Global Clinical Dementia Rating Research Articles

Assessing the clinical meaningfulness of slowing CDR-SB progression with disease-modifying therapies for Alzheimer disease.

For many patients and caregivers, a major goal of disease-modifying treatments (DMT) for Alzheimer disease (AD) dementia is to extend independence in instrumental and basic activities of daily living (IADLs and BADLs). The goal of this study was to estimate the effect of treatments on the time remaining independent in IADLs and BADLs. Participants at the Knight Alzheimer Disease Research Center were selected who were potentially eligible for recent DMT trials: age ≥ 60 years at baseline, clinical diagnosis of very mild or mild AD dementia (global Clinical Dementia Rating® (CDR®) score 0.5 or 1), biomarker confirmation of amyloid pathology, and at least one follow-up CDR assessment within 5 years. For IADLs, a subset of the Functional Assessment Questionnaire (FAQ) was examined that rated the degree of independence in the following: paying bills, driving, remembering medications and appointments, and preparing meals. For BADLs, the Personal Care domain of the CDR was used. Mixed-effects logistic and ordinal regression models were used to examine the relationship between CDR Sum Boxes (CDR-SB) and the individual functional outcomes and their components. The change in CDR-SB over time was estimated with linear mixed effects models. 282 participants were followed for an average of 2.9 years (SD 1.3 years). For 50% of individuals, loss of independence in IADLs occurred at CDR-SB>4.5 and in BADLs at CDR-SB>11.5. For individuals with a baseline CDR-SB=2, treatment with lecanemab would extend independence in IADLs for 10 months (95% CI 4-18 months) and treatment with donanemab in the low/medium tau group would extend independence in IADLs by 13 months (95% CI 6-24 months). Independence in ADLs can be related to CDR-SB and used to demonstrate the effect of AD treatments in extending the time of independent function, a meaningful outcome for patients and their families.

Characterization of African-American Super-Agers in the National Alzheimer's Coordinating Center cohort.

"Super-agers" are adults aged ≥80 with cognitive performance similar to persons two to three decades younger. Characteristics such as larger hippocampal volume, APOE-ε4 allele absence, higher educational attainment, female sex, and lifelong cognitive stimulation are associated with cognitive performance compatible with super-aging. These findings are based on predominantly white research samples. Limited data are available on African-American super-agers. To fill this gap, we explored potential factors associated with super-aging in older African-American adults. Data from African-American participants aged ≥80 in the National Alzheimer's Coordinating Center (NACC) dataset were analyzed. Using global Clinical Dementia Rating (CDR) scores, participants were first categorized as impaired (score ≥0.5) or non-impaired/normal cognition (NC) (score = 0). From the NC group, super-agers were identified using NACC-data-driven cutoffs. Participants were considered super-agers if their memory performance was similar to persons aged 50-60 with NC, and their performance on other domains was within one standard deviation of the mean for persons aged ≥80. We examined group characteristics (NC, super-ager, impaired) using chi-square and ANOVA with pairwise comparisons. Multinomial logistic regression, adjusted for sex and education, evaluated correlates of super-ager group assignment. Data for 1285 African-American participants aged ≥80 were analyzed. We identified 24.7% (n = 316) NC, 4.8% (n = 61) super-agers, and 70.6% (n = 905) impaired. Super-agers were mostly female and more educated, had similar vascular comorbidities as the other groups, and had less sleep disorders, depression, and alcohol use. After adjusting for sex and education, super-ager group assignment was associated with less sleep disorders, less depression, and moderate alcohol use. Participants with controlled vascular risk, mental health, alcohol use, and sleep disorders tended to be in the super-ager group. These factors may be important focus areas in clinical practice to support cognitive resilience with aging in older African-American adults.

Higher amyloid is associated with greater loneliness among cognitively normal older adults during the COVID-19 pandemic

Background Loneliness has been associated with several consequences, including increased risk of developing Alzheimer disease (AD). Loneliness may arise during the preclinical phase of AD, but little is known about the relationship between loneliness and amyloid accumulation consistent with preclinical AD. Therefore, the purpose of this study was to examine the relationship between amyloid accumulation and subjective experiences of loneliness among cognitively normal older adults during the COVID-19 pandemic. Methods A global Clinical Dementia Rating ® Scale score of 0 was required for enrollment. Cortical amyloid burden was measured using [11C] Pittsburgh compound B or [18F]-Florbetapir PET tracers. Centiloids were used to synchronize measures. Demographic characteristics and measures of loneliness, anxiety, and depression were collected via self-report. Multiple linear regression was used to examine the relationship between loneliness and amyloid accumulation. Results The 108 participants had a mean age of 75.0 and an average amyloid accumulation of 22.2 ± 31.9. Mean UCLA Loneliness Scale scores were 31.6 ± 10.8. A significant positive association was detected between loneliness and amyloid accumulation (β = 0.064, SE = 0.027, 95% CI = [0.011, 0.118], p = 0.018). Conclusions These findings highlight the relationship between higher amyloid accumulation and greater loneliness during the COVID-19 pandemic. Healthcare professionals should include routine assessments for characteristics of loneliness in routine clinical evaluations and integrate loneliness reduction and prevention treatments among older adults experiencing loneliness. Additional research is needed with a larger, more diverse sample to examine the relationship between loneliness and amyloid accumulation.

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans.

This study was undertaken to evaluate the frequency of modifiable dementia risk factors and their association with cognitive impairment and rate of decline in diverse participants engaged in studies of memory and aging. Modifiable dementia risk factors and their associations with cognitive impairment and cognitive decline were determined in community-dwelling African American (AA; n = 261) and non-Hispanic White (nHW; n = 193) participants who completed ≥2 visits at the Mayo Clinic Alzheimer Disease Research Center in Jacksonville, Florida. Risk factors and their associations with cognitive impairment (global Clinical Dementia Rating [CDR] ≥ 0.5) and rates of decline (CDR Sum of Boxes) in impaired participants were compared in AA and nHW participants, controlling for demographics, APOE ɛ4 status, and Area Deprivation Index. Hypertension, hypercholesterolemia, obesity, and diabetes were overrepresented in AA participants, but were not associated with cognitive impairment. Depression was associated with increased odds of cognitive impairment in AA (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 2.13-8.67) and nHW participants (OR = 2.79, 95% CI = 1.21-6.44) but uniquely associated with faster decline in AA participants (β = 1.71, 95% CI = 0.69-2.73, p = 0.001). Fewer AA participants reported antidepressant use (9/49, 18%) than nHW counterparts (57/78, 73%, p < 0.001). Vitamin B12 deficiency was also associated with an increased rate of cognitive decline in AA participants (β = 2.65, 95% CI = 0.38-4.91, p = 0.023). Modifiable dementia risk factors are common in AA and nHW participants, representing important risk mitigation targets. Depression was associated with dementia in AA and nHW participants, and with accelerated declines in cognitive function in AA participants. Optimizing depression screening and treatment may improve cognitive trajectories and outcomes in AA participants. ANN NEUROL 2024;95:518-529.

Gender Differences in Items of the Instrumental Activities of Daily Living in Mild Cognitive Impairment and Alzheimer's Disease Dementia.

Each item in the instrumental activities of daily living (IADL) questionnaire has differential importance to an individual's life functioning based on gender. However, IADL has mostly been utilized for its total score alone, without gender specificity. We identify the impact of each item on the transition from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease dementia (ADD), and determine if the impact of each item differs by gender. Subjects were aMCI or ADD with a global clinical dementia rating of 0.5 or 1. The sample size was 146 men and 154 women. We used logistic regression analysis to determine the effect of each item of IADL on the transition from aMCI to ADD. The odds ratio (OR) for "remembering recent events" had similar values: 27.2 for men, and 27.7 for women. Gender difference was identified in the item with the highest OR value. For women, the "using transportation" item was 63.3, and for men, "conducting financial affairs" was overwhelmingly high at 89.1. Functional decline on items with relatively higher ORs may indicate higher probability of a transition from aMCI to ADD. The OR of "conducting financial affairs" was relatively higher for both genders. In terms of gender differences, "conducting home repair" for men, and "using transportation" for women, have relatively higher impact. This study demonstrates that during the transition from aMCI to ADD, each item of IADL shows a staggered decline in functioning, and that this decline is gender-specific.

Association Between Executive Dysfunction-Related Activities of Daily Living Disability and Clinical Dementia Rating Domain Patterns in Patients With Vascular Dementia and Age-Matched Patients With Alzheimer's Dementia.

Although the Clinical Dementia Rating (CDR) scale was originally developed to stage Alzheimer's dementia (AD), it is now used globally for various types of dementia. The aim of this study was to investigate the characteristic pattern of CDR domains and its association with neuropsychological findings and activities of daily living (ADL) in patients with vascular dementia (VaD) and patients with AD. We recruited very mild to mild VaD and AD patients who were age-matched among the first visitors to a dementia clinic. All subjects underwent a standardized clinical interview, physical and neurological examinations, and laboratory tests, including brain magnetic resonance imaging, according to the protocol of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease assessment battery. A total of 105 pairs of VaD and AD patients participated in this study. Although the adjusted scores on Korean version of the Mini-Mental State Examination were similar between the two groups, the VaD patients performed better on the Boston Naming Test, Word List Memory, Word List Recall, Word List Recognition, and Constructional Recall Test. However, the scores on global CDR, CDR sum of boxes, and ADL-related CDR domains were higher in VaD patients than in AD patients (p<0.001). The VaD patients also showed poor performances on the Disability Assessment for Dementia Scale, Frontal Assessment Battery, Executive Clock Drawing Task, and Stroop tests. Despite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.

Retention of Study Partners in Longitudinal Studies of Alzheimer Disease

AbstractBackgroundAlzheimer Disease Research Centers (ADRCs) require study partners (SPs) for all participants. SPs accompany participants to study visits, ensure protocol compliance and serve as informants for outcomes and adverse event reporting. Their attitudes and beliefs may therefore affect longitudinal data collection and retention for AD studies. However, little research has examined barriers and facilitators to SP participation in longitudinal AD investigations.ObjectiveA random sample of study partners (N = 212) of participants who had no or mild symptoms (global Clinical Dementia Rating [CDR]≤1) at four ADRCs were surveyed to examine facilitators and barriers to continued participation in AD studies.MethodsReasons for participation were analyzed with factor analysis and regression analysis. Effects of complaints and goal fulfillment on attendance were estimated with fractional logistic models.ResultsStudy partners most often participated in ADRC research for personal benefit and altruism. A majority of study partners rated ADRC participation as positive and meeting their goals. Although half reported at least one complaint, few regretted participating. When the participants had a CDR&gt;0, spouse study partners (p&lt;.01) and sibling study partners (p&lt;.01) were more likely to emphasize personal benefits than were children of participants (p&lt;.01) Spousal caregivers of participants with CDR&gt;0, cited personal benefit as their primary motivation to participate while adult children of cognitively normal participants (CDR = 0) cited personal benefit. Respondents whose personal goals were met had fewer complaints and were more likely to have perfect attendance. More feedback about test results and study findings and better management of study visits were the most common recommendations.ConclusionStudy partners are motivated by both personal and altruistic goals. The salience of each goal depends on study partner type and the participant’s cognitive status. Fulfilling these goals may improve retention and reduce study partner complaints.

Depression is associated with dementia and accelerated cognitive decline in African Americans

AbstractBackgroundAfrican Americans (AA) represent 12% of the United States population ≥65 years‐old, but 19% of persons with dementia. Inequalities in social determinants of health may influence access to healthcare resources contributing to increased dementia risk. Modifiable risk factors, including vascular risk factors and depression, may contribute up to 40% of dementia risk and are overrepresented in AA. Accordingly, risk factor modification in AA may improve disparities and decrease dementia risk.MethodDementia risk factors were evaluated in community‐dwelling AA (n = 261) and non‐Hispanic White (NHW; n = 193) participants who completed ≥2 research visits in studies of memory and aging at the Mayo Clinic Florida Alzheimer Disease Research Center. The association between modifiable risk factors and cognitive impairment (global Clinical Dementia Rating® [CDR] ≥0.5), and rates of decline in impaired participants (measured using the CDR Sum‐of‐Boxes; CDR‐sb) were compared between AA and NHW, while controlling for demographics, APOEe4 status, and Area Deprivation Index.ResultModifiable dementia risk factors were common in AA and NHW participants. The ADI was higher in AA denoting greater socioeconomic and environmental deprivation [7.8 (2.3) vs. 4.0 (2.1); p&lt;0.001]. History of stroke/transient ischemic attack (OR, CI95% = 2.52, 1.08‐5.83) was associated with an increased odds of dementia in AA participants only, while depression was associated with an increased odds of dementia in both AA (3.10, 1.52‐6.30) and NHW (3.46, 1.14‐10.48) participants. Moreover, depression (β, CI95% = 1.55, 0.5‐2.6), p = 0.004) was associated with a faster rate of decline (CDR‐sb) in cognitively impaired AA participants. AA participants with depression were disproportionately less likely to report use of antidepressant medications than NHW counterparts (40/45, 89% vs. 21/44, 48%); p&lt;0.001).ConclusionModifiable risk factors associated with dementia were common in AA and NHW participants. Depression was associated with dementia in both AA and NHW but uniquely associated with an accelerated rate of cognitive decline in AA participants. Disparities in use of antidepressant medications may contribute to these differences. Optimizing depression treatment in AA communities may improve cognitive trajectories and dementia risk in this population.

Diagnostic utility of culture/language‐specific normative data on the Version 3 of the Uniform Data Set Neuropsychological Battery for differentiating stages of cognitive impairment among Latinos in the United States

AbstractBackgroundAccurate detection of neurocognitive disorders of aging among Latinos in the United States (U.S.) is an important step towards addressing disparities in Alzheimer’s disease and related dementias (ADRDs) and promoting health equity in this group. Federally‐funded Alzheimer’s Disease Research Centers (ADRCs) in the U.S. have utilized the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set Version 3 Neurobehavioral Battery (UDS3‐NB) since 2015. Normative data on this battery adjusted for age, education and sex were published for English‐speakers in 2018 (Weintraub et al., 2018) and expanded to consider differences among non‐Hispanics White and Black people in 2020 (Sachs et al., 2020). We aimed to determine whether the use of newly developed culture/language‐specific neuropsychological normative data for Spanish‐ and English‐speaking Latinos in the U.S. improved diagnostic accuracy of the UDS3‐NB in this group.MethodParticipants included 1,018 Latino adults age 50+ enrolled in ADRCs. Table 1 presents participant demographics by global Clinical Dementia Rating (CDR) score, as indicative of stage of neurocognitive impairment (0 = normal, 0.5 = questionable impairment, 1 = mild impairment, 2‐3 = moderate‐to‐severe impairment). Individual test raw scores were converted to demographically‐adjusted z scores utilizing normative data on the UDS3‐NB developed for Latinos and for other culture/language groups. Individual tests z scores were converted to deficit scores and averaged to compute global deficit scores and determine global neurocognitive impairment (NCI). Rates of NCI based on culture/language specific normative data were compared across the four CDR groups via Chi‐Square tests. Sensitivity and specificity were computed for differentiating participants with CDR = 0 (normal) and CDR = 1 (mild impairment) based on different sets of normative data.ResultsUtilizing culture/language‐specific normative data significantly differentiated CDR groups (p&lt;.001; Figure 1). These culture/language specific normative data performed better in differentiating between CDR = 0 and 1, than utilizing normative data developed for non‐Hispanic English speakers (Table 2).ConclusionCulture/language‐specific normative data improve diagnostic accuracy for neurocognitive impairment among Latinos in the U.S. relative to existing normative data developed for other groups. These culture/language‐specific norms can be used in research and clinical practice to enhance ADRD diagnosis among Latinos and represent an important step towards addressing ADRD disparities in this group.

Comparison of Vascular Health in Super‐Agers and Cognitively Normal Adults 80 Years and Older

AbstractBackgroundUnraveling factors associated with cognitive resilience and super‐agers might reduce expected increases in Alzheimer’s disease and related dementia (ADRD). Vascular disease can impair the cerebral circulation and increase risk for cognitive decline and ADRD. However, data in persons aged 80+ suggests that maintained vascular health can preserve key brain regions for normal cognition.MethodUsing National Alzheimer’s Coordinating Center (NACC) data from January 2005 ‐ December 2020, we found 9,581 participants age 80+ (white: 8,296 vs. AA: 1,285,p&lt;.0001) at the baseline visit. We defined cognitive groups per global Clinical Dementia Rating (CDR) and Memory subscale scores. Normal cognition (NC) was defined as a global CDR and memory subscale score = 0. To identify super‐agers (SA), we utilized data‐derived cutoffs from cognitive test performances consistent with prior reports. The operationalized definition was created from: 1) Mean Craft delayed recall scores in 50–60‐year‐olds with NC; 2) Craft scores among age 80+ with NC group were standardized to the mean score for age 50‐60 with NC; and 3) Standardized mean scores for non‐memory measures (trail making test‐B, phonemic fluency, and multilingual naming test) for age 80+ with NC. SA were defined as age 80+ with episodic memory performance (Craft scores) ≥ 1 standard deviation (SD) of the standardized mean for the age 50‐60 group and non‐memory scores ≥ 1 SD of the standardized mean for the 80+ age group.ResultWe identified 4.5% (n = 431) SA and 27.7% (n = 2,654) NC (p&lt;.01) to compare vascular variables. Compared to NC, SA were younger (83.5±3.4 vs. 84.7±4.0, p&lt;.01), had more education (16.5±2.8 vs. 15.2±3.1, p&lt;.01), higher diastolic blood pressure (DBP) (73.9±10.5 vs. 71.9±10.5, p&lt;.01), and mean arterial pressure (MAP) (95.5±11.8 vs. 93.5±11.5, p&lt;.01). Pulse pressure (PP) was similar for both groups (67.5±17.1 vs. 68.1±10.5, p = .33).ConclusionOur results suggest that vascular health could impact cognition in aged 80+ adults. SA may have higher cerebral perfusion (CP) per MAP. Although DBP can decrease with aging, higher values in our sample may contribute to CP. The PP in our sample is similar to reported values for healthy 70‐year‐old adults. Further study of vascular health and super‐aging is needed.

Real‐world one‐year estimation of the candidates for lecanemab in a South Korean memory clinic

AbstractBackgroundResults from an 18‐month Phase 3 clinical trial showed that lecanemab reduced markers of amyloid on early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. As the lecanemab recently received accelerated approval by the US Food and Drug Administation, consideration for prescribing it in the right person, at the right dose and in a very carefully monitored way in a real‐world practice is necessary now.MethodIn this study, we aimed to estimate the candidates for lecanemab in a South Korean memory clinic based on one‐year clinical data. We reviewed retrospectively the medical records of a total 344 patients (211 females, 69.7±9.3 years old) who visited the memory clinic and took the amyloid PET at the department of Neurology, Ajou University Hospital in 2022. We tried to find the patients whose clinical characteristics fit with the inclusion as well as exclusion criteria from the Phase 4 clinical trial of lecanemab.ResultThe patients consisted of 14 subjective cognitive complaints, 139 mild cognitive impairments (MCI), 107 Alzheimer’s disease (AD) dementia, or 84 other neurodegenerative diseases whose amyloid positivity was 28.6%, 43.2%, 72.0%, or 10.7%, respectively. Among patients with evidence of amyloid deposition, 4 MCI and 38 AD dementia were within the exclusion criteria because they scored less than 22 at the Mini‐Mental State Examination (MMSE). Other 7 patients with AD dementia would be also excluded because they scored both Global Clinical Dementia Rating (CDR) score greater than 1 and &lt;22 at the MMSE. One more AD dementia patient had no data of cognitive test. Finally, 56 patients with MCI and 31 patients with AD dementia met the criteria for using the lecanemab.ConclusionOur study showed that amyloid PET was already integrated in the real‐world Korean practice. In addition, the amyloid‐positivity data from real‐world practice in a South Korean memory clinic matched well with previous research data. It is expected that this pattern of the Korean practice might contribute to give real‐world data for prescribing the lecaemab in the future.

Evaluating the global cortical Centiloid value for predicting functional decline

AbstractBackgroundPrevious results on amyloid‐PET imaging for predicting functional decline are conflicting. Given that the Centiloid approach (CL) may serve for inclusion in anti‐amyloid trials, we investigated the extent to which CL may predict functional decline in the AMYPAD‐Prognostic and Natural History Study (PNHS), including 1094 participants.MethodWe analyzed, cross‐sectionally and longitudinally, the associations between CL and global and sum‐of‐boxes (SOB) Clinical Dementia Rating (CDR), and Instrumental Activity of Daily Living (IADL) scores. Mean follow‐up duration ranged from 2.7‐3.0 years (±1.1‐1.6) depending on the functional score. Longitudinal CDR‐SOB and IADL changes were modeled using linear mixed‐effects models with random intercepts and slopes, covarying age and sex, stratified by CDR global score. Analyses included comparisons between three CL groups (Aβ‐: CL&lt;12; grey‐zone: CL = 12‐50; Aβ+: CL&gt;50) and correlation between the baseline CL and the time for progression on the CDR global score.ResultThe baseline CL was significantly higher in CDR = 0 (Mdn = 6.6) than in CDR = 0.5 participants (Mdn = 17.2; p&lt;.001). Baseline CDR‐SOB was significantly higher in Aβ+ (M = 0.48) than in Aβ‐ (M = 0.12) and grey‐zone participants (M = 0.13, p‐values &lt;.001). Baseline IADL was (marginally) significantly lower in Aβ+ (Mdn = 81.3) than in Aβ‐ (Mdn = 82.8, p = .02) and grey‐zone participants (Mdn = 83.5, p = .08, Table 1). Baseline CL significantly predicted subsequent changes in CDR‐SOB and IADL, both in CDR = 0 and CDR = 0.5 participants, but only in the CL&gt;50 groups (βCL12‐50 = 0.03, p = .32,βCL&gt;50 = 0.14, p&lt;.001 for CDR‐SOB in CDR = 0 participants;βCL12‐50 = 0.19, p = .31,βCL&gt;50 = 1.04, p = .01 for CDR‐SOB in CDR = 0.5 participants;βCL12‐50 = ‐0.002, p = .99, βCL&gt;50 = ‐1.00, p = .08 for IADL in CDR = 0 participants; Fig.1). The participants who progressed from global CDR = 0 to CDR = 0.5 (N = 90) had a higher baseline CL (Mdn = 15.16) than stable participants (Mdn = 5.95, p = .002). However, the baseline CL was not associated with a shorter time of clinical progression (rs= ‐.02, p = .8; Fig.2).ConclusionCross‐sectionally, amyloid burden expressed in CL units was associated with functional outcomes. A baseline CL&gt;50 predicted subsequent functional decline in CDR‐SOB and IADL scores in clinically normal and mildly clinically impaired participants. At lower CL values, no functional decline was observed during a three‐year follow‐up. Clinically normal individuals with increasing global CDR scores had higher baseline CL values, but these values were not associated with faster clinical progression.

The relationship between executive dysfunction‐associated activities of daily living (ADL) and the pattern of Clinical Dementia Rating (CDR) in patients with vascular dementia and age‐matched patients with Alzheimer’s disease

AbstractBackgroundClinical dementia rating (CDR) scale was originally developed to stage the severity of Alzheimer’s dementia (AD) but is now used globally regardless of types of dementia. This study aims to investigate the relationship between the characteristic pattern of CDR domains, neuropsychological findings, and activities of daily living (ADL) in patients with vascular dementia (VaD), compared with age‐matched patients with AD.MethodVery mild to mild VaD and AD patients matched for age were recruited among the first visitors to a dementia clinic. All subjects were administered a standardized clinical interview, physical and neurological examinations, and laboratory tests including the brain MRI according to the protocol of the Korean version of the CERAD assessment battery.ResultOne hundred and five pairs of VaD and AD patients participated in this study. Although the adjusted scores on MMSE were similar between two groups and the performances on Boston naming, word list memory, word list recall, word list recognition, constructional recall test were better in VaD patients, the scores on global CDR, CDR sum of box (SOB), and ADL‐related CDR domains were higher in VaD patients than in AD patients (p&lt;0.001). The poor performances on disability assessment for dementia scale, frontal assessment battery, executive clock drawing task, and Stroop tests were observed in VaD patients.ConclusionDespite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.

Memory Performance in Mild Sporadic and Familial Behavioral Variant Frontotemporal Dementia: Findings from the ALLFTD Consortium

AbstractBackgroundMemory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria.MethodAssessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating &gt;0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer’s Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5.ResultData from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings &gt;0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p&gt;0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%).ConclusionThese data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD.

Life course neighborhood social determinants of health and longitudinal changes in cognition in three Alzheimer’s Disease Research Center cohorts

AbstractBackgroundSeminal studies on exposure to life course social determinants of health, such as neighborhood racial segregation and neighborhood poverty, suggest detrimental associations with poorer cognitive function. We aimed to test the opposite by examining the relationship between self‐reported exposure to health‐promoting neighborhood environments over the life course and cognitive function among older adults.MethodParticipants were persons living without dementia at three US Alzheimer’s Disease Research Centers (University of California, Davis in Sacramento (UCD); Washington University in Saint Louis (WU); and Wake Forest University in Winston‐Salem (WFU)). An ancillary study (K01AG063895, PI: Besser) included the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) comprised of indices like neighborhood measures of socioeconomic status (NSES), walking and biking frequency, and greenness from childhood, midlife, and late life. LSNEQ data were linked with late‐life cognitive test z‐scores (Animals and Vegetables Category Fluency, Trail Making Parts A and B) from the National Alzheimer’s Coordinating Center Uniform Data Set. Multivariable linear mixed effects models tested associations between the LSNEQ index scores (composite values over childhood and mid‐ and late‐life) and baseline and longitudinal change in cognitive function controlling for demographics, Center, and baseline global Clinical Dementia Rating (0 or 0.5).ResultThe sample (n = 322) included 65% women, 17% Black, 76% White, and 7% other/mixed racialized group participants and was, on average, 70±7 years old and followed for 2.5±3.2 years. Life Course NSES was lower for UCD (mean = 12.7, SD = 3.5) versus WU (mean = 13.9, SD = 3.2) and WFU (mean = 14.3, SD = 3.2). Life Course Neighborhood Walking and Biking frequency did not differ by Center. Life Course Neighborhood Greenness differed across Centers, and was lowest for WU (mean = 4.8, SD = 1.3) and highest for WFU (mean = 5.6; SD = 1.2). In multivariable analyses, greater Life Course Neighborhood Walking and Biking was associated with higher baseline Trail A scores (estimate = 0.83, 95% CI = 0.08‐1.58) and slower decline on Animals over time (estimate = 0.024, 95% CI = 0.002‐0.045). Greater Life Course Neighborhood Greenness was associated with slower decline on Vegetables over time (estimate = 0.035, 95% CI = 0.001‐0.069).ConclusionThese preliminary findings suggest self‐reported, life course neighborhood exposures and behaviors (i.e., greenness and neighborhood walking/biking) may be associated with better cognition and slower decline in later life.

Clinical Manifestations.

Patterns of cognitive performance associated with different stages of dementia have been primarily studied in Non-Hispanic White (NHW) populations. This study compares patterns of cognitive performance, on a brief neuropsychological battery, in Caribbean Hispanic (CH) and NHW individuals with mild cognitive impairment, based on Clinical Dementia Rating (CDR) staging scores. Our data included 427 individuals including 299 self-identified CH (mean age = 76.0; 69.6% female; mean education = 11.9) and 128 NHW (mean age = 72.9; 61.7% female; mean education = 13.8) who completed the CDR and a brief neuropsychological battery. Participants with other medical conditions known to impact cognition were excluded. Sex-, age-, and education-adjusted Z-scores were calculated for all cognitive tests (Logical Memory (Immediate and Delayed recall), Digit Span (Forward and Backward), and Verbal Fluency (Animals and Vegetables)). ANOVAs were used to examine the effects of ethnicity (NHW, CH) and CDR Global Score (0.5, 1.0) on the adjusted Z-scores for all cognitive tests. CDR score distribution was adjusted through factorial ANOVA (ethnicity x CDR). Descriptive analyses included independent t-tests to examine differences between ethnicity groups on age, sex, education, percent AD, percent Unclear, and CDR Global Score. There was a main effect of ethnicity on Digit Span Forward (p < 0.001), Digit Span Backward (p < 0.001), and Verbal Fluency - Vegetables (p < 0.01), where CH individuals showed greater impairment regardless of Global CDR score. We found a main effect of Global CDR score on all cognitive tests, where individuals with Global CDR score of 1.0 demonstrated more impairment than individuals with a Global CDR score of 0.5. No ethnicity x CDR interactions were significant. Our sample of older CH and NHW individuals, presumed to have mild cognitive impairments based on CDR staging, did not differ in memory abilities. However, the CH group scored significantly lower on measures of attention and working memory. Finally, semantic fluency performance was variable and possibly influenced by cultural familiarity with different semantic categories. Among older CH individuals with mild dementia, cognitive difficulties may extend beyond memory problems and include attentional and executive function difficulties. These findings have clinical implications for diagnosis and management of CH patients.

Resting-State Functional Connectivity Difference in Alzheimer's Disease and Mild Cognitive Impairment Using Threshold-Free Cluster Enhancement.

The disruption of functional connectivity is one of the early events that occurs in the brains of Alzheimer's disease (AD) patients. This paper reports a study on the clustering structure of functional connectivity in eight important brain networks in healthy, AD, and prodromal stage subjects. We used the threshold-free cluster enhancement (TFCE) method to explore the connectivity from resting-state functional MR images (rs-fMRIs). We conducted the study on a total of 32 AD, 32 HC, and 31 MCI subjects. We modeled the brain as a graph-based network to study these impairments, and pairwise Pearson's correlation-based functional connectivity was used to construct the brain network. The study found that connections in the sensory motor network (SMN), dorsal attention network (DAN), salience network (SAN), default mode network (DMN), and cerebral network were severely affected in AD and MCI. The disruption in these networks may serve as potential biomarkers for distinguishing AD and MCI from HC. The study suggests that alterations in functional connectivity in these networks may contribute to cognitive deficits observed in AD and MCI. Additionally, a negative correlation was observed between the global clinical dementia rating (CDR) score and the Z-score of functional connectivity within identified clusters in AD subjects. These findings provide compelling evidence suggesting that the neurodegenerative disruption of functional magnetic resonance imaging (fMRI) connectivity is extensively distributed across multiple networks in individuals diagnosed with AD.

The effects of low-dose radiation therapy in patients with mild-to-moderate Alzheimer's dementia: an interim analysis of a pilot study.

We aimed to determine whether low-dose radiotherapy (LDRT) is effective in patients with Alzheimer disease (AD). We included patients according to the following criteria: probable Alzheimer's dementia according to the New Diagnostic Criteria for Alzheimer's Disease; confirmation of amyloid plaque deposits on baseline amyloid positron emission tomography (PET); a Korean Mini-Mental State Examination 2nd edition (K-MMSE-2) score of 13-26; and a Global Clinical Dementia Rating (CDR) score of 0.5-2 points. LDRT was performed six times at 0.5 Gy each. Post-treatment cognitive function tests and PET-CT examinations were performed to evaluate efficacy. The medication for AD treatment was maintained throughout the study period. At 6 months after LDRT, neurological improvement was seen in 20% of patients. Patient #2 showed improvement in all domains of the Seoul Neuropsychological Screening Battery II (SNSB-II). Moreover, the K-MMSE-2 and Geriatric Depression Score-Short Form scores improved from 20 to 23 and from 8 to 2, respectively. For patient #3, the CDR score (sum of box score) improved from 1 (4.0) to 1 (3.5) at 3 months follow-up. Moreover, the Z scores for language and related functions, memory, and frontal executive function improved to -2.56, -1.86, and -1.32, respectively at the 6-month follow-up. Two patients complained of mild nausea and mild hair loss during LDRT, which improved after treatment. One of the five patients with AD treated with LDRT experienced a temporary improvement in SNSB-II. LDRT is tolerable in patients with AD. We are currently under follow-up and will conduct cognitive function tests after 12 months after LDRT. A large-scale randomized controlled trial with a longer follow-up period is warranted to determine the effect of LDRT on patients with AD.

Distinct and shared neuropsychiatric phenotypes in FTLD-tauopathies.

Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau) commonly causes dementia syndromes that include primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD). Cognitive decline in PPA and bvFTD is often accompanied by debilitating neuropsychiatric symptoms. In 44 participants with PPA or bvFTD due to autopsy-confirmed FTLD-tau, we characterized neuropsychiatric symptoms at early and late disease stages and determined whether the presence of certain symptoms predicted a specific underlying FTLD-tauopathy. Participants completed annual research visits at the Northwestern University Alzheimer's Disease Research Center. All participants had an initial Global Clinical Dementia Rating (CDR) Scale score ≤ 2, and neuropsychiatric symptoms were evaluated via the Neuropsychiatric Inventory-Questionnaire (NPI-Q). We assessed the frequency of neuropsychiatric symptoms across all participants at their initial and final visits and performed logistic regression to determine whether symptoms predicted a specific FTLD-tau pathologic diagnosis. Across the FTLD-tau cohort, irritability and apathy were most frequently endorsed at initial and final visits, respectively, whereas psychosis was highly uncommon at both timepoints. Irritability at initial visit predicted greater odds of a 4-repeat compared to a 3-repeat tauopathy (OR = 3.95, 95% CI = 1.10-15.83, p < 0.05). Initial sleep disturbance predicted greater odds of progressive supranuclear palsy (PSP) compared to other FTLD-tau subtypes (OR = 10.68, 95% CI = 2.05-72.40, p < 0.01). Appetite disturbance at final evaluation predicted lower odds of PSP (OR = 0.15, 95% CI = 0.02-0.74, p < 0.05). Our findings suggest that characterization of neuropsychiatric symptoms can aid in the prediction of underlying FTLD-tauopathies. Given considerable pathologic heterogeneity underlying dementias, neuropsychiatric symptoms may be useful for differential diagnosis and treatment planning.

Generalized q‐sampling imaging‐based fiber tracking measures of white matter tracts in cognitive impairment

AbstractBackgroundDiffusion magnetic resonance imaging (dMRI) is a non‐invasive technique for exploring white matter fiber organization of the brain. As traditional diffusion tensor imaging (DTI) methods may provide inaccurate descriptions of local crossing and diverging fibers, we examined generalized q‐sampling imaging (GQI), a novel method providing better directional and quantitative information using dMRI data from community‐dwelling older adults.MethodWe examined baseline dMRI data from 227 adults aged 71±8 on average from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core, who had baseline and year‐1 follow‐up global Clinical Dementia Rating (CDR) score of 0 (indicates normal cognitive function) and 0.5 (akin to MCI). The primary outcome measure was cognitive migration status determined by CDR increase/decrease between baseline and follow‐up (mean difference = 13.9 months), shown in Figure. We performed atlas‐based fiber tracking analysis using GQ in DSI Studio to generate normalized quantitative anisotropy (NQA), DTI fractional anisotropy (DTI_FA) and restricted diffusion (RDI) measures in several AD‐related white matter (WM) tracts: Corpus Callosum (CC), Fornix, Cingulum bundle/Parahippocampal tracts (see Table 2: CFP; CP; CPP), Uncinate Fasciculus (UF), Superior Longitudinal Fasciculus (SLF) and Inferior Fronto‐Occipital Fasciculus (IFOF). We performed multinomial logistic regression (MLR) models adjusted for age, sex, and education, using cognitive migration status as the outcome and standardized GQI‐based diffusion indices sNQA, sRDI, and sDTI_FA as predictors.Result Table 1 lists the baseline demographics and biomarker characteristics for cognitive migration groups. MLR results in Table 2 show significant associations between diffusion indices and tracts for outcome 4 (Reversion) in reference to outcome 1 (stability of normal cognition). Decrease in sNQA in bilateral CP and right Fornix was significantly associated with higher odds of Reversion relative to the reference. Increase in sDTI_FA in left IFOF was associated with higher odds of reversion relative to reference. Decrease in sRDI in bilateral CFP, CPP, Fornix and UF and right CP was associated with higher reversion relative to reference.ConclusionIn early trajectories of cognitive impairment, RDI may be a sensitive diffusion marker for cognitive reversion in several AD‐related WM tracts. Future work will validate these markers in other cognitive migration groups (negative migration and MCI stability).