-
Journal of Alzheimer's Disease : JAD Jun 2024Portable digital health technologies (DHTs) could help evaluate non-cognitive symptoms, but evidence to support their use in patients with dementia with Lewy bodies...
BACKGROUND
Portable digital health technologies (DHTs) could help evaluate non-cognitive symptoms, but evidence to support their use in patients with dementia with Lewy bodies (DLB) is uncertain.
OBJECTIVE
1) To describe portable or wearable DHTs used to obtain digital biomarkers in patients with DLB, 2) to assess the digital biomarkers' ability to evaluate non-cognitive symptoms, and 3) to assess the feasibility of applying digital biomarkers in patients with DLB.
METHODS
We systematically searched databases MEDLINE, Embase, and Web of Science from inception through February 28, 2023. Studies assessing digital biomarkers obtained by portable or wearable DHTs and related to non-cognitive symptoms were eligible if including patients with DLB. The quality of studies was assessed using a modified check list based on the NIH Quality assessment tool for Observational Cohort and Cross-sectional Studies. A narrative synthesis of data was carried out.
RESULTS
We screened 4,295 records and included 20 studies. Seventeen different DHTs were identified for assessment of most non-cognitive symptoms related to DLB. No thorough validation of digital biomarkers for measurement of non-cognitive symptoms in DLB was reported. Studies did not report on aspects of feasibility in a systematic way.
CONCLUSIONS
Knowledge about feasibility and validity of individual digital biomarkers remains extremely limited. Study heterogeneity is a barrier for establishing a broad evidence base for application of digital biomarkers in DLB. Researchers should conform to recommended standards for systematic evaluation of digital biomarkers.
PubMed: 38943394
DOI: 10.3233/JAD-240327 -
Journal of Alzheimer's Disease : JAD Jun 2024The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient's awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly...
The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient's awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly affects MoCA testing when administered by the intravesical route. MoCA scores were lower with increasing age and higher in more formally educated individuals. Patients receiving BCG tended to maintain their MoCA scores, whereas almost half the control cases tended to show reduced scores. This benefit is supported by reduced pre-amyloid biomarkers in BCG-injected healthy volunteers and a favorable effect on neuronal dendritic development in animal models. Our results suggest that BCG has a beneficial impact on the cognitive status of older individuals.
PubMed: 38943393
DOI: 10.3233/JAD-240307 -
Journal of Alzheimer's Disease : JAD Jun 2024Traumatic brain injury (TBI) may confer risk for Alzheimer's disease (AD) through amyloid-β (Aβ) overproduction. However, the relationship between TBI and Aβ levels...
BACKGROUND
Traumatic brain injury (TBI) may confer risk for Alzheimer's disease (AD) through amyloid-β (Aβ) overproduction. However, the relationship between TBI and Aβ levels in cerebrospinal fluid (CSF) remains unclear.
OBJECTIVE
To explore whether Aβ overproduction is implicated in the relationship between TBI and AD, we compared CSF levels of Aβ in individuals with a TBI history versus controls (CTRLs) and related CSF Aβ levels to cognitive markers associated with preclinical AD.
METHODS
Participants were 112 non-impaired Veterans (TBI = 56, CTRL = 56) from the Alzheimer's Disease Neuroimaging Initiative-Department of Defense database with available cognitive data (Boston Naming Test [BNT], Rey Auditory Verbal Learning Test [AVLT]) and CSF measures of Aβ42, Aβ40, and Aβ38. Mediation models explored relationships between TBI history and BNT scores with Aβ peptides as mediators.
RESULTS
The TBI group had higher CSF Aβ40 (t = -2.43, p = 0.017) and Aβ38 (t = -2.10, p = 0.038) levels than the CTRL group, but groups did not differ in CSF Aβ42 levels or Aβ42/Aβ40 ratios (p > 0.05). Both Aβ peptides negatively correlated with BNT (Aβ40: rho = -0.20, p = 0.032; Aβ38: rho = -0.19, p = 0.048) but not AVLT (p > 0.05). Aβ40 had a significant indirect effect on the relationship between TBI and BNT performance (β= -0.16, 95% CI [-0.393, -0.004], PM = 0.54).
CONCLUSIONS
TBI may increase AD risk and cognitive vulnerability through Aβ overproduction. Biomarker models incorporating multiple Aβ peptides may help identify AD risk among those with TBI.
PubMed: 38943392
DOI: 10.3233/JAD-240254 -
Journal of Alzheimer's Disease : JAD Jun 2024Marital factor has been associated with dementia and Alzheimer's disease, but there is limited evidence on the impact of holistic marital history over time.
BACKGROUND
Marital factor has been associated with dementia and Alzheimer's disease, but there is limited evidence on the impact of holistic marital history over time.
OBJECTIVE
This study aimed to examine association of marital history with cognition.
METHODS
The study included 24,596 dementia-free participants from the Chinese Longitudinal Healthy Longevity Study (CLHLS). Holistic marital history was collected at baseline, categorizing participants into five groups: widow-single, widow-remarried, divorce-single, divorce-remarried and married based on the first two marriages. Dementia was collected at follow-up through self-report or from a delegate if the participant was deceased. For 15,355 participants, the Chinese Mini-Mental Status Examination (CMMSE) was administered at both baseline and follow-ups. Cognitive impairment was defined as a follow-up CMMSE score below 18, and rate of cognitive change was calculated as the change in CMMSE score between consecutive visits divided by the duration.
RESULTS
Compared with married older adults, widow-single group had significantly higher risk of dementia (HR 1.28, 95% CI 1.05, 1.54), cognitive impairment (HR 1.31, 95% CI 1.17, 1.47) and significantly faster decline of MMSE score (β -0.09, 95% CI -0.17, -0.01). Meanwhile, widow-remarried group had significantly lower risk of dementia, cognitive impairment and slower MMSE score decline than widow-single group, although the differences were only significant among female but not male.
CONCLUSIONS
In this prospective cohort, married older adults and those widowed but with a second marriage had significantly better cognition than widowed individuals who did not remarry.
PubMed: 38943391
DOI: 10.3233/JAD-240176 -
Journal of Alzheimer's Disease : JAD Jun 2024Disease-modifying therapies (DMT) for Alzheimer's disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts... (Review)
Review
Disease-modifying therapies (DMT) for Alzheimer's disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success.
PubMed: 38943390
DOI: 10.3233/JAD-240146 -
Journal of Alzheimer's Disease : JAD Jun 2024With the arrival of disease-modifying treatments, it is mandatory to find new cognitive markers that are sensitive to Alzheimer's disease (AD) pathology in preclinical...
BACKGROUND
With the arrival of disease-modifying treatments, it is mandatory to find new cognitive markers that are sensitive to Alzheimer's disease (AD) pathology in preclinical stages.
OBJECTIVE
To determine the utility of a newly developed Learning and Associative Memory face test: LAM test. This study examined the relationship between AD cerebrospinal fluid (CSF) biomarkers and performance on LAM test, and assessed its potential clinical applicability to detect subtle changes in cognitively healthy subjects at risk for AD.
METHODS
We studied eighty cognitively healthy volunteers from the Valdecilla cohort. 61% were women and the mean age was 67.34 years (±6.416). All participants underwent a lumbar puncture for determination of CSF biomarkers and an extensive neuropsychological assessment, including performance on learning and associative memory indices of the LAM-test after 30 min and after 1 week, and two classic word lists to assess verbal episodic memory: the Rey Auditory Verbal Learning Test (RAVLT) and the Free and Cued Selective Reminding Test (FCSRT). We analyzed cognitive performance according to amyloid status (A+ versus A-) and to ATN model (A-T-N-; A+T-N-; A+T+N-/A+T+N+).
RESULTS
Performance on the LAM-test was significantly correlated with CSF Aβ ratio. A+ participants performed worse on both learning (mean difference = 2.19, p = 0.002) and memory LAM measures than A- (mean difference = 2.19, p = 0.004). A decline in performance was observed along the Alzheimer's continuum, with significant differences between ATN groups.
CONCLUSIONS
Our findings suggest that LAM test could be a useful tool for the early detection of subjects within the AD continuum, outperforming classical memory tests.
PubMed: 38943389
DOI: 10.3233/JAD-240067 -
Journal of Alzheimer's Disease : JAD Jun 2024Antipsychotics are widely used in the elderly due to the high prevalence of neuropsychiatric associated with dementia.
BACKGROUND
Antipsychotics are widely used in the elderly due to the high prevalence of neuropsychiatric associated with dementia.
OBJECTIVE
To analyze potential disparities in antipsychotic use in the general population of Gipuzkoa by socioeconomic status (SES) and diagnosis of Alzheimer's disease and related dementia (ADRD) adjusting for somatic and psychiatric comorbidities, age, and sex.
METHODS
A retrospective observational study was carried out in all the 221,777 individuals over 60 years of age (Gipuzkoa, Spain) to collect diagnosis of ADRD, the Charlson Comorbidity Index, and psychiatric comorbidities considering all primary, outpatient, emergency and inpatient care episodes and first- and second-generation antipsychotics, and sociodemographic variables, namely, age, sex, SES and living in a nursing home. Logistic regression was used for multivariate statisticalanalysis.
RESULTS
Use of any antipsychotic was greater in women, individuals over 80 years old, living in a nursing home, with a diagnosis of dementia, somatic and psychiatric comorbidities, and low SES. Quetiapine was the most used drug. The likelihood of any antipsychotic use was significantly associated with low SES (odds ratio [OR]: 1.60; confidence interval [CI]: 1.52-1.68), age over 80 years (OR: 1.56; CI: 1.47-1.65), institutionalization (OR: 12.61; CI: 11.64-13.65), diagnosis of dementia (OR: 10.18; CI: 9.55-10.85) and the comorbidities of depression (OR: 3.79; CI: 3.58-4.01) and psychosis (OR: 4.96; CI: 4.64-5.30).
CONCLUSIONS
The greater levels of antipsychotic use and institutionalization in people of low SES indicate inequity in the management of neuropsychiatric symptoms. Increasing the offer of non-pharmacological treatments in the health system might help reduce inequity.
PubMed: 38943388
DOI: 10.3233/JAD-240004 -
Journal of Alzheimer's Disease : JAD Jun 2024Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite...
BACKGROUND
Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data.
OBJECTIVE
Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features.
METHODS
AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women).
RESULTS
Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status.
CONCLUSIONS
Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons.
PubMed: 38943387
DOI: 10.3233/JAD-231321 -
Journal of Alzheimer's Disease : JAD Jun 2024Ferroptosis is extremely relevant to the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). Ubiquitin-specific proteases (USP) can affect the...
BACKGROUND
Ferroptosis is extremely relevant to the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). Ubiquitin-specific proteases (USP) can affect the NADPH oxidase family.
OBJECTIVE
Our study aimed to elucidate the potential role and molecular basis of a certain USP19 in reducing ferroptosis and mitochondrial injury in AD cells by targeting NOX4 stability.
METHODS
The deubiquitinase USP family gene USP19, which affects the stability of NOX4 protein, was first screened. The cell model of AD was constructed after interfering with SH-SY5Y cells by Aβ1-40, and then SH-SY5Y cells were infected with lentiviral vectors to knock down USP19 and overexpress NOX4, respectively. Finally, the groups were tested for cell viability, changes in cellular mitochondrial membrane potential, lipid reactive oxygen species, intracellular iron metabolism, and NOX4, Mf1, Mf2, and Drp1 protein expression.
RESULTS
5 μmol/L Aβ1-40 intervened in SH-SY5Y cells for 24 h to construct a cell model of AD. Knockdown of USP19 decreased the expression of NOX4 protein, promoted the expression of mitochondrial fusion proteins Mnf1 and Mnf2, and inhibited the expression of the splitting protein Drp1. Furthermore, USP19 knockdown decreased mitochondrial membrane potential, SOD, MDA, intracellular iron content and increased GSH/GSSG ratio in SH-SY5Y cells. Our study revealed that NOX4 protein interacts with USP19 and knockdown of USP19 enhanced ubiquitination to maintain NOX4 protein stability.
CONCLUSIONS
USP19 attenuates mitochondrial damage in SH-SY5Y cells by targeting NOX4 protein with Aβ1-40.
PubMed: 38943386
DOI: 10.3233/JAD-231193 -
The Journals of Gerontology. Series A,... Jun 2024The association between cardiometabolic risk factors and cognitive function has been well documented, but the underlying mechanisms are not fully understood. This...
The association between cardiometabolic risk factors and cognitive function has been well documented, but the underlying mechanisms are not fully understood. This longitudinal study aimed to investigate the potential mediating role of DNA methylation in this association. We conducted the analyses in 3708 participants (mean [SD] age: 67.3 [9.49], women: 57.9%) from the Health and Retirement Study who were assessed in the 2014 to 2020 waves, had Infinium Methylation EPIC BeadChip methylation assays from the 2016 Venous Blood Study, and had cognitive assessment between 2016-2020. Causal mediation analyses were used to test the mediation role of DNA methylation in the associations between cardiometabolic risk factors and cognition, adjusting for demographic, socioeconomic, and lifestyle factors. Hypertension (-0.061 in composite cognitive z-score; 95% CI: (-0.119, -0.004)) and diabetes (-0.134; 95% CI: (-0.198, -0.071)) were significantly associated with worse cognitive function while abnormal BMI and hypercholesterolemia were not. An increased number of cardiometabolic risk factors was associated with worse cognitive function (P=0.002). DNA methylation significantly mediated the association of hypertension (mediated effect on composite cognitive z-score: -0.023; 95% CI: (-0.033, -0.014)), diabetes (-0.022; 95% CI: (-0.032, -0.014)), and obesity (-0.021; 95% CI: (-0.033, -0.011)) with cognitive function, while the mediation effect was not observed for having hypercholesterolemia. The estimated proportions mediated were 37.4% for hypertension and 16.7% for diabetes. DNA methylation may be an important mediator linking cardiometabolic risk factors to worse cognition and might even provide a potential target for dementia prevention.
PubMed: 38943310
DOI: 10.1093/gerona/glae167