vitamin B12, folic acid levels between the two cohorts showed significant difference, with higher levels of Hcy (median (IQR)) = (17.08 (11) vs 14.63 (10); p <0.001), vitamin B12 (247 (252) vs 220 (143); p <0.001) and folic acid (8.55 (9) vs 5.55(4); p <0.05) in TLSA than SANSCOG. Significant difference seen in Hcy (17.73(11) vs 14.73 (10); p <0.001), vitamin B12 (246 (249) vs 220 (136); p <0.001) and folic acid (8.42 (9) vs 5.53 (4): p <0.001) levels for healthy subjects between cohorts, higher levels were seen in TLSA subjects. Hcy (16.08 (8) vs 14.43 (12); p <0.001) vitamin B12 (305 (341) vs 216 (174); p = 0.03) and folic acid (8.52 (9) vs 5.34 (4): p <0.001) levels were significantly high in TLSA than SANSCOG for MCI subjects. However, these levels were not significantly different between healthy and MCI subjects within cohorts.ConclusionConsistently elevated levels of Hcy was observed in urban cohort. Though elevated level of Hcy was observed with normal vitamin B12 and folic acid, it was not associated with MCI.

Plasma biomarkers across the spectrum of Alzheimer’s and Parkinson’s disease: Association with cortical thickness and cognitive dysfunction

AbstractBackgroundPlasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition.Method290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education.ResultThere was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C).ConclusionWe conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients.

Wisconsin Longitudinal Study (WLS), the Initial Lifetime’s Impact on Alzheimer’s Disease (WLS‐ILIAD): A Novel Opportunity to Study the Influence of Education on ADRD

AbstractBackgroundThe importance of education in shaping brain health and dementia risk are increasingly supported, although the mechanisms by which these life course factors impact late life cognition remain elusive due to a scarcity of full life‐course longitudinal studies. A new data collection wave of the Wisconsin Longitudinal Study (WLS), the Initial Lifetime’s Impact on Alzheimer’s Disease (WLS‐ILIAD), stands to address this gap. The WLS cohort is a randomly selected community sample that’s been followed since 1957, offering a wealth of prospectively collected lifespan data to pull from. Now that this cohort has reached their 80’s, the ILIAD study aims to detect dementia prevalence in this sample, and when combined with prior data waves, offers an unparalleled opportunity to explore how full life‐course and sociodemographic factors shape the relationship between education and dementia risk and resilience.MethodWLS‐ILIAD employs a multi‐phasic study design. In Phase 1, the modified Telephone Interview for Cognitive Status (TICS‐m) was administered to all eligible participants to screen for dementia risk. Those performing below cutoff (TICS‐m≤28) were selected for Phase 2 to complete more robust cognitive assessment and to obtain comprehensive health history. Cognitive diagnoses were determined by multidisciplinary consensus panel. Proxy assessments were employed for participants who were deceased or unable to complete the assessment.ResultPreliminary results indicate a response rate of ∼78%. Approximately 4,800 participants completed Phase 1, with 1,227 (26%) falling below cutoff for dementia risk (TICS‐m≤28). Of those completing Phase 2, 460 participants were classified as normal cognition, 443 mild cognitive impairment (MCI), and 197 dementia. Another 300 dementia cases were identified via proxy. Participants diagnosed with MCI or dementia tended to be older, ApoeE‐4 allele carriers, and had a lower high school IQ. Of those diagnosed with dementia, 88% reported no prior clinical workup or existing cognitive diagnosis.ConclusionResults of the WLS‐ILIAD study yields detailed cognitive diagnostic classifications for this sample. When combined with prospectively collected life course data, the WLS cohort offers a unique opportunity to explore the impact of education on risk and resilience factors for dementia outcomes, leading to important public policy and public health implications.

Examination of plasma YKL‐40 as a clinical biomarker for Alzheimer’s disease

AbstractBackgroundBlood biomarkers represent a potential non‐invasive and cost‐effective strategy for the clinical detection and monitoring of neurodegenerative conditions including Alzheimer’s disease (AD). YKL‐40 is a secreted glycoprotein associated with inflammatory processes, and elevated cerebrospinal fluid levels have been observed in AD and other neurodegenerative conditions. Fewer studies have examined plasma YKL‐40. We examined relationships between plasma YKL‐40 and clinical indices of AD in a large cross‐sectional sample from a clinical cohort registry.MethodThe sample included 569 participants from the Boston University Alzheimer’s Disease Research Center, including participants with normal cognition (NC; n = 235), mild cognitive impairment due to suspected AD (MCI; n = 181), and AD dementia (n = 153). Blood plasma samples were analyzed using standard ELISA methods; values were log transformed and standardized into z‐scores. Cross‐sectional analyses investigated the relationships between YKL‐40 and clinical indices of functioning including diagnostic status, dementia severity (on the Clinical Dementia Rating scale [CDR]), and neuropsychological test performance. Age, sex, education, race, and APOE ε4 carrier status were included as covariates in all analyses.ResultNo significant differences in plasma YKL‐40 were observed between participants with NC, MCI, and AD dementia after accounting for covariates. The comparison between MCI and dementia was marginally significant (p = .07), with an adjusted mean difference of Z = 0.19. For participants with dementia (CDR scores 1‐3), non‐significant trends were observed for relationships between plasma YKL‐40 values and dementia severity, including for Sum of Boxes (Pearson partial correlation: r = .14, p = .10) and Total Score (ordinal logistic regression: OR = 1.38; 95% CI: [0.98,1.93]), p = .06. Modest but significant correlations were observed between YKL‐40 and performance on 4/12 neuropsychological tests including Animal Fluency (r = ‐.10), Vegetable Fluency (r = ‐.09), and Neuropsychological Assessment Battery List Learning Trials 1‐3 (r = ‐.10) and Short Delay (r = ‐.12).ConclusionPlasma YKL‐40 biomarker levels were modestly related to neuropsychological assessments of language and memory but not significantly related to cognitive diagnosis of AD or dementia severity. This biomarker may reflect underlying inflammatory processes in the context of AD. However, the use of plasma YKL‐40 to assess the presence and severity of AD in a larger cross‐sectional sample size, and using a multiple biomarker approach, warrant further study.

Development of an innovative computerized assessment of instrumental activities of daily living

AbstractBackgroundFunctional impairment is a diagnostic criterion for dementia and distinguishes mild cognitive impairment (MCI) from dementia. Self‐ or informant reports are most commonly used but can be biased and may not reflect actual functional ability. Alternatives include performance‐based assessments, such as the Sydney Test of Activities of daily living in Memory disorders (STAM). The aim of this study is to develop, and validate, a new computerised diagnostic tool (C‐STAM) to assess functional ability that can be administered remotely to increase accessibility. The C‐STAM will realistically simulate everyday activities to assess functional performance.MethodThe C‐STAM is being developed by a multidisciplinary team of psychologists, old age psychiatrists, occupational therapists, and computer scientists. A Delphi study with 31 international experts was conducted to select and refine suitable tasks. An additional step is consultation with consumers (i.e., older people with and without cognitive impairment) and caregivers who have an active role in shaping the C‐STAM. A pilot study with 30 people aged 60+ with normal cognition, MCI, and dementia plus their informants will assess feasibility and user‐experience. After adjustments based on the pilot study, we will conduct a validation study with 180 participants and their informants.ResultThe Delphi study resulted in nine C‐STAM tasks, addressing the domains of communication, shopping, dressing, community mobility, handling finances, managing medications, and memory. Feasibility and acceptability of these tasks will be confirmed through pilot testing and the validation study. We will develop an automated scoring and interpretation guide, age‐ and sex‐specific norms, and clinical cut‐offs to differentiate the three diagnostic groups. Automated data exporting and reporting will be useful for clinical referrals and in research and will facilitate interpretation and communication of results across different clinical settings.ConclusionThe C‐STAM will facilitate early diagnosis of dementia and MCI and will enable a better understanding of disease progression by monitoring functional ability in a time‐ and resource‐efficient way. Results will be used to inform service development to better meet the needs of people with dementia for access to appropriate assessments of functional performance. The C‐STAM will be freely available for use by clinicians and in research.

Clinical Manifestations.

Cognitive decline is most often assessed mean group differences on static measures of cognitive abilities (MacDonald et al., 2009). Another, perhaps more dynamic, method to understanding cognitive functioning is to evaluate variability in performance within an individual, termed intraindividual variability (IIV), which has been associated with reduction in gray matter and less efficient cognitive processing. Using results from a multi-site, longitudinal ARMADA study that validated NIH Toolbox across the cognitive aging spectrum, we investigated whether IIV in reaction time processing can differentiate between older adults with normal cognition, mild cognitive impairment (MCI), or dementia of the Alzheimer type (DAT), as well as the relative magnitude of differences between groups. As part of the Advancing Reliable Measurement in Alzheimer's Disease and cognitive Aging study (ARMADA; Weintraub et al 2020), participants completed the NIH Toolbox Cognition Battery, including two measures of executive functioning, Dimensional Change Card Sort and Flanker Inhibitory Control, which include granular reaction time data in milliseconds. We analyzed standard deviation and mean absolute deviation of item-level data of all trials, correct trials only, and incorrect trials only for three groups: normal controls, those with amnestic MCI, and those with mild DAT. We observe large effect sizes of reaction time by clinical group, with the mild DAT group demonstrating mean standard error across trials of approximately .5 seconds throughout, compared with .25 seconds for MCI and .10 seconds for the control group (Figure 1). This translates to an approximate 5-fold increase in processing speed in the most severe clinical group. Examining time trends, we see that while the NC and MCI group were faster as the test progressed; there is no similar learning effect for the mild DAT group. Similar effect sizes were observed for the Flanker test. This study represents one of the first studies to examine clinical performance using process data from two executive functioning measures on the NIH Toolbox across the cognitive aging spectrum. Future work will explore more definitions of IIV to determine which measure will maximally differentiate between established clinical groups and examine longitudinal differences.

PREVENT‐AD cohort: from normal to impaired cognition, who are declining and why? Preliminary results

AbstractBackgroundThe StoP‐Alzheimer Center follows a cohort of cognitively normal participants at risk of developing Alzheimer’s disease (AD) due to their parental history (PREVENT‐AD cohort). Cognitive impairments were detected in 17% of the cohort (66 out of 386) mostly after between 4 to 6 years of follow‐up, at an average age of 70 ± 7 years of age.MethodWe looked at various variables at baseline (demographics, blood results, medical history, cognition, genetic variants, AD pathology, mood) to describe the differences between the participants who maintained a normal cognition versus those who declined.ResultDifference in ApoE4 status was not as important as expected with 39.4% ApoE4 carriers in the decliner group compared to 38.2% in the normal group (Table 1). Despite a normal cognition at baseline, we found subtle but significant lower cognitive performance in the decliner group on the MoCA (‐1 pt) and the Repeatable Battery for the Assessment of Neuropsychological Status (‐5 pts). Systolic blood pressure and glycosylated hemoglobin were slightly more elevated in the decliner group (132 mmHg versus 128 mmHg and 5.6% versus 5.4% respectively). When asked about their past medical history, more participants were treated for hypertension, hyperlipidemia and diabetes in the decliner group. At the level of brain AD pathology measured by PET, the decliner group presented higher levels (standard uptake values) of amyloid and tau. Overall, 27% of the decliner group were amyloid AND tau positive compared to 7% in the normal group. The decliner group also showed lower smell identification performances at baseline when compared to the group who didn’t decline.ConclusionMain differences between the groups at baseline are related to AD pathology, vascular risk factors and cognitive and smell identification capacities. Other available variables such as brain structure, cerebrospinal fluid proteins, additional cognitive tests, lifestyle questionnaires, and genetics variants need to be analyzed along with trajectories and change over time. As a growing number of participants are declining cognitively and are still followed annually with multimodal evaluations, we trust that further investigations will help better understand the development of cognitive impairment.

AD8 revisited: what’s the optimal cutoff value?

AbstractBackgroundThe 8‐item Informant Interview to Differentiate Aging and Dementia (AD8) was developed as a screening tool for dementia with a cutoff of 2 suggested by the initial study. However, various studies found different cutoff values, and many suggested a cutoff of 2 might result in a high false positive rate (up to > 80%). A higher false positive rate in Taiwan was repeatedly shown when AD8 was self‐administered in local government screening programs. This study aimed to examine the performance of AD8, determine its best cutoff value, and discuss factors that may affect the performance of AD8.MethodWe recruited 119 participant‐informant dyads from a psychiatric outpatient clinic of a university medical center. For each dyad, the AD8 was administered first, and then Mini‐Mental Status Examination (MMSE) and the Clinical Dementia Rating (CDR) to minimize contamination effect. Two geriatric psychiatrists made a consensus clinical diagnosis for each subject based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) using all available clinical information, including MMSE, CDR, clinical history, other past neuropsychological tests, and neuroimaging examinations (if available).ResultThere were 37 subjects with normal cognition, 44 with mild neurocognitive disorder (mild NCD), and 28 with major neurocognitive disorder (major NCD). When the cutoff value was 2 for the differentiation between major NCD and no‐dementia subjects (including normal cognition and mild NCD), the AD8 had an AUC of 0.756, a sensitivity of 0.929, and a specificity of 0.582. But the optimal cutoff value was 4 according to the Youden index, with an AUC of 0.888, a sensitivity of 0.786, and a specificity of 0.835.ConclusionAlthough many studies recommended 2 as the best cutoff value for screening dementia, our findings and those of others suggest a cutoff of 2 may result in a high false positive rate. Many factors could affect the performance of AD8, including sample characteristics (e.g. education level), region, conduct of the test, flow of the administration (whether AD8 is administered first or contaminated by other tests), etc. Details will be discussed during the AAIC meeting.

P33: A Re-Evaluation Study and Literature Review on AD8 as a Screening Tool

Objective:The 8-Item Informant Interview to Differentiate Aging and Dementia (AD8) was developed as a screening tool for dementia with a cutoff of 2 suggested by the initial study. However, various studies found different cutoff values, and many found a cutoff of 2 might result in a high false positive rate. Furthermore, a higher false positive rate in Taiwan was repeatedly shown when AD8 was self-administered in local government screening programs. This study aimed to test the performance of AD8, define its best cutoff value, review factors that may affect its performance, and reconsider its proper role in clinical practice.Methods:We recruited 118 participant-informant dyads from a university teaching hospital. For each informant, the AD8 was administered first and then the Clinical Dementia Rating to minimize contamination effect. For each participant, two geriatric psychiatrists considered history, physical and mental status examination, laboratory testing, neuropsychological testing, and neuroimaging results to make the final consensus diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. The receiver operator characteristic curve was used to assess the diagnostic performance of AD8.Results:There were 59 subjects with normal cognition, 28 with mild neurocognitive disorder, and 31 with major neurocognitive disorder or dementia. To discriminate between dementia and non- dementia, a cutoff of 2 resulted in a sensitivity of 0.903, specificity of 0.598, and area under the curve (AUC) of 0.751. Moving the cutoff to 3 and 4 led to better specificity (0.7126, 0.8621) and greater AUC (0.776, 0.818), albeit some loss in sensitivity (0.8387, 0.7742). The best cutoff score was 4 based on the Youden index. Without considering the mild cognitive impairment group, the optimal cutoff remained at 4, with equal sensitivity and even higher specificity.Conclusion:Our findings suggest the AD8 may perform better and have a lower false positive rate with a cutoff value higher than 2. A literature review found its performance could be affected by disease prevalence across various healthcare settings, education level, regions, respondents’ personality and understanding of questions, conduct of test, flow of test administration, etc. We will discuss the details and best screening strategies at the IPA Congress.

Diffusion MRI free water in hippocampal subfields CA3 and CA1 tracks progression in prodromal and overt synucleinopathy

AbstractBackgroundPostmortem study of the hippocampal subfields in the Lewy body dementias has revealed selective involvement of CA3 with synuclein pathology and CA1 with amyloid and tau, i.e., Alzheimer’s disease (AD) co‐pathology (Coughlin et al., 2020, PMID:32892355). However, new neuroimaging methods are needed to study the hippocampal subfields in vivo in synucleinopathies. Diffusion MRI free water (FW) measurement detects increased hippocampal FW in AD (Ofori et al., 2019, PMID:31470214). However, typical diffusion MRI protocols have voxels = 2 mm3 making hippocampal subfield imaging infeasible due to volume averaging effects. To address this, we developed a high‐resolution diffusion MRI protocol capable of imaging the hippocampal subfields. We applied this approach to study a prodromal synucleinopathy group – idiopathic REM sleep behavior disorder (iRBD), as well as PD with normal cognition (PD‐NC), PD with cognitive impairment (PD‐CI), and dementia with Lewy bodies (DLB).MethodParticipants with PD‐NC, PD‐CI, DLB, and polysomnographically confirmed iRBD were recruited at Emory University. T1 MPRAGE (0.8mm3 voxels) and high‐resolution diffusion MRI (b = 0, 500mm2/sec; 30 diffusion directions; 1.1mm3 voxels) data were acquired with a Siemens 3T Prisma‐fit system. FreeSurfer v7 was used to segment hippocampal subfields. FW was measured as described in Ofori, et al (2017, PMID:28714593). Groups were compared using ANCOVA followed by post‐hoc tests, and clinical and MRI features were correlated.ResultTable 1 shows group demographic and clinical characteristics. A progressive increase in CA3 and CA1 FW was observed from iRBD to PD‐NC to PD‐CI and DLB, and the ANCOVA model, controlling for age, found a statistically significant difference between groups for CA3 FW (Figure 1). Figure 2 shows statistically significant negative correlations between MoCA and hippocampal FW measures and between years of education and FW in CA3 and CA1.ConclusionCA3 and CA1 FW are significantly increased in advanced synucleinopathy (DLB, PD‐CI) as compared to iRBD, and PD‐NC has intermediate values. Strong negative correlations between CA3 and CA1 FW and cognition further indicate that these measures may track disease progression. The negative correlations between CA3 and CA1 FW and education also suggest that these measures may be biological correlates of cognitive reserve.

Amyloid‐β and tau accumulation in traumatic brain injury: A study of Vietnam war veterans

AbstractBackgroundTraumatic brain injury (TBI) is widely viewed as a risk factor for dementia. Since amyloid‐β and tau pathology have been reported in up to a third of individuals with TBI – even after a single TBI event – their accumulation could be a potential mechanism underlying this association. The aim of this study was to examine the relationship between TBI and amyloid‐β and tau pathology more closely and to assess whether the association between amyloid‐β and tau is influenced by TBI status.MethodA total of 102 Vietnam war veterans (79% normal cognition, 21% mild cognitive impairment; 23% amyloid‐β positive) were included from the Alzheimer’s Disease Neuroimaging Initiative Department Of Defense study. Among these individuals, 65 had a history of TBI (42 mild and 23 moderate/severe TBI) whereas 37 did not. Amyloid‐PET ([18F]florbetapir) and tau‐PET ([18F]flortaucipir) SUVRs were assessed within regions from the Schaefer atlas. For both amyloid‐PET and tau‐PET ROI‐wise and global TBI group differences were determined by ANCOVAs. Moderating effects of TBI status on the association between ROI‐wise amyloid‐PET and tau‐PET SUVRs were tested using linear regression. Analyses were adjusted for age, sex, education, clinical diagnosis, and, where applicable, global amyloid‐PET and time lag between amyloid‐ and tau‐PET scans.ResultTBI groups did not show significant increases in amyloid‐ or tau‐PET uptake compared to no‐TBI groups, neither globally nor on the ROI‐level (i.e. all p>0.05 after correcting for multiple comparisons, Fig. 1). However, we found that a history of (particularly moderate/severe) TBI was associated with a weaker relationship between amyloid‐PET and tau‐PET uptake in temporal and parietal brain regions compared to no history of TBI (Fig. 2). This effect seemed to be driven by the amyloid‐β positive group. TBI groups did not differ regarding age and APOE‐status.ConclusionWhile amyloid‐β is known to promote tau spreading in Alzheimer’s disease (AD), our results indicate that in TBI there might be a detachment of amyloid‐β and tau pathology in AD‐susceptible temporo‐parietal brain regions. This finding is supportive of the view that TBI could lead to distinct changes in the interplay of pathological proteins, potentially underlying the link between TBI and dementia.

Using plasma ptau181 in Lewy Body Disease spectrum for the identification of Alzheimer’s disease co‐pathology

AbstractBackgroundLewy body disease (LBD) patients frequently present with Alzheimer’s disease (AD) co‐pathology, which influences disease progression, cognitive decline, and brain atrophy. AD‐related pathology can be identified with new blood‐based biomarkers like plasma phosphorylated‐tau181 (ptau181).We aimed to determine whether plasma ptau181 helps identify AD‐related co‐pathology in LBD, and whether plasma ptau181 is associated with clinical features, and AD cerebrospinal (CSF) biomarkers.MethodFrom a total of 632 Stanford research participants, we selected 245: 115 cognitively normal (CN), 47 Parkinson’s disease (PD) with normal cognition, 47 on the LBD spectrum (31 MCI and 16 dementia), and 36 on the AD spectrum (14 MCI and 22 dementia). Plasma ptau181 levels were measured with Lumipulse G fully automated platform by Fujirebio with Lumipulse G Assays. A subset of the participants had available AD CSF biomarkers (N = 201) and/or 18F‐Florbetaben PET imaging (N = 73). Diagnostic accuracy was evaluated with area‐under‐the‐curve (AUC) values from receiver‐operating characteristic (ROC) analyses. Linear regression models adjusted for confounding factors were used to analyze effects of baseline plasma ptau181 levels on global cognition (MoCA), global function (CDR‐SOB), motor function (UPDRS Part III), and functional disability (Hoehn and Yahr).ResultPlasma ptau181 levels were higher in the LBD spectrum group compared to CN and PD with normal cognition groups, but lower than in the AD spectrum group.Plasma ptau181 levels predicted CSF ptau181/Aβ42 ratio in LBD spectrum patients with an AUC = 0.87. Including age, sex, years of education, and APOE E4 genotype levels improved the prediction of the model (AUC = 0.94).In the LBD spectrum group, males and females showed similar plasma ptau181 levels, and we found no association between plasma ptau181 levels with age, sex, years of education, MoCA, CDR‐SOB, UPDRS Part III, or Hoehn and Yahr. Nevertheless, plasma ptau181 levels were associated with CSF ptau181 levels and amyloid‐β42/40 after controlling for age and sex.ConclusionPlasma ptau181 levels help identify LBD patients with AD co‐pathology, and are associated with AD CSF biomarkers. These findings support the use of plasma ptau181 as a screening tool for AD co‐pathology in patients with LBD and cognitive impairment.

Fatigue Interacts with Amyloid Status To Predict Daily Working Memory Performance in Preclinical Alzheimer’s Disease

AbstractBackgroundSmartphone‐based cognitive assessment has the potential to reduce barriers to cognitive screening and increase sensitivity to detect preclinical Alzheimer’s disease (AD). Ecological momentary assessment of cognition is novel, and it is not yet well understood how psychological factors (i.e., mood, stress, and fatigue) may impact cognitive performance in remote, real‐world settings. We aimed to evaluate whether psychological factors influence daily cognitive performance differently between older adults with and without AD‐related pathologic change.MethodParticipants (N = 73) were cognitively unimpaired adults aged 60‐80 years (71% female, 89% White, 16.5 mean years of education) recruited for a digital cognitive assessment study. Participants had amyloid (Aβ) PET imaging results available from prior research participation [(n = 25 Aβ positive (Aβ+) and n = 48 Aβ negative (Aβ‐)]. A modified Telephone Interview for Cognitive Status (TICSm) score of ≥34 was used to indicate normal cognition. Participants completed 8 consecutive days of cognitive assessment using Mobile Monitoring of Cognitive Change (M2C2), a smartphone‐based testing platform developed as part of the National Institute of Aging’s Mobile Toolbox. Brief (i.e., 3‐4 minute) M2C2 sessions were assigned three times daily (morning, afternoon, and evening). Tasks included measures of visual working memory (WM, “Color shapes”), processing speed (PS, “Symbol search”), and episodic memory (EM, “Prices”). Multilevel modeling was used to examine the impact of self‐reported mood, stress, fatigue, and Aβ status on daily cognitive performance while controlling for age, sex, education, and time of day.ResultDaily fatigue was found to interact with amyloid status such that Aβ+ individuals performed worse on the WM task when experiencing higher levels of fatigue (Est. = .004, p = .01) Higher levels of daily stress were associated with poorer performance on the PS task (Est. = ‐.0005, p = .03) but no interaction with Aβ status was observed. There were no significant relationships between mood and cognitive performance.ConclusionWe demonstrated that psychological factors including fatigue and stress may impact performance on remote cognitive assessments. Results also suggested that fatigue may impact daily cognitive performance more among those with AD pathological change. These preliminary results suggest that psychological factors should be considered when determining optimal windows for remote cognitive screening.

Biomarkers of synaptic and neuronal dysfunction in relation to mild behavioral impairment: a study of dementia‐free older adults

AbstractBackgroundMild behavioral impairment (MBI) represents a high‐risk state for incident cognitive decline and dementia, capturing later‐life emergent and persistent neuropsychiatric symptoms in five domains: 1) decreased motivation; 2) affective dysregulation 3) impulse dyscontrol; 4) social inappropriateness; and 5) psychosis. We examined cross‐sectional associations between MBI and cerebrospinal fluid levels of markers of synaptic/neuronal dysfunction including 1) alpha‐synuclein (α‐syn); 2) growth‐associated protein 43 (GAP‐43); 3) neurogranin (NGRN); 4) synaptosomal‐associated protein 25 (SNAP‐25); 5) visinin‐like protein 1 (VILIP‐1); and 6) chitinase‐3‐like protein 1 (YKL‐40). Longitudinally, we determined associations between these biomarkers and incident MBI or dementia.MethodAlzheimer’s Disease Neuroimaging Initiative participants with normal cognition and mild cognitive impairment were included (n = 853). MBI scores were derived from the Neuropsychiatric Inventory using a published algorithm. Participants were classified as MBI+ if MBI symptoms were present at ≥2 consecutive visits.Cross‐sectional associations between MBI total score and each log‐transformed biomarker were modelled using multivariable‐adjusted linear regression. Biomarkers with cross‐sectional associations meeting a pre‐defined p‐value threshold (p<0.1) were then incorporated as exposures into adjusted longitudinal Cox proportional hazard regression models (n = 111) of 1) MBI and 2) dementia as the outcomes, the latter of which also included interactions between MBI status and biomarker levels.ResultDemographics are summarized in Table 1. Cross‐sectionally, only MBI associations with VILIP‐1 (beta = 3.3%, 95%CI:+0.2% to +6.5%, p = 0.04) and SNAP‐25 (beta = 2.0%, 95%CI:‐0.4% to 6.3%, p = 0.09) met the pre‐defined p‐value for inclusion in Cox models. Longitudinally, higher VILIP‐1 levels were associated with a 3.02‐fold greater rate of incident MBI (95%CI:1.43‐6.40, p = 0.004) and a 3.83‐fold greater rate of incident dementia (95%CI:1.22‐12.03, p = 0.021). The relationship between VILIP‐1 and dementia did not depend on participants having MBI. MBI status predicted incident dementia with an HR = 4.75 (95%CI:2.36‐9.55, p<0.001) and HR = 4.06 (95%CI:2.01‐8.21, p<0.001) after adjusting for VILIP‐1.ConclusionElevated VILIP‐1 levels are associated with greater incidence of MBI and greater incidence of dementia, suggesting that synaptic dysfunction traditionally related to cognitive decline and dementia may also contribute to behavioral changes. Treatments aimed to mitigate MBI symptoms and dementia may explore VILIP‐1—a neuronal calcium‐sensor protein—as a therapeutic target, though more research is needed.

P194: A comparison study between AD8 and modified AD8 for dementia screening

Objective:The 8-item Informant Interview to Differentiate Aging and Dementia (AD8) was developed as a screening tool for dementia with a cutoff of 2 suggested by the initial study. However, various studies found different cutoff values, and many suggested a cutoff of 2 might result in a high false positive rate. A higher false positive rate in Taiwan was repeatedly shown when AD8 was self-administered in local government screening programs. We have developed a modified version of AD8 (m-AD8) with the purpose of enhancing its specificity. This study aimed to compare the performance of AD8 and m-AD8.Methods:The m-AD8 consists of all items adapted from the original AD8. Modifications included: (1) limiting the evaluated period to the past year instead of the past several years, (2) reselecting examples to reflect the socio-cultural context in Taiwan, and (3) rearranging the order of questions according to their complexity. We recruited 118 participant-informant dyads from a university teaching hospital. For each informant, the AD8 was administered first and then the Clinical Dementia Rating (CDR) to minimize contamination effect. The m-AD8 was administered 7 days later. Two geriatric psychiatrists made the final consensus DSM-5 diagnosis for each subject after considering all clinical information, including history, Mini-Mental State Examination (MMSE), CDR, and, if available, other past neuropsychological tests and neuroimaging.Results:There were 59 subjects with normal cognition, 28 with mild neurocognitive disorder, and 31 with dementia (major neurocognitive disorder). When comparing dementia vs. non-dementia, the optimal cutoff value was 4 for both versions according to the Youden index. The AUC, sensitivity, and specificity were 0.893, 0.774, 0.862 for AD8, and 0.883, 0.741, 0.954 for m-AD8, respectively. The m-AD8 showed improved specificity, which was also true when the cutoff value was set as 2 or 3.Conclusion:The optimal cutoff value for both versions was 4. The modification may change the performance of AD8 with improved specificity. These findings suggest that, depending on different situations, AD8 with a cutoff value higher than 2 may perform better in dementia screening.

Apolipoprotein E4 affects locus coeruleus functional connectivity in preclinical Alzheimer’s disease

AbstractBackgroundRecent studies have demonstrated the pivotal implications of the locus coeruleus (LC) and in the early phase of Alzheimer’s disease (AD). However, the effects of apolipoprotein E4(APOE4) carrier status on the LC functional connectivity (FC) in preclinical AD remain elusive. We aimed to demonstrate disparities in LC FC in preclinical AD with regard to APOE4 carrier status.MethodsA total of 112 patients with who were amyloid beta (Aβ) positive([18F] flutemetamol +) were recruited in the study, and they all had normal cognition. Seed to voxel analysis was conducted to measure LC FC differences between APOE4 non‐carrier and carrier. In addition, group by amyloid beta (Aβ) interactive effects on FC values were analyzed with a general linear model.ResultThe LC FC with intracalcarine cortex, lingual gyrus, occipital fusiform gyrus of the both hemispheres was reduced in APOE4 carrier. Moreover, there was a statistically significant group by regional standardized uptake value ratio interactions in LC FC with frontal, occipital cortices, the precuneus and the cerebellum.ConclusionThe aforementioned findings suggest that there are differential patterns of LC FC in APOE4 non‐carrier and carrier with preclinical AD, which interact with regional Aβ deposition.

Relationships between neuroimaging parameters, APOE genotypes and composite scores for memory, executive functioning and language from the National Alzheimer’s Coordinating Center (NACC)

AbstractBackgroundWe harmonized composite scores for memory, executive functioning (EF), and language from granular cognitive data from the National Alzheimer’s Coordinating Center (NACC) uniform dataset on 39,965 individuals. We explored if our cognitive scores correlated with APOE genotype and structural magnetic resonance imaging data.MethodIn our previously published harmonization methods we used confirmatory factor analysis models, guided by theoretical considerations from content experts, to estimate domain scores. For this cross‐sectional analysis of last visits in participants over age 60, we obtained APOE genotype data (n = 28,558 individuals) and FreeSurfer regional volume data (n = 2,404 individuals). We looked at relationship between cognitive performance and APOE genotype grouping by disease group (normal cognition, mild cognitive impairment (MCI), or AD dementia). We ran student’s two sample t‐test to assess the effect of APOE ε4 genotype on cognitive domain score. We also ran regression models for cognitive domain scores on each FreeSurfer region selected a priori on the basis of assumed association on that index domain adjusting for age, gender and APOE genotype.ResultRelevant demographic and clinical data are summarized in Table 1. Associations with APOE genotype and each cognitive domain are shown in Figure 1. As expected, participants with at least one APOE ε4 alleles compared with none had lower composite memory scores (p<0.01, t‐test) compared with those with none in participants with dementia and MCI. APOE ε4 carriers also had lower language scores in participants with dementia (p = 0.037, t‐test). Among the FreeSurfer regions, composite memory scores were strongly associated with hippocampal volume, parahippocampus and entorhinal cortex thickness across all dementia categories (Table 2). EF scores were associated with 2 EF brain regions of interest in participants with dementia. Language scores were associated with 2 language regions of interest in participants with dementia.ConclusionOur analyses shows composite scores are associated with APOE genotype in participants with dementia and relevant brain regions in the memory domain across all dementia categories. Our analyses shows that our cognitive scores correlate with memory brain regions and APOE genotype in expected directions.

Comparison of two semi‐quantitative amyloid PET analysis methods with and without MRI in Alzheimer’s Disease Spectrum Disorder

AbstractBackgroundStandardized uptake value ratio (SUVR) is a standard method for amyloid PET analysis. 3D T1 MRI imaging is required for accurate spatial normalization in SUVR measurement to overcome regional cortical atrophy in neurodegenerative disorders like Alzheimer’s disease spectrum disorders. The SUVR method without 3D MRI has recently been developed for clinical application. We compared two SUVR methods with and without 3D MRI for the semi‐quantitative analysis of global and regional amyloid loading in Alzheimer’s disease spectrum disorders.Method75 subjects (normal cognition 8, subjective cognitive decline 20, mild cognitive impairment 23, Alzheimer’s disease dementia 24) were selected in the single dementia clinic for the analysis. For the SUVR measurement with 3D T1 MRI, in‐house software with SPM8 and MATLAB was used. For the SUVR measurement without 3D T1 MRI, AI‐based automated PET quantitative analysis software (called ‘BTXBrain‐Amyloid‐Research’) was developed by Brightonix Imaging Inc. With the visual PET reading as a gold standard, we compared regional and global SUVR between groups. Intra‐class correlation coefficient(ICC) was used to test the validity of the two methods.ResultGlobal SUVR was higher in amyloid PET positive SCD group (SUVR with MRI (1.205 V.S. 1.635), SUVR without MRI (1.210 V.S. 1.599)). The mean global SUVR with MRI and without MRI of 75 subjects were 1.400 (S.D. 0.264) and 1.390(S.D. 0.237). ICC of global SUVR between the two methods was 0.950, p = 0.0001. Regional SUVR ICC were 0.941 in the prefrontal cortex, 0.953 in the orbitofrontal cortex, 0.947 in the anterior cingulate, 0.844 in the posterior cingulate, 0.955 in the lateral parietal cortex, 0.962 in the precuneus, 0.959 in the lateral temporal cortex, and 0.94 in the occipital cortex. The area under the curve of ROC curve analysis of both two methods to diagnose amyloid PET positivity was 0.98 and 0.97.ConclusionAI‐based automated PET quantitative analysis software of Brightonix imaging without MRI was valid as an MRI‐based SUVR method in Alzheimer’s disease spectrum disorders with variable brain atrophy. Short processing time (30 ‐40 seconds) and reliable SUVR measurement without 3D MRI benefit the Alzheimer’s disease diagnosis in clinical practice.Grant from the Ministry of Health and Welfare, HI18C0530, Seoul R&BD Program(BT200151)

Multimorbidity and competing risks for incident dementia and dementia‐free death in an ADRC cohort

AbstractBackgroundOlder adults are often affected by more than one coexisting chronic disease, a condition referred to as multimorbidity. Multimorbidity associates with poor physical and mental health outcomes, cognitive decline, and higher mortality. This study aims to assess the association between the number of self‐reported chronic conditions (CC) and risks for dementia and dementia‐free death in a cohort of older adults.MethodWe examined data from the University of Kentucky Alzheimer’s Disease Research Center cohort, a convenience sample of community‐based older adults followed longitudinally until death. Adults ≥50 years with normal cognition at baseline and data available on 11 measured CC and mental and physical components of SF‐36 (health‐related quality of life measure) were included in this study. The cohort was stratified at baseline based on self‐reported CC into 3 groups: 0, 1, and ≥2. A competing risk analysis using Fine‐Gray subdistribution hazard models was performed to estimate associations between the number of comorbidities and incident dementia or dementia‐free death.ResultAmong 772 adults (mean age 73.1±6.7 years, 66.6% female, 89.0% white), a majority (64.4%) reported ≥2 of the measured 11 CC at baseline; 22.8% had one, and 12.8% had none (Figure 1). These groups did not significantly differ in main demographic characteristics (Table 1). Individuals with multimorbidity had lower physical component scores of SF‐36 indicating worse self‐perceived physical health than other groups. Almost half (45.9%) of the overall cohort reported a history of smoking, which was most common in the ≥2 CC group. Unadjusted and adjusted Fine‐Gray models did not show an association between the number of CC at baseline and incident dementia, accounting for competing risk of death during mean 6.8±3.9 annual follow‐up visits. There was a significant association between the number of CC at baseline and dementia‐free death, accounting for competing event dementia, in unadjusted analyses; this association did not remain significant in the adjusted analyses(Table 2).ConclusionMultimorbidity is prevalent in this cohort of older adults. When accounting for competing risks of death, the number of CC was not associated with incident dementia. Further studies are needed to examine associations with mild cognitive impairment and cognitive decline.