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Introduction: Prediction of the dementia progression is important for patient management. We aimed to investigate the cognitive trajectories of Alzheimer's disease dementia (ADD) and dementia with Lewy bodies (DLB) according to the initial structural change measured by comprehensive visual rating scales (CVRS). Methods: We retrospectively included the patients who initially visited the Dementia Clinic of Chonnam National University Hospital between 2010 and 2012. All patients underwent dementia workup including neuropsychological battery (Seoul Neuropsychological Screening Battery, SNSB). We recruited the participant who underwent SNSB annually for 3 years successively. A total of 136 patients of ADD and 63 patients of DLB were included for analysis. We analyzed the decline pattern of the cognitive profile according to the initial brain structural changes. Results: The general cognitive trajectories between ADD and DLB patients were not different. However, DLB patients showed more rapid decline of cognitive function in language and related function, visual memory function, and frontal executive function. The scores were lower in participants with DLB with the lesser atrophy group in attention, visuospatial function, and frontal executive function. In analysis of the cognitive trajectories, the visual memory domain declined rapidly in the DLB with lesser atrophy group compared with the ADD with lesser atrophy group. Conclusion: We founded that the differences in the visual cognitive profile in ADD and DLB patients in serial follow-up of neuropsychological tests. It is prominent in the mild structural change group of ADD and DLB. [ABSTRACT FROM AUTHOR]

Abstract Background Transcriptome-wide association study (TWAS) is an influential tool for identifying genes associated with complex diseases whose genetic effects are likely mediated through transcriptome. TWAS utilizes reference genetic and transcriptomic data to estimate effect sizes of genetic variants on gene expression (i.e., effect sizes of a broad sense of expression quantitative trait loci, eQTL). These estimated effect sizes are employed as variant weights in gene-based association tests, facilitating the mapping of risk genes with genome-wide association study (GWAS) data. However, most existing TWAS of Alzheimer's disease (AD) dementia are limited to studying only cis-eQTL proximal to the test gene. To overcome this limitation, we applied the Bayesian Genome-wide TWAS (BGW-TWAS) method to leveraging both cis- and trans- eQTL of brain and blood tissues, in order to enhance mapping risk genes for AD dementia. Methods We first applied BGW-TWAS to the Genotype-Tissue Expression (GTEx) V8 dataset to estimate cis- and trans- eQTL effect sizes of the prefrontal cortex, cortex, and whole blood tissues. Estimated eQTL effect sizes were integrated with the summary data of the most recent GWAS of AD dementia to obtain BGW-TWAS (i.e., gene-based association test) p-values of AD dementia per gene per tissue type. Then we used the aggregated Cauchy association test to combine TWAS p-values across three tissues to obtain omnibus TWAS p-values per gene. Results We identified 85 significant genes in prefrontal cortex, 82 in cortex, and 76 in whole blood that were significantly associated with AD dementia. By combining BGW-TWAS p-values across these three tissues, we obtained 141 significant risk genes including 34 genes primarily due to trans-eQTL and 35 mapped risk genes in GWAS Catalog. With these 141 significant risk genes, we detected functional clusters comprised of both known mapped GWAS risk genes of AD in GWAS Catalog and our identified TWAS risk genes by protein-protein interaction network analysis, as well as several enriched phenotypes related to AD. Conclusion We applied BGW-TWAS and aggregated Cauchy test methods to integrate both cis- and trans- eQTL data of brain and blood tissues with GWAS summary data, identifying 141 TWAS risk genes of AD dementia. These identified risk genes provide novel insights into the underlying biological mechanisms of AD dementia and potential gene targets for therapeutics development.

Introduction: Dementia is caused by various diseases, including Alzheimer’s disease dementia (ADD) and dementia with Lewy bodies (DLB). We often encounter patients with dementia who have limited shoulder joint range of motion (ROM), especially those with behavioral and psychological symptoms of dementia (BPSD). But the relationship between the diseases of dementia and restricted shoulder joint ROM is currently unclear. Methods: We examined cognitive function and shoulder joint ROM in 234 new outpatients at 7 memory clinics in Japan. We assessed cognitive function using the Mini-Mental State Examination (MMSE) and Revised Hasegawa Dementia Scale (HDS-R) and BPSD using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Patients were categorized by dementia diagnosis (ADD, DLB, other dementia, and control). Right, left, and total shoulder joint ROM was assessed using validated the Japanese Orthopaedic Association (JOA) score. Results: We found significant associations of lower right, left, and total shoulder joint ROM scores with male sex, advanced age, higher NPI-Q score, lower HDS-R, and MMSE scores. Little difference was found between right and left shoulder joint ROM scores. Restricted shoulder joint ROM was related to serial 7, verbal frequency domain scores on the HDS-R and repeat score on the MMSE. It was also related to the hallucinations, irritability/lability and nighttime disturbances scores on the NPI-Q. Furthermore, the dementia groups, especially the DLB group, showed worse shoulder joint ROM than the control group. Conclusions: Dementia was significantly related to restricted shoulder joint ROM. Maintaining communication and social interaction may help maintain shoulder joint ROM. [ABSTRACT FROM AUTHOR]

Background: Transcriptome-wide association study (TWAS) is an influential tool for identifying genes associated with complex diseases whose genetic effects are likely mediated through transcriptome. TWAS utilizes reference genetic and transcriptomic data to estimate effect sizes of genetic variants on gene expression (i.e., effect sizes of a broad sense of expression quantitative trait loci, eQTL). These estimated effect sizes are employed as variant weights in gene-based association tests, facilitating the mapping of risk genes with genome-wide association study (GWAS) data. However, most existing TWAS of Alzheimer's disease (AD) dementia are limited to studying only cis-eQTL proximal to the test gene. To overcome this limitation, we applied the Bayesian Genome-wide TWAS (BGW-TWAS) method to leveraging both cis- and trans- eQTL of brain and blood tissues, in order to enhance mapping risk genes for AD dementia. Methods: We first applied BGW-TWAS to the Genotype-Tissue Expression (GTEx) V8 dataset to estimate cis- and trans- eQTL effect sizes of the prefrontal cortex, cortex, and whole blood tissues. Estimated eQTL effect sizes were integrated with the summary data of the most recent GWAS of AD dementia to obtain BGW-TWAS (i.e., gene-based association test) p-values of AD dementia per gene per tissue type. Then we used the aggregated Cauchy association test to combine TWAS p-values across three tissues to obtain omnibus TWAS p-values per gene. Results: We identified 85 significant genes in prefrontal cortex, 82 in cortex, and 76 in whole blood that were significantly associated with AD dementia. By combining BGW-TWAS p-values across these three tissues, we obtained 141 significant risk genes including 34 genes primarily due to trans-eQTL and 35 mapped risk genes in GWAS Catalog. With these 141 significant risk genes, we detected functional clusters comprised of both known mapped GWAS risk genes of AD in GWAS Catalog and our identified TWAS risk genes by protein-protein interaction network analysis, as well as several enriched phenotypes related to AD. Conclusion: We applied BGW-TWAS and aggregated Cauchy test methods to integrate both cis- and trans- eQTL data of brain and blood tissues with GWAS summary data, identifying 141 TWAS risk genes of AD dementia. These identified risk genes provide novel insights into the underlying biological mechanisms of AD dementia and potential gene targets for therapeutics development. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging‐defined subgroups. METHODS: We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid‐negative controls. We used voxel‐based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD‐Memory. RESULTS: There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD‐Memory, lower left hemisphere GMV for AD‐Language, anterior lower GMV for AD‐Executive, and posterior lower GMV for AD‐Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD‐Language group than any other group (p = 1.15 × 10−10). For overlap between imaging‐defined and cognitively defined subgroups, AD‐Memory matched up with an imaging‐defined limbic predominant group. DISCUSSION: MRI findings differ across cognitively defined AD subgroups. [ABSTRACT FROM AUTHOR]

Objectives Working memory performances are based on brain functional connectivity, so that connectivity may be deranged in individuals with mild cognitive impairment (MCI) and patients with dementia due to Alzheimer's disease (ADD). Here we tested the hypothesis of abnormal functional connectivity as revealed by the imaginary part of coherency (ICoh) at electrode pairs from event-related electroencephalographic oscillations in ADD and MCI patients. Methods The study included 43 individuals with MCI, 43 with ADD, and 68 demographically matched healthy controls (HC). Delta, theta, alpha, beta, and gamma bands event-related ICoh was measured during an oddball paradigm. Inter-hemispheric, midline, and intra-hemispheric ICoh values were compared in ADD, MCI, and HC groups. Results The main results of the present study can be summarized as follows: (1) A significant increase of midline frontal and temporal theta coherence in the MCI group as compared to the HC group; (2) A significant decrease of theta, delta, and alpha intra-hemispheric coherence in the ADD group as compared to the HC and MCI groups; (3) A significant decrease of theta midline coherence in the ADD group as compared to the HC and MCI groups; (4) Normal inter-hemispheric coherence in the ADD and MCI groups. Conclusions Compared with the MCI and HC, the ADD group showed disrupted event-related intra-hemispheric and midline low-frequency band coherence as an estimate of brain functional dysconnectivity underlying disabilities in daily living. Brain functional connectivity during attention and short memory demands is relatively resilient in elderly subjects even with MCI (with preserved abilities in daily activities), and it shows reduced efficiency at multiple operating oscillatory frequencies only at an early stage of ADD. [ABSTRACT FROM AUTHOR]

Background: Evidence on health and social care resource utilisation and associated costs, and how this varies across people with Alzheimer's disease (AD) dementia is limited. Methods: Retrospective cohort, using the Discover dataset, which includes linked health and social care records for approximately 2.5 million people in North-West London. Individuals were followed up from the latter of 2010 or from diagnosis of AD dementia (index) up to 2019. Outcomes were overall survival, care home admission, health and social care utilisation and associated costs, and cardiovascular outcomes. Variation was explored in subpopulations and by stratifying by cost quintile. Generalised linear modelling was used to estimate the association between clinical and demographic characteristics and healthcare costs. Results: The cohort included 18,116 people diagnosed with AD dementia whose mean age at index was 81 years, 62 % were female and 65 % were of white ethnicity. Median survival from index was 4.9 years (95 %CI: 4.8–5.0). Mean healthcare costs were £4,548(£4,491–£4,604) per person year(ppy). Healthcare costs for the 48 % who used social care were £5,433ppy(£5,353–£5,514) and social care costs were £24,374ppy(£24,372–£24,376). In the overall cohort costs in the highest cost quintile were £13,665ppy(£13,420–£13,911), of which 70 % was from inpatient hospitalisation. Subpopulations admitted to care home (£7,535 £7,362–£7,709), with cardiovascular disease (£6,106;£5,990–£6,222) and with type 2 diabetes (£6,049;£5,901–£6,198) accrued the highest healthcare costs. Factors most strongly associated with cost were dying during follow up (+£2,224;£2,010–£2,493), being frail (+£1,246;£1,051–£1,440) and prior stroke (+£1,207;£908–£1,507). Conclusion: Characteristics of individuals with high healthcare costs include requirement for social care and cardiometabolic comorbidities. Identifying individuals early in their disease course may improve health outcomes and reduce the cost of AD dementia in later life.

Introduction: Diagnostic classification systems and guidelines posit distinguishing patterns of impairment in Alzheimer's (AD) and vascular dementia (VaD). In our study, we aim to identify which diagnostic instruments distinguish them. Methods: We searched PubMed and PsychInfo for empirical studies published until December 2020, which investigated differences in cognitive, behavioral, psychiatric, and functional measures in patients older than 64years and reported information on VaD subtype, age, education, dementia severity, and proportion of women. We systematically reviewed these studies and conducted Bayesian hierarchical metaregressions to quantify the evidence for differences using the Bayes factor (BF). The risk of bias was assessed using the Newcastle-Ottawa-Scale and funnel plots. Results: We identified 122 studies with 17,850 AD and 5,247 VaD patients. Methodological limitations of the included studies are low comparability of patient groups and an untransparent patient selection process. In the digit span backward task, AD patients were nine times more probable (BF = 9.38) to outperform VaD patients (βg = 0.33, 95% ETI = 0.12, 0.52). In the phonemic fluency task, AD patients outperformed subcortical VaD (sVaD) patients (βg = 0.51, 95% ETI = 0.22, 0.77, BF = 42.36). VaD patients, in contrast, outperformed AD patients in verbal (βg = -0.61, 95% ETI = -0.97, -0.26, BF = 22.71) and visual (βg = -0.85, 95% ETI = -1.29, -0.32, BF = 13.67) delayed recall. We found the greatest difference in verbal memory, showing that sVaD patients outperform AD patients (βg = -0.64, 95% ETI = -0.88, -0.36, BF = 72.97). Finally, AD patients performed worse than sVaD patients in recognition memory tasks (βg = -0.76, 95% ETI = -1.26, -0.26, BF = 11.50). Conclusion: Our findings show inferior performance of AD in episodic memory and superior performance in working memory. We found little support for other differences proposed by diagnostic systems and diagnostic guidelines. The utility of cognitive, behavioral, psychiatric, and functional measures in differential diagnosis is limited and should be complemented by other information. Finally, we identify research areas and avenues, which could significantly improve the diagnostic value of cognitive measures. [ABSTRACT FROM AUTHOR]

Background: Assessments of Alzheimer's disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. Objective: Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. Methods: Autopsies were obtained in decedents with cognitive testing (n = 300). Aβ plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n = 14), brainstem (n = 5), olfactory bulb, and four spinal cord levels. Since spinal Aβ were absent in the first 165 cases, it was not assessed in the remaining cases. Results: Age at death was 91 years old. About 90% had Aβ in cerebrum and of these, half had Aβ in the brainstem. Of the latter, 85% showed Aβ in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aβ in one or more regions. In a logistic model controlling for demographics, Aβ and tau-tangles within the cerebrum, the presence of Aβ in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. Conclusion: Regional differences in Aβ and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum. [ABSTRACT FROM AUTHOR]

IntroductionDiagnostic classification systems and guidelines posit distinguishing patterns of impairment in Alzheimer’s (AD) and vascular dementia (VaD). In our study, we aim to identify which diagnostic instruments distinguish them.MethodsWe searched PubMed and PsychInfo for empirical studies published until December 2020, which investigated differences in cognitive, behavioral, psychiatric, and functional measures in patients older than 64 years and reported information on VaD subtype, age, education, dementia severity, and proportion of women. We systematically reviewed these studies and conducted Bayesian hierarchical meta-regressions to quantify the evidence for differences using the Bayes factor (BF). The risk of bias was assessed using the Newcastle-Ottawa-Scale and funnel plots.ResultsWe identified 122 studies with 17,850 AD and 5,247 VaD patients. Methodological limitations of the included studies are low comparability of patient groups and an untransparent patient selection process. In the digit span backward task, AD patients were nine times more probable (BF = 9.38) to outperform VaD patients (βg = 0.33, 95% ETI = 0.12, 0.52). In the phonemic fluency task, AD patients outperformed subcortical VaD (sVaD) patients (βg = 0.51, 95% ETI = 0.22, 0.77, BF = 42.36). VaD patients, in contrast, outperformed AD patients in verbal (βg = −0.61, 95% ETI = −0.97, −0.26, BF = 22.71) and visual (βg = −0.85, 95% ETI = −1.29, −0.32, BF = 13.67) delayed recall. We found the greatest difference in verbal memory, showing that sVaD patients outperform AD patients (βg = −0.64, 95% ETI = −0.88, −0.36, BF = 72.97). Finally, AD patients performed worse than sVaD patients in recognition memory tasks (βg = −0.76, 95% ETI = −1.26, −0.26, BF = 11.50).ConclusionOur findings show inferior performance of AD in episodic memory and superior performance in working memory. We found little support for other differences proposed by diagnostic systems and diagnostic guidelines. The utility of cognitive, behavioral, psychiatric, and functional measures in differential diagnosis is limited and should be complemented by other information. Finally, we identify research areas and avenues, which could significantly improve the diagnostic value of cognitive measures.

Background: We aimed to investigate the incidence of dementia by age and year as well as the population-attributable fractions (PAFs) for known dementia risk factors in Republic of Korea. Methods: A 12-year, nationwide, population-based, retrospective cohort study was conducted. We used customized health information from the National Health Insurance Service (NHIS) data from 2002 to 2017. We analyzed ageand sex-adjusted incidence rates and PAF of dementia for each risk factor such as depression, diabetes, hemorrhagic stroke, ischemic stroke, hypertension, osteoporosis and physical inactivity using Levin's formula. Results: Of the 794,448 subjects in the dementia-free cohort, 49,524 (6.2%) developed dementia. Dementia incidence showed annual growth from 1.56 per 1,000 person-years in 2006 to 6.94 per 1,000 person-years in 2017. Of all dementia cases, 34,544 subjects (69.8%) were female and 2,479 subjects (5.0%) were early onset dementia. AD dementia accounted for 66.5% of the total dementia incidence. Considering relative risk and prevalence, physical inactivity attributed the greatest to dementia (PAF, 8.1%), followed by diabetes (PAF, 4.2%), and hypertension (PAF, 2.9%). Altogether, the significant risk factors increased the risk of dementia by 18.0% (overall PAF). Conclusion: We provided the incidence of dementia and PAFs for dementia risk factors in Republic of Korea using a 12-year, nationwide cohort. Encouraging lifestyle modifications and more aggressive control of risk factors may effectively prevent dementia. [ABSTRACT FROM AUTHOR]

Background: The majority of previous studies showed that older adults with mild cognitive impairment (MCI) as well as Alzheimer's disease dementia (ADD) had impaired cognition and mood status, as well as increased behavioral disturbances after the first wave of the COVID-19 pandemic. However, there are still controversial data as regards the multifactorial impact of the restrictive measures on cognition, mood and daily function in older adults with MCI and ADD. Aim: In the current study, the scope is to identify possible deterioration by means of cognitive and functional level due to mood and behavioral alterations during the second quarantine imposed in Greece between November 2020 and May 2021, as well as one year after the second quarantine, in May 2022. Methods: Participants were recruited from the two day centers of the Greek Association of Alzheimer Disease and Related Disorders (GAADRD). They underwent three yearly follow up assessments from May 2020 to May 2022 and participated in cognitive training interventions (through digital online means) during the aforementioned period. Mixed measures analyses of variance as well as path models were used for the study's purposes. Results: The study sample comprised 210 participants (175 people with MCI and 35 people with ADD). The mean age was 71.59 and 77.94 for people with MCI and mild ADD, respectively, whereas the average number of years of education was 12.65 for those with MCI and 9.83 for people with mild ADD. The results show that participants' deterioration rate (D), calculated by means of their performance in neuropsychological and functional assessments between 2020 and 2021 (D1) and 2021 and 2022 (D2), did not change significantly, except for the Rey Auditory Verbal Learning Test (RAVLT), since both groups displayed a larger D2 across the test conditions (immediate recall, fifth trial and delayed recall). Trail Making Test-B (TMT-B) performance, applied only in the MCI group, decreased more in relation to the deterioration rate D2. Additionally, two path models were applied to measure the direct relationships between diagnosis, performance in tests measuring mood and neuropsychiatric disturbances (NPI) and cognition, as measured by the RAVLT, in the 2020–2022 assessments. TMT-B was administered only in the MCI population, and therefore was not included in path models. The results show that participants' scores in RAVLT conditions were related to diagnosis and NPI performance, which was positively affected by diagnosis. No other relationships between RAVLT with mood tests were observed. Conclusions: Our results show that after the second lockdown period, the neuropsychological performance of people with MCI and ADD, calculated by means of their D2, did not change, except from their verbal memory, as well as visual scanning and information processing, measured using the TMT-B. Therefore, it can be assumed that those who were enrolled in digital non-pharmacological interventions during the COVID-19 pandemic home restrictions did not experience increased cognitive and functional deterioration due to mood and behavioral alterations after the pandemic. [ABSTRACT FROM AUTHOR]

Abstract Background In the present study, we examined the distinguishing ability of a mild cognitive impairment (MCI) assessment tool for rapid screening using a computer (MARC) for Alzheimer’s disease dementia (ADD), MCI, and non-demented controls (NDC) with no cognitive impairment, as well as its validity and reliability, as part of a preliminary trial for the development of the tool. Methods A total of 64 participants (23 in the ADD group, 17 in the MCI group, and 24 in the NDC group) were analyzed. The participants were administered MARC and a pre-existing computerized Alzheimer’s dementia screening test (MSP), and 31 participants (14 in the MCI group, 17 in the NDC group) were readministered MARC within 4 months from the first test. Results The median (interquartile range) test time for MARC was 401 (350–453) s. Total MARC scores were significantly worse in the MCI and ADD groups than in the NDC group (p

Background. Vitamins A, D and E and beta-carotene may have a protective function for cognitive health, due to their antioxidant capacities. Methods. We analyzed data from 1334 non-demented participants (mean age 84 years) from the AgeCoDe study, a prospective multicenter-cohort of elderly general-practitioner patients in Germany, of whom n = 250 developed all-cause dementia and n = 209 developed Alzheimer's dementia (AD) during 7 years of follow-up. We examined whether concentrations of vitamins A (retinol), D (25-hydroxycholecalciferol) and E (alpha-tocopherol) and beta-carotene, would be associated with incident (AD) dementia. Results. In our sample, 33.7% had optimum vitamin D concentrations (≥50 nmol/L). Higher concentrations of vitamin D were associated with lower incidence of all-cause dementia and AD (HR 0.99 (95%CI 0.98; 0.99); HR0.99 (95%CI 0.98; 0.99), respectively). In particular, subjects with vitamin D deficiency (25.3%, <25 nmol/L) were at increased risk for all-cause dementia and AD (HR1.91 (95%CI 1.30; 2.81); HR2.28 (95%CI 1.47; 3.53), respectively). Vitamins A and E and beta-carotene were unrelated to (AD) dementia. Conclusions. Vitamin D deficiency increased the risk to develop (AD) dementia. Our study supports the advice for monitoring vitamin D status in the elderly and vitamin D supplementation in those with vitamin D deficiency. We observed no relationships between the other vitamins with incident (AD) dementia, which is in line with previous observational studies. [ABSTRACT FROM AUTHOR]

Background: In the present study, we examined the distinguishing ability of a mild cognitive impairment (MCI) assessment tool for rapid screening using a computer (MARC) for Alzheimer's disease dementia (ADD), MCI, and non-demented controls (NDC) with no cognitive impairment, as well as its validity and reliability, as part of a preliminary trial for the development of the tool. Methods: A total of 64 participants (23 in the ADD group, 17 in the MCI group, and 24 in the NDC group) were analyzed. The participants were administered MARC and a pre-existing computerized Alzheimer's dementia screening test (MSP), and 31 participants (14 in the MCI group, 17 in the NDC group) were readministered MARC within 4 months from the first test. Results: The median (interquartile range) test time for MARC was 401 (350–453) s. Total MARC scores were significantly worse in the MCI and ADD groups than in the NDC group (p < 0.05 and p < 0.01, respectively). In the receiver operating characteristic (ROC) analysis, the area under the ROC curve (AUC) when comparing the NDC and MCI groups was 0.866 (95% CI, 0.759–0.974), when comparing the NDC and AD groups was 0.989 (95% CI, 0.970–1.000), and when comparing the MCI and AD groups was 0.889 (95% CI, 0.790–0.988). Furthermore, there was a significant correlation with the results of the existing test, MSP (r = 0.839, p < 0.001). In addition, the intraclass correlation coefficient (ICC) (1,1) when the first and second MARC scores were compared was 0.740 (95% CI, 0.529–0.865; p < 0.001). Conclusions: MARC is considered capable of distinguishing MCI with high accuracy. The tool has good validity and reliability, and it can be administered in a short period of time without the need for a specialist. [ABSTRACT FROM AUTHOR]

With an increase in the number of patients with Alzheimer's disease dementia (ADD), new health technologies have been developed to address the problem. We propose an optimal way to assess the disease burden and treatment value of ADD in Japan by considering the characteristics of the disease. We performed literature searches and a group interview with professional care workers to obtain information on the items that would facilitate the assessment of the value of ADD intervention. We determined the items as patient quality of life (QOL), medical costs, caregiver QOL, public long-term care costs, and informal care costs. There are several limitations to how QOL is measured, particularly for patients with ADD. Public long-term care costs represent a substantial proportion of total costs and should be included in the assessment and decision-making of ADD, even from the payer's perspective. Following that, a process is required to take informal care costs into account in decision-making, regardless of whether they are included or not in a base-case analysis. The importance of other elements of care burden that cannot be quantitatively measured should also be recognized and reflected in decision-making. [ABSTRACT FROM AUTHOR]

Objective Testamentary capacity (TC) is a legal construct, which concerns a person's mental capacity to make or amend a will. Although expert clinicians are frequently asked to assess TC in forensic settings, there are few instruments and little empirical research to inform and guide their assessments. The present study describes the development and psychometric properties of a standardized assessment measure of TC (Testamentary Capacity Instrument-TCI), and investigates its reliability and validity. Methods The TCI is an interview-based, psychometric measure, which assesses a testator's knowledge of four conceptual elements, which together comprise the legal basis for TC in the Anglo-American legal system: (1) what a will is, (2) nature and extent of assets/property, (3) possible heirs/claimants to property, and (4) plan to distribute assets to heirs after death. Cronbach's alpha and percentage exact agreement were used to examine TCI element reliabilities. Using independent samples t -tests, MANOVA and MANCOVA, we investigated validity by comparing TCI element performance of cognitively intact older adults (n  = 22) and older adults with ad dementia (n  = 20). Results The TCI elements showed good internal consistency and good inter-rater reliability. The ad group performed significantly below the control group on all four TCI elements, with effect sizes exceeding 1.2, suggesting that the TCI has content and construct validity. Conclusions Relative to cognitively intact older adults, older adults with ad dementia showed significant impairment on all four TCI conceptual elements. The TCI has promise as a standardized quantitative measure of TC to support clinical assessment of TC in forensic settings. [ABSTRACT FROM AUTHOR]

Background: Many groups have been using immunomagnetic reduction (IMR) for assaying plasma amyloid-β 1-40 (Aβ 1-40 ) peptide, Aβ 1-42 peptide and total tau protein (T-Tau) in cognitively normal controls (NC), patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD). Tremendous results have been independently reported., Objective: We used traditional knowledge databases (e.g., PubMed, Embase), papers published at international conferences, and private communications to obtain data involving the use of IMR assay for plasma biomarkers of plasma Aβ 1-40 , Aβ 1-42 , and T-Tau in NC, aMCI, and ADD., Methods: Results of thirty studies were analyzed, including twenty-five studies published in papers, two studies presented at conferences and three unpublished studies., Results: Among the thirty studies, there were 1189 subjects of NC, 544 aMCI patients and 853 ADD patients. The average value of plasma Aβ 1-40 in subjects significantly decreased from NC (59.72 pg/ml) to aMCI (45.92 pg/ml, p  < 0.0001), which was no significant different from ADD (48.34 pg/ml, p  > 0.05). The average level of plasma Aβ 1-42 significantly increased from NC (15.72 pg/ml) to aMCI (17.66 pg/ml, p  < 0.0001), which was not significantly different from ADD (19.39 pg/ml, p  > 0.05). However, the average level of plasma T-Tau significantly increased from NC (17.92 pg/ml) to aMCI (28.26 pg/ml, p  < 0.0001), further significantly increased to AD (35.51 pg/ml, p  < 0.001)., Conclusions: Plasma Aβ 1-40 , Aβ 1-42 , and T-Tau levels are able to discriminate NC from patients with aMCI and ADD. Plasma T-Tau levels are disease-severity dependent., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The majority of previous studies showed that older adults with mild cognitive impairment (MCI) as well as Alzheimer’s disease dementia (ADD) had impaired cognition and mood status, as well as increased behavioral disturbances after the first wave of the COVID-19 pandemic. However, there are still controversial data as regards the multifactorial impact of the restrictive measures on cognition, mood and daily function in older adults with MCI and ADD. Aim: In the current study, the scope is to identify possible deterioration by means of cognitive and functional level due to mood and behavioral alterations during the second quarantine imposed in Greece between November 2020 and May 2021, as well as one year after the second quarantine, in May 2022. Methods: Participants were recruited from the two day centers of the Greek Association of Alzheimer Disease and Related Disorders (GAADRD). They underwent three yearly follow up assessments from May 2020 to May 2022 and participated in cognitive training interventions (through digital online means) during the aforementioned period. Mixed measures analyses of variance as well as path models were used for the study’s purposes. Results: The study sample comprised 210 participants (175 people with MCI and 35 people with ADD). The mean age was 71.59 and 77.94 for people with MCI and mild ADD, respectively, whereas the average number of years of education was 12.65 for those with MCI and 9.83 for people with mild ADD. The results show that participants’ deterioration rate (D), calculated by means of their performance in neuropsychological and functional assessments between 2020 and 2021 (D1) and 2021 and 2022 (D2), did not change significantly, except for the Rey Auditory Verbal Learning Test (RAVLT), since both groups displayed a larger D2 across the test conditions (immediate recall, fifth trial and delayed recall). Trail Making Test-B (TMT-B) performance, applied only in the MCI group, decreased more in relation to the deterioration rate D2. Additionally, two path models were applied to measure the direct relationships between diagnosis, performance in tests measuring mood and neuropsychiatric disturbances (NPI) and cognition, as measured by the RAVLT, in the 2020–2022 assessments. TMT-B was administered only in the MCI population, and therefore was not included in path models. The results show that participants’ scores in RAVLT conditions were related to diagnosis and NPI performance, which was positively affected by diagnosis. No other relationships between RAVLT with mood tests were observed. Conclusions: Our results show that after the second lockdown period, the neuropsychological performance of people with MCI and ADD, calculated by means of their D2, did not change, except from their verbal memory, as well as visual scanning and information processing, measured using the TMT-B. Therefore, it can be assumed that those who were enrolled in digital non-pharmacological interventions during the COVID-19 pandemic home restrictions did not experience increased cognitive and functional deterioration due to mood and behavioral alterations after the pandemic.

Objectives: Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia following Alzheimer's disease dementia (ADD). This study investigated the diagnostic role of the gesture imitation test in detecting DLB and differentiating DLB from ADD. Methods: A total of 63 patients with DLB, 93 patients with ADD, and 88 healthy controls were included in this study. All participants were administered the gesture imitation test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the clock drawing test (CDT), and other neuropsychological tests. Results: The patients with DLB performed worse than the healthy controls in the global scores and on every item of the gesture imitation test (p < 0.001). The area under the curve (AUC) for the global scores was 0.889 (p < 0.001) in differentiating the DLB and control groups. Item 4 was a better discriminator, with a sensitivity of 79.37% and a specificity of 79.55%. The AUC for the global scores decreased to 0.593 and the difference was marginal (p = 0.079) in differentiating the DLB and ADD groups. The patients with DLB performed worse on Items 1 and 4 compared with the patients with ADD (p = 0.040, 0.004). The gesture imitation test was positively correlated with the scores of the MMSE (r = 0.355, p = 0.017), the MoCA (r = 0.382, p = 0.010), and the CDT (r = 0.407, p = 0.005) in patients with DLB. Conclusion: The gesture imitation test is an easy, rapid tool for detecting DLB and has a role in differentiating DLB from ADD, especially in Items 1 and 4. [ABSTRACT FROM AUTHOR]

Background: Normal pressure hydrocephalus is a neurologic disease leading to enlargement of ventricles which is presented with gait and balance disturbance, cognitive decline, and urinary incontinence. Diagnosis of normal pressure hydrocephalus is challenging due to the late onset of signs and symptoms. In this review, we summarize the cerebrospinal fluid, plasma, pathology, and genetic biomarkers of normal pressure hydrocephalus and related disorders. Body: Recently, cerebrospinal fluid and serum biomarkers analysis alongside gene analysis has received a lot of attention. Interpreting a set of serum and cerebrospinal fluid biomarkers along with genetic testing for candidate genes could differentiate NPH from other neurological diseases such as Alzheimer’s disease, Parkinson’s disease with dementia, and other types of dementia. Conclusion: Better understanding the pathophysiology of normal pressure hydrocephalus through genetic studies can aid in evolving preventative measures and the early treatment of normal pressure hydrocephalus patients. [ABSTRACT FROM AUTHOR]

Introduction: This study assessed the construct validity and clinical utility of the National Alzheimer's Coordinating Center Lewy Body Dementia (LBD) Module, consisting of the Speeded Attention and Noise Pareidolia Tasks. Methods: Participants included 459 older adults diagnosed as cognitively normal (n = 202), or with non‐amnestic mild cognitive impairment (n = 61), amnestic mild cognitive impairment (n = 96), Alzheimer's disease dementia (n = 44), or LBD (n = 56). Results: Speeded Attention demonstrated strong convergent validity and moderate discriminant validity when compared to established neuropsychological tests. Noise Pareidolia demonstrated strong discriminant validity, but limited convergent validity. Noise Pareidolia scores were significantly lower in those with reported hallucinations, delusions, or REM sleep behavior disorder symptoms. LBD Module tests discriminated well between cognitively normal adults and those with LBD. Discussion: The LBD Module demonstrates promising construct validity and clinical utility, which support its use across research and clinical settings. [ABSTRACT FROM AUTHOR]

Introduction: Automated speech analysis has emerged as a scalable, cost‐effective tool to identify persons with Alzheimer's disease dementia (ADD). Yet, most research is undermined by low interpretability and specificity. Methods: Combining statistical and machine learning analyses of natural speech data, we aimed to discriminate ADD patients from healthy controls (HCs) based on automated measures of domains typically affected in ADD: semantic granularity (coarseness of concepts) and ongoing semantic variability (conceptual closeness of successive words). To test for specificity, we replicated the analyses on Parkinson's disease (PD) patients. Results: Relative to controls, ADD (but not PD) patients exhibited significant differences in both measures. Also, these features robustly discriminated between ADD patients and HC, while yielding near‐chance classification between PD patients and HCs. Discussion: Automated discourse‐level semantic analyses can reveal objective, interpretable, and specific markers of ADD, bridging well‐established neuropsychological targets with digital assessment tools. [ABSTRACT FROM AUTHOR]

Background: The driving behavior of patients with mild Alzheimer's disease dementia (ADD) and patients with mild cognitive impairment (MCI) is frequently characterized by errors. A genetic factor affecting cognition is apolipoprotein E4 (APOE4), with carriers of APOE4 showing greater episodic memory impairment than non-carriers. However, differences in the driving performance of the two groups have not been investigated.Objective: To compare driving performance in APOE4 carriers and matched non-carriers.Methods: Fourteen APOE4 carriers and 14 non-carriers with amnestic MCI or mild ADD underwent detailed medical and neuropsychological assessment and participated in a driving simulation experiment, involving driving in moderate and high traffic volume in a rural environment. Driving measures were speed, lateral position, headway distance and their SDs, and reaction time. APOE was genotyped through plasma samples.Results: Mixed two-way ANOVAs examining traffic volume and APOE4 status showed a significant effect of traffic volume on all driving variables, but a significant effect of APOE4 on speed variability only. APOE4 carriers were less variable in their speed than non-carriers; this remained significant after a Bonferroni correction. To further examine variability in the driving performance, coefficients of variation (COV) were computed. Larger headway distance COV and smaller lateral position COV were observed in high compared to moderate traffic. APOE4 carriers had smaller speed COV compared to non-carriers.Conclusion: The lower speed variability of APOE4 carriers in the absence of neuropsychological test differences indicates reduced speed adaptations, possibly as a compensatory strategy. Simulated driving may be a sensitive method for detecting performance differences in the absence of cognitive differences. [ABSTRACT FROM AUTHOR]

Introduction: We identified a "cognitive clock," a novel indicator of brain health that provides person‐specific estimates of cognitive age, and tested the hypothesis that cognitive age is a better predictor of brain health than chronological age in two independent datasets. Methods: The initial analyses were based on 1057 participants from the Rush Memory and Aging Project and the Religious Orders Study who began without impairment and underwent cognitive assessments up to 24 years. A shape invariant model characterized the latent pattern of cognitive decline, conceptualized here as the "cognitive clock," and yielded person‐specific estimates of cognitive age. Survival analyses examined cognitive versus chronological age for predicting Alzheimer's disease dementia, mild cognitive impairment and mortality, and regression analyses examined associations of cognitive versus chronological age with neuropathology and brain atrophy. Finally, we applied the cognitive clock to an independent validation sample of 2592 participants from the Chicago Health and Aging Project, a biracial population‐based study, to confirm the predictive utility of cognitive age. Results: The "cognitive clock" showed that cognition remained stable until a cognitive age of about 80, then declined moderately until 90, then declined precipitously. In the initial dataset, cognitive age was a better predictor of dementia, mild cognitive impairment and mortality than chronological age, and was more strongly associated with neuropathology and brain atrophy. Application of the cognitive clock to the independent validation sample provided further support for the utility of cognitive age as a strong prognostic indicator of adverse outcomes. Discussion: Cognitive age is a robust prognostic indicator of adverse health outcomes and may serve as a useful biomarker in aging research. [ABSTRACT FROM AUTHOR]

Introduction: The impact of cardiovascular risk burden on brain pathologies remains unclear. We aimed to examine the association of the Framingham General Cardiovascular Risk Score (FGCRS) with dementia risk, and brain pathologies. Methods: Within the Rush Memory and Aging Project, 1588 dementia‐free participants were assessed on FGCRS at baseline and followed up to 21 years. During the follow‐up, 621 participants died and underwent autopsies. Results: The multi‐adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of FGCRS were 1.03 (1.00–1.07) for dementia and 1.04 (1.01–1.07) for Alzheimer's disease (AD) dementia. Further, a higher FGCRS was associated with higher gross chronic cerebral infarctions (odds ratio [OR] 1.08, 95% CI 1.02–1.14), cerebral atherosclerosis (OR 1.10, 95% CI 1.03–1.17), and global AD pathology (OR 1.06, 95% CI 1.01–1.12). Conclusions: A higher FGCRS is associated with an increased risk of dementia and AD dementia. Both vascular and AD pathologies in the brain may underlie this association. [ABSTRACT FROM AUTHOR]

Background. Vitamins A, D and E and beta-carotene may have a protective function for cognitive health, due to their antioxidant capacities. Methods. We analyzed data from 1334 non-demented participants (mean age 84 years) from the AgeCoDe study, a prospective multicenter-cohort of elderly general-practitioner patients in Germany, of whom n = 250 developed all-cause dementia and n = 209 developed Alzheimer’s dementia (AD) during 7 years of follow-up. We examined whether concentrations of vitamins A (retinol), D (25-hydroxycholecalciferol) and E (alpha-tocopherol) and beta-carotene, would be associated with incident (AD) dementia. Results. In our sample, 33.7% had optimum vitamin D concentrations (≥50 nmol/L). Higher concentrations of vitamin D were associated with lower incidence of all-cause dementia and AD (HR 0.99 (95%CI 0.98; 0.99); HR0.99 (95%CI 0.98; 0.99), respectively). In particular, subjects with vitamin D deficiency (25.3%,

Background: Alzheimer's disease dementia (ADD) is the leading cause of long-term care in Japan.Objective: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families.Methods: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged 20-69 and informal care costs for all ADD family caregivers were estimated.Results: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR 0.5, CDR 1, and CDR 2, respectively, but increased to JPY 447 billion (48%) for CDR 3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20-69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion.Conclusion: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease dementia (ADD) is an important health problem in the world.Objective: The present study investigated the validity and reliability of a new version of the Frontal Assessment Battery (FAB) named the FAB-phonemic (FAB-P).Methods: A total of 76 patients with ADD, 107 patients with amnestic mild cognitive impairment (aMCI), 37 patients with non-amnestic MCI (naMCI), and 123 healthy controls were included in this study. All participants were evaluated with the FAB-P and the cognitive assessments according to a standard procedure.Results: The global FAB-P scores in patients with ADD were lower than those of patients with aMCI, patients with naMCI, and healthy controls (p < 0.001). Patients with aMCI performed worse than healthy controls (p < 0.001). The interrater reliability, test-retest reliability, and Cronbach's alpha coefficient for the FAB-P were 0.997, 0.819, and 0.736, respectively. The test could distinguish the patients with mild ADD, aMCI, and naMCI from healthy controls with classification accuracy of 89.4%, 70.9%, and 61.6%, respectively. It could also discriminate between the patients with ADD and aMCI, between those with ADD and naMCI, and between those with aMCI and naMCI with classification accuracy of 73.8%, 83.9%, and 58.0%, respectively. The regression analysis revealed that the Montreal Cognitive Assessment and the Stroop Color Word Test Part C had the greatest contribution to FAB-P score variance.Conclusion: The FAB-P is a valid and reliable tool for evaluating frontal lobe function and can effectively discriminate ADD, aMCI, and naMCI. [ABSTRACT FROM AUTHOR]

Abstract Introduction Diversity in cognition among apolipoprotein E (APOE) ε4 homozygotes can range from early‐onset Alzheimer's disease (AD) to a lifetime with no symptoms. Methods We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy APOE ε4 homozygotes aged ≥75 years (n = 213) and early‐onset APOE ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results The PRS for AD was significantly higher in APOE ε4 homozygote AD cases compared to older cognitively healthy APOE ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0–35.2; P = .003). The difference in the same PRS between APOE ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98–9.92; P = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case‐controls. Discussion A PRS for AD contributes to modified cognitive expression of the APOE ε4/ε4 genotype at phenotypic extremes of risk.

Abstract Introduction Measurement of amyloid beta (Aβ40 and Aβ42) and tau (phosphorylated tau [p‐tau] and total tau [t‐tau]) in cerebrospinal fluid (CSF) can be utilized to differentiate clinical and preclinical Alzheimer's disease dementia (AD) from other neurodegenerative processes. Methods CSF biomarkers were measured in 150 participants from the Mayo Clinic Study of Aging and the Alzheimer's Disease Research Center. P‐tau/Aβ42 (Roche Elecsys, Fujirebio LUMIPULSE) and Aβ42/40 (Fujirebio LUMIPULSE) ratios were compared to one another and to amyloid positron emission tomography (PET) classification. Results Strong correlation was observed between LUMIPULSE p‐tau/Aβ42 and Aβ42/40, as well as Elecsys and LUMIPULSE p‐tau/Aβ42 and Aβ42/40 (Spearman's ρ = –0.827, –0.858, and 0.960, respectively). Concordance between LUMIPULSE p‐tau/Aβ42 and Aβ42/40 was 96% and between Elecsys p‐tau/Aβ42 and both LUMIPULSE ratios was 97%. All ratios had > 94% overall, positive, and negative percent agreement with amyloid PET classification. Discussion These data suggest that p‐tau/Aβ42 and Aβ42/40 ratios provide similar clinical information in the assessment of amyloid pathology.

Background: Cognitively normal (CN) older adults participating in Alzheimer's disease (AD) research increasingly ask for their research results-including genetic and neuroimaging findings-to understand their risk of developing AD dementia. AD research results are typically not returned for multiple reasons, including possible psychosocial harms of knowing one is at risk of a highly feared and untreatable disease.Objective: We developed materials that convey information about 5-year absolute risk of developing AD dementia based on research results.Methods: 20 CN older adults who received a research brain MRI result were interviewed regarding their wishes for research results to inform material development (Pilot 1). Following material development, 17 CN older adults evaluated the materials for clarity and acceptability (Pilot 2). All participants were community-dwelling older adults participating in longitudinal studies of aging at a single site.Results: Participants want information on their risk of developing AD dementia to better understand their own health, satisfy curiosity, inform family, and future planning. Some articulated concerns, but the majority wanted to know their risk despite the limitations of information. Participants found the educational materials and results report clear and acceptable, and the majority would want to know their research results after reviewing them.Conclusion: These materials will be used in a clinical study examining the psychosocial and cognitive effects of offering research results to a cohort of CN older adults. Future AD research may incorporate the return of complex risk information to CN older adults, and materials are needed to communicate this information. [ABSTRACT FROM AUTHOR]

Introduction: Diversity in cognition among apolipoprotein E (APOE) ε4 homozygotes can range from early‐onset Alzheimer's disease (AD) to a lifetime with no symptoms. Methods: We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy APOE ε4 homozygotes aged ≥75 years (n = 213) and early‐onset APOE ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results: The PRS for AD was significantly higher in APOE ε4 homozygote AD cases compared to older cognitively healthy APOE ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0–35.2; P = .003). The difference in the same PRS between APOE ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98–9.92; P = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case‐controls. Discussion: A PRS for AD contributes to modified cognitive expression of the APOE ε4/ε4 genotype at phenotypic extremes of risk. [ABSTRACT FROM AUTHOR]

Introduction: Measurement of amyloid beta (Aβ40 and Aβ42) and tau (phosphorylated tau [p‐tau] and total tau [t‐tau]) in cerebrospinal fluid (CSF) can be utilized to differentiate clinical and preclinical Alzheimer's disease dementia (AD) from other neurodegenerative processes. Methods: CSF biomarkers were measured in 150 participants from the Mayo Clinic Study of Aging and the Alzheimer's Disease Research Center. P‐tau/Aβ42 (Roche Elecsys, Fujirebio LUMIPULSE) and Aβ42/40 (Fujirebio LUMIPULSE) ratios were compared to one another and to amyloid positron emission tomography (PET) classification. Results: Strong correlation was observed between LUMIPULSE p‐tau/Aβ42 and Aβ42/40, as well as Elecsys and LUMIPULSE p‐tau/Aβ42 and Aβ42/40 (Spearman's ρ = –0.827, –0.858, and 0.960, respectively). Concordance between LUMIPULSE p‐tau/Aβ42 and Aβ42/40 was 96% and between Elecsys p‐tau/Aβ42 and both LUMIPULSE ratios was 97%. All ratios had > 94% overall, positive, and negative percent agreement with amyloid PET classification. Discussion: These data suggest that p‐tau/Aβ42 and Aβ42/40 ratios provide similar clinical information in the assessment of amyloid pathology. [ABSTRACT FROM AUTHOR]

Introduction: We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging-defined subgroups., Methods: We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid-negative controls. We used voxel-based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD-Memory., Results: There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD-Memory, lower left hemisphere GMV for AD-Language, anterior lower GMV for AD-Executive, and posterior lower GMV for AD-Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD-Language group than any other group (p = 1.15 × 10 -10 ). For overlap between imaging-defined and cognitively defined subgroups, AD-Memory matched up with an imaging-defined limbic predominant group., Discussion: MRI findings differ across cognitively defined AD subgroups., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

William Montgomery,1 Amir Goren,2 Kristin Kahle-Wrobleski,3 Tomomi Nakamura,4 Kaname Ueda5 1Global Patient Outcomes & Real World Evidence, Eli Lilly Australia, NSW, Australia; 2Real World Evidence, Kantar Health, New York, NY, USA; 3Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA; 4Bio-Medicines, Medical Development Unit, Eli Lilly Japan K.K., Tokyo, Japan; 5Health Outcomes, Health Technology Assessment, & Real World Evidence, Medical Development Unit, Eli Lilly Japan K.K., Kobe, Japan Background: Dementia of Alzheimer’s disease (AD) imposes burdens on patients, caregivers, and society. This cross-sectional study examined caregiver-reported history of disease onset and AD dementia to inform efforts promoting early disease detection and diagnosis.Methods: An online survey collected self-reported cross-sectional data – demographic characteristics, diagnosis, treatment experiences, and other information on disease detection, diagnosis, and treatment – from caregivers of patients with AD dementia. These characteristics were examined as a function of AD dementia severity.Results: Three hundred patients with AD dementia were trichotomized by long-term care insurance levels reported by caregivers: 12.3% (n=37) as low severity, 63.7% (n=191) as medium severity, and 24.0% (n=72) as high severity. The Short-Memory Questionnaire and patient dependency scores both varied significantly across severity groups. AD dementia symptoms were most frequently first detected by a caregiver (58.7%) or the patient’s family (45.7%). However, in 13.7% of cases, symptoms were detected by a health care provider during a routine visit. Memory problems were the most frequent first symptoms (77.3%), followed by repetition (55.7%). Patients (73.7%) were taking symptomatic treatment such as acetylcholinesterase inhibitors or memantine. High-severity patients were older, had been diagnosed with AD dementia for a longer time, had more frequent reports of memory problems as the first symptoms detected, and required more hours of care per day, compared with low-severity patients.Conclusion: Caregivers and families play an integral role in the identification of AD dementia patients, with memory problems being common first symptoms noticed by caregivers that led to a diagnosis of AD dementia. These results provide novel insight into the detection, diagnosis, and treatment of AD dementia in Japan and how these factors differ across the spectrum of disease severity. Keywords: Alzheimer’s disease dementia, Japan, disease history, caregivers, treatment pattern

Abstract Background Alzheimer’s disease (AD) dementia, a progressive neurodegenerative disease, exerts significant burden upon patients, caregivers, and healthcare systems globally. The current study investigated the associations between AD dementia patient disease severity and health-related quality of life (HRQoL) of both patients (proxy report) and their caregivers living in Japan, as well as caregiving-related comorbidities such as depression. Methods This cross-sectional study used self-reported data from caregivers of people diagnosed with AD dementia by a healthcare provider in Japan. Caregivers were identified via online panels and invited to participate in an online survey between 2014 and 2015. Caregivers completed survey items for themselves, in addition to providing proxy measures for patients with AD dementia for whom they were caring. Patient and caregiver HRQoL was measured using the EuroQoL 5-Dimension (EQ-5D). Additional outcomes for caregivers of AD dementia patients included the Patient Health Questionnaire (PHQ-9) of depressive symptomology, as well as comorbidities experienced since initiating caregiving for their AD dementia patients. These outcomes were examined as a function of AD dementia severity, as measured by long-term care insurance (LTCI) categories. Bivariate analyses between LTCI and outcomes were conducted using independent t-tests and chi-square tests. Multivariable analyses, controlling for potential confounders, were conducted using generalized linear models (GLMs) specifying a normal distribution. Results Across 300 caregiver respondents, multivariable results revealed that increasing AD dementia severity was significantly associated with poorer patient and caregiver EQ-5D scores and a high proportion of caregivers (30.0%) reported PHQ-9 scores indicative of major depressive disorder (MDD). The most frequent comorbidities experienced after becoming caregivers of AD dementia patients included hypertension (12.7%) and insomnia (11.0%). Depression and other comorbidities did not differ significantly by patient severity. Conclusions The current study provides unique insight into the specific degree of incremental burden associated with increasing AD dementia severity among patients and caregivers alike. Importantly, greater disease severity was associated with poorer quality of life among both patients and caregivers. These results suggest that earlier detection and treatment of AD dementia may provide an opportunity to reduce the burden of disease for patients, caregivers, and society at large.

Objective: To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms.Methods: Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ42, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses.Results: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ42, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ42 and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning.Conclusion: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning. [ABSTRACT FROM AUTHOR]

• The AD biomarker - affective symptoms relationship shows inconsistent evidence. • Study designs assessing this relationship are very heterogeneous. • Majority of studies on depression show no relationship with AT(N) markers. • Future research should focus on possible subtypes of affective symptoms. Alzheimer's disease (AD) biomarkers such as amyloid, p-tau and neuronal injury markers have been associated with affective symptoms in cognitively impaired individuals, but results are conflicting. CINAHL, Embase, PsycINFO and PubMed were searched for studies evaluating AD biomarkers with affective symptoms in mild cognitive impairment and AD dementia. Studies were classified according to AT(N) research criteria. Forty-five abstracts fulfilled eligibility criteria, including in total 8,293 patients (41 cross-sectional studies and 7 longitudinal studies). Depression and night-time behaviour disturbances were not related to AT(N) markers. Apathy was associated with A markers (PET, not CSF). Mixed findings were reported for the association between apathy and T(N) markers; anxiety and AT(N) markers; and between agitation and irritability and A markers. Agitation and irritability were not associated with T(N) markers. Whereas some AD biomarkers showed to be associated with affective symptoms in AD, most evidence was inconsistent. This is likely due to differences in study design or heterogeneity in affective symptoms. Directions for future research are given. [ABSTRACT FROM AUTHOR]

Introduction: We examined the influence of enrollment factors demonstrated to differ by race on incident mild cognitive impairment and dementia using Alzheimer's Disease Center data. Methods: Differences in rates of incident impairment between non‐Latino Whites and Blacks (n = 12,242) were examined with age‐at‐progression survival models. Models included race, sex, education, source of recruitment, health factors, and family history of dementia. Results: No significant race differences in progression were observed in cognitively unimpaired participants. In those with mild cognitive impairment at baseline, Whites evidenced greater risk for progression than Blacks. Enrollment factors, for example, referral source, were significantly related to progression. Discussion: The finding that Blacks demonstrated lower rate of progression than Whites is contrary to the extant literature. Nested‐regression analyses suggested that selection‐related factors, differing by race, may account for these findings and influence our ability to accurately estimate risk for progression. It is potentially problematic to make racial comparisons using Alzheimer's Disease Center data sets. [ABSTRACT FROM AUTHOR]

Autonomic dysfunction is common in α-synucleinopathies such as Lewy Body dementias (LBD), Parkinson's disease (PD), and isolated REM Sleep Behavior Disorder (iRBD). We analyzed pulse-rate changes during sleep to index autonomic nervous system (ANS) dysfunction in patients with α-synucleinopathies vs. non-synucleinopathy groups expected to have normal ANS function. Patients with LBD (n = 16), PD (PD, n = 14) or iRBD (n = 12) were compared to the non-synucleinopathy groups Alzheimers disease dementia (ADem, n = 26), mild cognitive impairment (MCI, n = 34) or controls (CG, n = 54). Sleep Profiler was used to derive a sleep autonomic activation index (AAI), i.e., ≥6 beat-per-minute increase/decrease, pulse rate coefficient of variation (PR-CV), and automated sleep staging with sleep-spindles and non-REM hypertonia (NRH). Analysis included statistical group comparisons and receiver operating characteristics curves to determine optimal classification of groups. AAI and PR-CV were moderately correlated across all recordings (r s = 0.58, P < 0.0001), except in the LBD and PD groups. AAI but not PR-CV differentiated the LBD, PD and iRBD from non-Parkinsonian groups. AAI was decreased in LBD and PD patients compared to the CG (p < 0.003) and MCI (p < 0.03). AAI decreased based on age and its receiver operating characteristic area under the curve ranged from 0.63 to 0.75. AAI had a weak negative correlation to NRH (r s ≤ −0.26) but not sleep-spindles. Synucleinopathy-related ANS dysfunction can reasonably discriminate prodromal and manifest PD/LBD diseased groups from non-synucleinopathies. Further studies incorporating AAI into a multivariate classifier of neurodegenerative disorders based on sleep characteristics acquired in the patient's home are planned. • The autonomic activation index (AAI) detects sharp changes in pulse rate. • The AAI is generally blunted in patients with Parkinsonian spectrum disorders. • The proportion with blunted AAI is consistent with disease progression. • AAI during sleep is unrelated to sleep spindles. • AAI is weakly negatively correlated with non-REM hypertonia (NRH). [ABSTRACT FROM AUTHOR]

Recent studies deal with disorders and deficits caused by vascular syndrome in efforts for prediction and prevention. Cardiovascular health declines with age due to vascular risk factors, and this leads to an increasing risk of cognitive decline. Mild cognitive impairment (MCI) is defined as the negative cognitive changes beyond what is expected in normal aging. The purpose of the study was to compare older adults with vascular risk factors (VRF), MCI patients, and healthy controls (HC) in social cognition and especially in theory of mind ability (ToM). The sample comprised a total of 109 adults, aged 50 to 85 years (M = 66.09, SD = 9.02). They were divided into three groups: (a) older adults with VRF, (b) MCI patients, and (c) healthy controls (HC). VRF and MCI did not differ significantly in age, educational level or gender as was the case with HC. Specifically, for assessing ToM, a social inference test was used, which was designed to measure sarcasm comprehension. Results showed that the performance of the VRF group and MCI patients is not differentiated, while HC performed higher compared to the other two groups. The findings may imply that the development of a vascular disorder affecting vessels of the brain is associated from its “first steps” to ToM decline, at least regarding specific aspects of it, such as paradoxical sarcasm understanding.

Background: Metabolic patterns on brain F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) can predict the decline in amnestic mild cognitive impairment (aMCI) to Alzheimer's disease dementia (AD) or other dementias.Objective: This study was undertaken to evaluate the diagnostic accuracy of baseline F-18 FDG-PET in aMCI for predicting conversion to AD or other dementias on follow-up.Patients and Methods: A total of 87 patients with aMCI were enrolled in the study. Each patient underwent a detailed clinical and neuropsychological examination and FDG-PET at baseline. Each PET scan was visually classified based on predefined dementia patterns. Automated analysis of FDG PET was performed using Cortex ID (GE Healthcare). The mean follow-up duration was 30.4 ± 9.3 months (range: 18-48 months). Diagnosis of dementia at follow-up (obtained using clinical diagnostic criteria) constituted the reference standard, and all the included aMCI patients were divided into two groups: the aMCI converters (MCI-C) and MCI nonconverters (MCI-NC). Diagnostic accuracy of FDG PET was calculated using this reference standard.Results: There were 23 MCI-C and 64 MCI-NC. Of the 23 MCI-C, 19 were diagnosed as probable AD, 1 as frontotemporal demetia (FTD), and 3 as vascular dementia (VD). Of the 64 MCI-NC, 9 had subjective improvement in cognition, and 55 remained stable. The conversion rate for all types of dementia in our series was 26.4% (23/87) and for Alzheimer's type dementia was 21.8% (19/87). The of PET-based visual interpretation was 91.9%. Sensitivity, specificity, positive predictive value, and negative predictive value for FDG-PET-based prediction of dementia conversion were 86.9% [confidence interval (CI) 66.4%-97.2%)], 93.7% (CI 84.7%-98.2%), 83.3% (CI 65.6%-92.9%), and 95.2% (CI 87.4%-98.9%), respectively. Kappa for agreement between visual and Cortex ID was 0.94 indicating excellent agreement. In the three aMCI patients progressing to VD, no specific abnormality in metabolic pattern was noted; however, there was marked cortical atrophy on computed tomography.Conclusion: FDG-PET-based visual and cortex ID classification has a good accuracy in predicting progression to dementia including AD in the prodromal aMCI phase. Absence of typical metabolic patterns on FDG-PET can play an important exclusionary role for progression to dementia. Vascular cognitive impairment with cerebral atrophy needs further studies to confirm and uncover potential mechanisms. [ABSTRACT FROM AUTHOR]

Rationale: Growing evidence suggests that compromised lung health may be linked to dementia and worsening cognitive ability. Objectives: To test the hypothesis that impaired lung function or lung disease in midlife is associated with greater risk of incident dementia and mild cognitive impairment (MCI) later in life. Methods: A total of 14,184 Atherosclerosis Risk in Communities study participants who underwent spirometry and were asked about lung health (1987–1989) were followed. Dementia and MCI were defined by hospitalization diagnosis codes (1987–2013) in the whole cohort and with adjudication among 42% who attended a comprehensive neurocognitive examination (2011–2013). Measurements and Main Results: In analysis using adjudicated outcomes, odds of dementia or MCI were higher among participants with restrictive (multivariable-adjusted odds ratio, 1.58; 95% confidence interval, 1.14–2.19) and obstructive lung disease (multivariable-adjusted odds ratio, 1.33; 95% confidence interval, 1.07–1.64), compared with those without disease or respiratory symptoms. Associations were similar in analyses restricted to nonsmokers, and present for both Alzheimer’s disease–related dementia and cerebrovascular etiologies. Low FEV1% predicted and FVC% predicted were also associated with increased dementia risk. Conclusions: Midlife lung disease and reduced lung function were associated with modestly increased odds of dementia and MCI later in life. Magnitudes of association were more pronounced for restrictive impairment than for obstructive lung disease. These associations were present in smokers and nonsmokers. If the observed associations are causal, policy and public health efforts to reduce smoking and improve air quality may have the added benefit of preventing the development of dementia and MCI. [ABSTRACT FROM AUTHOR]

Background. Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties. Methods. We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer’s disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD. Results. During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia. Conclusions. Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age.

Background: A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18F-FDG PET in clinical practice in people with mild cognitive impairment (MCI).Objectives: To update the evidence and reassess the accuracy of 18F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease (AD) dementia at follow-up.Methods: A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies.Results: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56-100%, specificity 24-100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies.Conclusion: Systematic and comprehensive assessment of studies of 18FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18F-FDG PET in people with MCI is needed. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) dementia, a progressive neurodegenerative disease, exerts significant burden upon patients, caregivers, and healthcare systems globally. The current study investigated the associations between AD dementia patient disease severity and health-related quality of life (HRQoL) of both patients (proxy report) and their caregivers living in Japan, as well as caregiving-related comorbidities such as depression.Methods: This cross-sectional study used self-reported data from caregivers of people diagnosed with AD dementia by a healthcare provider in Japan. Caregivers were identified via online panels and invited to participate in an online survey between 2014 and 2015. Caregivers completed survey items for themselves, in addition to providing proxy measures for patients with AD dementia for whom they were caring. Patient and caregiver HRQoL was measured using the EuroQoL 5-Dimension (EQ-5D). Additional outcomes for caregivers of AD dementia patients included the Patient Health Questionnaire (PHQ-9) of depressive symptomology, as well as comorbidities experienced since initiating caregiving for their AD dementia patients. These outcomes were examined as a function of AD dementia severity, as measured by long-term care insurance (LTCI) categories. Bivariate analyses between LTCI and outcomes were conducted using independent t-tests and chi-square tests. Multivariable analyses, controlling for potential confounders, were conducted using generalized linear models (GLMs) specifying a normal distribution.Results: Across 300 caregiver respondents, multivariable results revealed that increasing AD dementia severity was significantly associated with poorer patient and caregiver EQ-5D scores and a high proportion of caregivers (30.0%) reported PHQ-9 scores indicative of major depressive disorder (MDD). The most frequent comorbidities experienced after becoming caregivers of AD dementia patients included hypertension (12.7%) and insomnia (11.0%). Depression and other comorbidities did not differ significantly by patient severity.Conclusions: The current study provides unique insight into the specific degree of incremental burden associated with increasing AD dementia severity among patients and caregivers alike. Importantly, greater disease severity was associated with poorer quality of life among both patients and caregivers. These results suggest that earlier detection and treatment of AD dementia may provide an opportunity to reduce the burden of disease for patients, caregivers, and society at large. [ABSTRACT FROM AUTHOR]

Introduction: Cross‐sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early‐frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information. Methods: We included 16 patients with Alzheimer's disease who completed follow‐up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed‐effects models and annual percentage change maps were used to examine longitudinal change. Results: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317. Discussion: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity. Highlights: Overlap between changes in perfusion, metabolism, and tau was assessed.Declines in perfusion and metabolism showed only partial spatial overlap.Minimal spatial overlap was found between declines in perfusion and increased tau.Perfusion measures related differently to FDG PET findings in terms of overlap. [ABSTRACT FROM AUTHOR]