Dementia Of The Alzheimer Type Research Articles

Dementia incidence varied by anticancer drugs and molecular targeted therapy in a population-based cohort study

Anticancer drugs may affect the incidence of dementia by modulating the common pathophysiology between cancer and dementia. However, there is a paucity of research that focused on anticancer drugs with different mechanisms of action and their associations with subtypes of dementia. Therefore, we aimed to investigate the incidence of dementia according to various groups of anticancer drugs. From the Korea National Health Insurance Service database, our retrospective population-based cohort study enrolled 116,506 cancer patients aged 65 years and older who received anticancer drugs between January 1, 2008 and December 31, 2018. The hazard ratio was determined using Cox proportional hazards regression models, comparing each group of anticancer drugs to all other anticancer drugs, after adjusting for covariates. Antimetabolites (HR = 0.91; 95% CI 0.84–0.97) and molecular targeted therapies (HR = 0.60; 95% CI 0.49–0.74) were associated with a decreased incidence of dementia of the Alzheimer type (DAT), but not with vascular dementia. Among molecular targeted therapies, epidermal growth factor receptor inhibitors (HR = 0.60; 95% CI 0.46–0.79) and multikinase inhibitors (HR = 0.49; 95% CI 0.27–0.89) were associated with a low incidence of DAT only. Our findings highlight the potential for targeted repurposing of anticancer drugs to prevent dementia.

Exploring the complex nexus of Alzheimers disease in down syndrome

In recent years, the life expectancy of individuals with Down Syndrome (DS) has increased significantly thanks to the advancements in healthcare and treatments, giving rise to an older population of people with DS. However, this demographic shift has brought about new concerns: as individuals with DS age, they face a higher incidence of early-onset Alzheimers Disease (EOAD) (i.e. the development of AD before the age of 65). Research has revealed an accelerated progression of symptoms, from onset of dementia to death, in DS patients. Thus, it is essential to identify the factors (both genetic and environmental) that underlie the development of different stages of AD-DS. Concomitantly, there is a pressing need to initiate intervention trials that could slow down or prevent the rapid advancement of AD-DS. This paper underscores the growing importance of addressing AD-DS in an ageing DS population. By elucidating genetic and environmental factors, clinical features, diagnostic challenges, roles of genes in the development of AD-DS, and potential future research directions, the article aims to contribute to a deeper understanding of dementia of the Alzheimer Type (DAT) and facilitate the development of effective treatments that could improve the lives of DS individuals affected by DAT.

Comparing intra‐individual variability on executive functioning tasks in individuals with Mild Cognitive Impairment and Dementia of the Alzheimer Type: Results from the ARMADA Study

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

Clinical Manifestations.

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

Clinical Manifestations.

Since the start of the Covid-19 Pandemic in 2020, we have seen interrupted outpatient care services for long periods of time, which has generated complications related to this new scenario: appearance of disorders neuropsychiatric disorders, complication in existing pictures, etc. The group of older adults has been more vulnerable in terms of the possible consequences of exposure to the virus without counting with immunization. Configuring a prone scenario to generate the increase in prevalence of risk factors for dementia of the Alzheimer type. The lack of information and the massiveness of the problem, added to the course of the peripandemic, requires a modification approach strategies, facilitating access to diagnostic and treatment services, constituting a new strategy adapted to a changing and dynamic demand. Semi-structured interviews with epidemiological and clinical variables are carried out charge of medical personnel; and MMSE in charge of Neuropsychologists. data analysis and interweaving of variables. 144 subjects attend, with an average age of 66.69 years, 92.37% present risk factors, the most frequent from the clinic: dyslipidemia, hypertension and diabetes; 75% presents mood, behavioral and/or cognitive disorders; 90.75% present evolution of more than a year; 20.83% of the contestants require a more complete ENC because they are below the cutoff for MMSE. Social isolation, lack of medical controls and affective changes were triggers of cognitive impairment.

Atopic dermatitis and cognitive dysfunction in middle-aged and older adults: A systematic review and meta-analysis.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that affects adults worldwide. Recent evidence suggests that AD may be associated with cognitive dysfunction, but the results of individual studies have been inconsistent. This systematic review and meta-analysis aimed to evaluate the association between AD and cognitive dysfunction in middle-aged and older adults. To find relevant research, a comprehensive search of electronic databases from the beginning to March 2023 was carried out. Data were taken from studies that were eligible, and a meta-analysis was done to determine the pooled hazard ratio (HR) and 95% confidence interval (CI). We searched three databases and found a total of 15 studied arms included in 5 cohort studies with over 8.5 million participants were included in the analysis. The results showed that individuals with AD had a higher risk of developing dementia of all-cause dementia (pooled hazard ratio (HR) = 1.16; 95% CI, 1.10-1.23,P<0.001) and the Alzheimer type (pooled HR = 1.28; 95% CI, 1.01-1.63,P<0.001) but not vascular dementia (pooled HR = 1.42; 95% CI, 0.99-2.04,P<0.001). Subgroup analyses showed that the association between atopic dermatitis and all-cause dementia was significant in Europe (P = 0.004) but not in Asia (P = 0.173) and was significant in prospective cohort studies (P<0.001) but not in non-prospective cohort studies (P = 0.068). Sensitivity analysis and publication bias detection confirmed the reliability of the overall findings. In conclusion, this study demonstrated that AD was associated with increased risk of cognitive dysfunction, particularly dementia of the Alzheimer type and all-cause dementia, in middle-aged and older participants. Further research is needed to understand the mechanisms behind this association and its potential implications for clinical practice. PROSPERO, identifier (CRD42023411627).

The Paradox in Positive and Negative Aspects of Emotional Functioning Among Older Adults with Early Stages of Cognitive Impairment.

Introduction: Emotional functioning in older adults is influenced by normal aging and cognitive impairment, likely heterogeneous across positive versus negative aspects of emotional functioning. Little is known about positive emotional experiences at the early stages of cognitive impairment. Methods: We assessed different aspects of emotional functioning among 448 participants aged 65+ (Normal Control (NC) = 276, Mild Cognitive Impairment (MCI) = 103, and mild dementia of the Alzheimer type (mild DAT) = 69) and tested moderators. Results: Compared to NC, older adults with MCI and mild DAT have maintained many positive aspects of emotional functioning, despite higher levels of negative affect, sadness, and loneliness. Among the oldest-old, the mild DAT group experienced higher fear and lower self-efficacy. Discussion: Older adults at early stages of cognitive impairment can experience positive aspects of emotional functioning, such as positive affect, purpose, and life satisfaction, all of which are important buildable psychological resources for coping.

A Randomized Double-blind Study to Assess the Skin Irritation and Sensitization Potential of a Once-weekly Donepezil Transdermal Delivery System in Healthy Volunteers.

A once-weekly donepezil transdermal delivery system (TDS; Adlarity; Corium, LLC) is indicated for the treatment of mild, moderate, and severe dementia of the Alzheimer type. In this placebo-controlled, randomized, double-blind phase 1 trial, healthy volunteers aged 40 years or older were randomized to receive a placebo and donepezil TDS and were evaluated for the primary endpoints of skin irritation and sensitization potential. Skin irritation was scored. Two hundred fifty-six participants were randomized and received ≥1 dose of any treatment. After the first weekly TDS application, no skin irritation or minimal irritation was evident between donepezil and placebo TDSs. At the third weekly TDS application, for donepezil TDS, the average of the mean combined skin irritation score was 0.55 of a possible maximum of 7, indicating none to minimal skin irritation, and for placebo, the score was 0.19, indicating no skin irritation. Of 198 participants, 4 (2.0%) were considered potentially sensitized to donepezil TDS, and 0 were potentially sensitized to placebo TDS. Once-weekly 5-mg/d donepezil TDS demonstrated minimal skin irritation under conditions of use of 3 consecutive weekly patch applications to the same skin site and minimal sensitization potential.

Facilitated lexical processing accuracy and reaction times following repetitive Transcranial Magnetic Stimulation in dementia of the Alzheimer type: a case study

ABSTRACT We investigated the potential effects of high-frequency (10 Hz) repetitive Transcranial Magnetic Stimulation (rTMS) of the bilateral Dorsolateral Prefrontal Cortex (DLPFC) (30-sessions; 2-sessions/day) on improving lexical processing in one participant with mild – Alzheimer’s disease (hereafter dementia of the Alzheimer type-DAT). Increased accuracy and faster reaction times (RTs) were reported in a lexical-decision task (LDT) up to 2-months post-intervention. The current findings indicate that high-frequency stimulation of the DLPFC might be a potential therapeutic tool to improve lexical processing in mild-DAT.

Application of the Semantic Fluency Test in the Screening of Mandarin-Chinese-Speaking Older Adults with Mild Dementia of the Alzheimer Type.

Semantic fluency tests have been widely used as a screening test for dementia of Alzheimer type. However, few studies have explored the application of semantic fluency tests in Mandarin Chinese speakers. This study aimed to explore the feasibility of using different semantic fluency test categories to distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan. A total of 58 healthy older adults and 54 individuals with dementia of Alzheimer type were recruited. Semantic categories of "animals", "fruits", "vegetables", "birds", "means of transportations" and "musical instruments" were administered to participants. The scores from two groups of participants for each category were analyzed. Significant differences in the test scores of each category between two groups of participants were found. The results also revealed that the variables related to whether the participant had dementia, gender, age, and years of schooling significantly influenced the semantic fluency scores for each category. Among all the demographic characteristic of participants, the diagnosis of dementia was the most determining factor. Furthermore, this study proposed optimal cutoff points and calculated the AUC for various test durations (i.e., 30 s, 45 s and 60 s) and semantic categories in the semantic fluency test, which may serve as a reference that would help clinical personnel distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan.

Multi-Center Validation of Pain Assessment in Advanced Dementia (PAINAD) Scale in Malaysia

The detection of pain in persons with advanced dementia is challenging due to their inability to verbally articulate the pain they are experiencing. Pain Assessment in Advanced Dementia (PAINAD) is an observer-rated pain assessment tool developed based on non-verbal expressions of pain for persons with severe dementia. This study aimed to perform construct validation of PAINAD for pain assessment in persons with severe dementia in Malaysia. This was a prospective cross-sectional study conducted from 27 April 2022 to 28 October 2022 in eight public hospitals in Malaysia. The PAINAD scale was the index test, and the Discomfort Scale—Dementia of the Alzheimer Type (DS-DAT) and Nurse-Reported Pain Scale (NRPS) were the reference tests for construct and concurrent validity assessment. Pain assessment for the study subjects was performed by two raters concurrently at rest and during activity. The PAINAD score was determined by the first rater, whereas the DS-DAT and NRPS were assessed by the second rater, and they were blinded to each other’s findings to prevent bias. PAINAD showed good positive correlations ranging from 0.325 to 0.715 with DS-DAT and NRPS at rest and during activity, with a p-value of &lt;0.05. It also demonstrated statistically significant differences when comparing pain scores at rest and during activity, pre- and post-intervention. In conclusion, the PAINAD scale is a reliable observer-rated pain assessment tool for persons with severe dementia in Malaysia. It is also sensitive to changes in the pain level during activity and at rest, pre- and post-intervention.

Description of the ARMADA (assessing reliable measurement in Alzheimer’s disease) general population study cohorts

AbstractBackgroundGiven the growing population of aging adults, and subsequently individuals with dementia, there is a need for instruments that can detect cognitive impairment in early stages. The NIH Toolbox® for Assessment of Neurological and Behavioral Function (NIHTB) is a computerized battery of assessments measuring multiple domains cognition, emotion, sensation, and motor abilities. The goal of the ARMADA study is to validate the NIHTB in individuals with mild cognitive impairment (MCI) and dementia of the Alzheimer type (DAT). Here, we describe the demographic and clinical characteristics of participants ages 65 to 85 from the general population sample.MethodNormal control (NC), MCI, and DAT groups racially proportional to the US population were recruited from existing cohorts across nine Alzheimer’s Disease Research Centers and sites with cognitive aging studies. Diagnoses were based on the Uniform Data Set methodology, and included multiple clinical and cognitive assessments. Participants completed the NIH Toolbox at baseline, 12‐, and 24‐month visits.ResultGroups were matched with respect to multiple demographic characteristics. There were some differences in age and sex, such that the NC group had more female participants and was the youngest. Dementia severity levels differed as expected, with the DAT group demonstrating greater cognitive and functional impairment compared to the MCI group, and the NC group demonstrating minimal cognitive or functional symptoms. Additionally, the DAT group reported more neuropsychiatric symptoms compared to the NC and MCI groups. There was no difference in reported family history of cognitive impairment across groups. Many participants across groups had at least one Alzheimer biomarker collected.ConclusionThe study cohorts included in the ARMADA study accurately reflect their respective clinical syndromes for validating the NIHTB across the cognitive aging spectrum. The goals for the ARMADA study include comparing performance on all four modules of the NIHTB across groups, evaluating the relationship between Alzheimer biomarkers and NIHTB measures, and measuring changes in performance longitudinally. Special emphasis groups, including individuals over age 85, African American participants, and Spanish‐Speaking participants, were also recruited and are reported elsewhere.

THE EFFECT OF HEMIC HYPOXIA THAT OCCURRED IN RATS WITH NITRITE-INDUCED DEMENTIA ON THE DYNAMICS OF BIOCHEMICAL INDICATORS OF ENERGY METABOLISM IN BRAINS

Have been considered the role of hemic hypoxia, which arose against the background of nitrite-induced dementia of the Alzheimer type in rats on the dynamics in biochemical indicators of energy metabolism, the degree of hypoxia, the content of acetylcholi

A Randomized Double-Blind Study to Assess the Skin Irritation and Sensitization Potential of Once-Weekly Donepezil Transdermal Delivery System (P8-6.009)

<h3>Objective:</h3> To assess the skin irritation and sensitization potential of once-weekly 5-mg/d donepezil transdermal delivery system (TDS). <h3>Background:</h3> Once-weekly donepezil TDS (Adlarity®) was approved in 2022 by the US FDA for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type. <h3>Design/Methods:</h3> In this placebo (vehicle), TDS-controlled, randomized, double-blind phase 1 trial (NCT03397862), healthy volunteers aged ≥40 years were evaluated for skin irritation and sensitization potential. Participants were randomized to receive weekly applications of 5-mg/d donepezil TDS on one side of the back and placebo TDS on the opposite side, or vice-versa, with 3 consecutive weekly TDS applications to the same skin site. During a challenge phase, donepezil TDS and placebo TDS were applied to naïve skin sites on opposite sides of the back in a randomized manner for 48 hours. Skin irritation scoring was performed weekly after TDS removal. <h3>Results:</h3> Among the 256 participants who received ≥1 dose of any treatment, the mean (SD) age was 54.3 years (9.4 years). After 3 weekly assessments of TDS, the average of the mean combined irritation score was 0.55 of a possible maximum 7 for donepezil TDS, indicating none-to-minimal skin irritation, and 0.19 for placebo TDS, indicating no skin irritation (treatment difference, −34 [95% CI, −0.43, −0.25]). There was a slight numerical trend of better skin tolerability in participants aged ≥65 versus &lt;65 years. Of 198 participants, 4 (2.0%) were considered potentially sensitized to donepezil TDS, and 0 were potentially sensitized to placebo TDS. <h3>Conclusions:</h3> Once-weekly 5-mg/d donepezil TDS demonstrated acceptable skin tolerability, with minimal skin irritation under conditions of use of 3 consecutive weekly patch applications to the same skin site and minimal sensitization potential, supporting its use as treatment for dementia of the Alzheimer type. <b>Disclosure:</b> Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for EIP Pharma. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Quince-Cortexyme. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheom. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF. Dr. Sabbagh has received publishing royalties from a publication relating to health care. Dr. MATHEW has nothing to disclose. Dr. Blau has received personal compensation for serving as an employee of Corium. Dr. Blau has stock in Johnson &amp; Johnson.

NEURONORMA Cognitive Battery Associations with Cerebrospinal Fluid Amyloid-β and Tau Levels in the Continuum of Alzheimer's Disease.

Neuropsychological assessments are essential to define the cognitive profile and contribute to the diagnosis of Alzheimer's disease (AD). The progress in knowledge about the pathophysiological process of the disease has allowed conceptualizing AD through biomarkers as a biological continuum that encompasses different clinical stages. To explore the association between cerebrospinal fluid (CSF) biomarkers of AD and cognition using the NEURONORMA battery, in a sample of cognitively unimpaired (CU), mild cognitive impaired (MCI), and mild dementia of the Alzheimer type (DAT) subjects, and to characterize the cognitive profiles in MCI subjects classified by A/T/N system. 42 CU, 35 MCI, and 35 mild DAT were assessed using the NEURONORMA battery. Core AD biomarkers [amyloid-β42 (Aβ42) peptide, total tau (t-tau), and phosphorylated tau 181 (p-tau181)] proteins were measured in CSF. Correlation coefficients, multivariate regression, and effect sizes were calculated. We explored the age- and education-adjusted cognitive profiles by A/T/N variants within the MCI group. Cognitive outcomes were directly associated with CSF Aβ42 and inversely with CSF tau measures. We found differences in both biomarkers and cognitive outcomes comparing all pairs except for CSF measures between cognitively impaired groups. The highest effect size was in memory tasks and biomarkers ratios. Lower performances were in memory and executive domains in MCI subjects with AD pathology (A+T+N±) compared to those with normal levels of AD biomarkers (A- T- N). This study provides further evidence of the validity of Spanish NEURONORMA cognitive battery to characterize cognitive impairment in the AD pathological continuum.

Sensory and Motor Differences in A Cognitive Aging Sample

AbstractBackgroundAging is associated with many different types of sensory, motor, and sensorimotor changes.Recent evidence suggests such behavior may be able to predict the risk of developing Alzheimer’s Disease, potentially even before cognitive symptoms manifest. Existing studies have generally examined only particular facets of sensation and motor, rendering comprehensive comparisons of sensorimotor behavior in this sample difficult. To fill this gap, we use the NIH Toolbox® Motor and Sensation Batteries in three groups: normal controls (NC), Mild Cognitive Impairment (MCI), and dementia of the Alzheimer type (DAT).MethodParticipants (N = 336) were consensus diagnosed and grouped into either NC (N = 161), MCI (N = 104), and DAT (N = 71). Participants completed the NIH Toolbox Motor and Sensation Batteries. The motor battery included measures of Standing Balance, Grip Strength for both dominant and non‐dominant hands, Pegboard (dexterity) for both dominant and nondominant hands, the Walk 2 Minute, and the Walk 4 Meter. The sensation battery included measures of Odor, Visual Acuity (vision), Words‐in‐Noise, and Pain Interference. One‐way ANOVAs were conducted for each measure; effect sizes were also calculated.ResultFor all motor measures with the exception of Standing Balance, there were significant diffrences. For grip strength, NC exhibited higher strength than those in the DAT sample (medium effect). For Pegboard, DAT exhibited the weakest performance, followed by MCI (medium to large effect). In general, the DAT walked slower than MCI and NC (large effect), respectively. For sensation measures, there were no differences in visual acuity or pain interference across cognitive groups. DAT participants had decreased olfactory capacity compared with MCI and MCI to NC (large effect). The DAT group and MCI group had more difficulty distinguishing noise from words than the NC counterparts (large effect).ConclusionThis represents one of the first studies to comprehensively characterize sensory and motor changes in a cross‐sectional sample of cognitive aging. Motor changes dominated; cognitive decline appeared more sensitive to both finer motor movements such as the pegboard task and gross movement such as walking. Sensation results were more mixed. We conclude with implications for sensorimotor changes and its relationship with cognitive performance in the latter life span.

Bioequivalence and safety comparison of once‐weekly donepezil transdermal system with oral donepezil: results of a phase 1 pharmacokinetic study in healthy volunteers

AbstractBackgroundOral donepezil, a reversible acetylcholinesterase inhibitor, is a widely prescribed treatment for dementia of the Alzheimer type. Dose escalation of oral donepezil can result in gastrointestinal distress, leading to treatment discontinuation, which emphasizes the need for a transdermal system (TDS). Donepezil TDS (Adlarity®) was recently approved for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type.MethodsAn open‐label, randomized, crossover, 3‐period trial (NCT04617782) with healthy volunteers (aged 18‐55 years) was conducted to assess bioequivalence of once‐weekly 10‐mg/d and 5‐mg/d donepezil TDS with once‐daily 10‐mg oral donepezil. All participants received 5‐mg/d donepezil TDS during the 5‐week Period 1, followed by 10‐mg/d TDS or 10‐mg/d oral donepezil in the 5‐week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state in Week 5 of each treatment. Safety and tolerability were also evaluated.ResultsOf 60 participants enrolled, all received 5‐mg/d TDS, 55 received 10‐mg/d TDS, and 56 received oral donepezil. At steady state, adjusted geometric mean ratio (GMR; % [90% CI]) of TDS to oral donepezil for maximum plasma concentration and area under the plasma concentration versus time curve (0‐168 h) were 88.7 (81.7‐96.2) and 108.6 (100.5‐117.4) for 10‐mg/d and 86.1 (79.8‐92.9) and 105.3 (97.6‐113.6) for 5‐mg/d TDS (dose normalized). The 90% CIs for the GMRs were generally within the accepted 80%–125% range for establishing bioequivalence. Adverse events (AEs) were reported in 80% of participants—53.3% for the 5‐mg/d TDS, 54.5% for the 10‐mg/d TDS, and 57.1% for oral donepezil. Except for abdominal pain (5.5% vs 1.8%), fewer gastrointestinal AEs were reported with 10‐mg/d TDS than oral donepezil (constipation, 5.5% vs 17.9%; nausea 1.8% vs 30.4%; diarrhea 3.6% vs 12.5%), respectively. There were also fewer AEs of dizziness (3.6% vs 19.6%) and no incidence of somnolence (0 vs 10.7%) reported with TDS. No serious AEs, AEs leading to treatment discontinuation, or deaths were reported.ConclusionBoth donepezil TDS strengths were bioequivalent to oral donepezil on a milligram‐per‐day basis. The safety profile of donepezil TDS supports its use in treating dementia of the Alzheimer type.

Next Generation Sequencing analysis of late‐onset dementia patients with a strong family history

AbstractBackgroundNext‐generation sequencing (NGS) techniques allow for efficient screening of potentially pathogenic variants by using gene panels that target the genes known to underlie neurodegenerative dementias. Most NGS studies are focused on cases with early‐onset disease, which have a higher genetic burden. The objective of this study is to identify known and/or novel rare variants in major candidate genes associated with neurodegenerative dementias in cases with a strong family history, including patients with late‐onset disease.MethodWe studied 53 patients (25 early‐ and 28 late‐onset) with a strong family history of dementia (Goldman scale 1 and 2) and phenotypes including dementia of the Alzheimer type (DAT), frontotemporal variants (FTD) and Lewy body type dementia. Presence of the C9Orf72 hexanucleotide repeat expansion had been ruled out and all cases had plasma progranulin levels within the normal range. The NGS panel included 20 genes. Variants identified were reviewed in genomic databases and analyzed for potential pathogenicity using prediction programs. Segregation was evaluated in available siblings.ResultPotentially pathogenic mutations (CADD &gt;20 and/or M‐CAP &gt; 0.025) were found in 20 cases (38%, 11 early‐onset and 9 late‐onset), with two cases carrying mutations in two different genes. We detected known pathogenic mutations in two cases with the SQSTM1 P392L variant, manifesting as bv‐FTD and Paget disease. Six cases had non‐described variants in the PSEN1, ADAM10, SORL1, UBQLN2, and TIROBP genes that were likely disease‐related, as further supported by segregation patterns. We also found rare, potentially pathogenic variants in the SORL1, SQSTM1, and FUS genes in four cases. Finally, ten cases carried variants of unknown‐impact in the following genes: MAPT, CSF1R, ADAM10, SORL1, and SERPINI1. In the late‐onset cases, frontotemporal phenotypes were more likely to have positive results and the potentially pathogenic variants were found in the PSEN1, ADAM10, SQSTM1, FUS, and CSF1R genes.ConclusionIt is worthwhile to screen for the genetic causes of the disease in cases with late‐onset dementia if there is a strong family history. Positive results are more likely obtained in frontotemporal phenotypes.

Comparison of Steady-State Pharmacokinetics of Donepezil Transdermal Delivery System with Oral Donepezil.

Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States. To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil. Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5. All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively). Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.

A transdiagnostic review of neuroimaging studies of apathy and disinhibition in dementia.

Apathy and disinhibition are common and highly distressing neuropsychiatric symptoms associated with negative outcomes in persons with dementia. This paper is a critical review of functional and structural neuroimaging studies of these symptoms transdiagnostically in dementia of the Alzheimer type, which is characterized by prominent amnesia early in the disease course, and behavioural variant frontotemporal dementia, characterized by early social-comportmental deficits. We describe the prevalence and clinical correlates of these symptoms and describe methodological issues, including difficulties with symptom definition and different measurement instruments. We highlight the heterogeneity of findings, noting however, a striking similarity of the set of brain regions implicated across clinical diagnoses and symptoms. These regions involve several key nodes of the salience network, and we describe the functions and anatomical connectivity of these brain areas, as well as present a new theoretical account of disinhibition in dementia. Future avenues for research are discussed, including the importance of transdiagnostic studies, measuring subdomains of apathy and disinhibition, and examining different units of analysis for deepening our understanding of the networks and mechanisms underlying these extremely distressing symptoms.