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Aging Cell Jul 2024Alzheimer's disease (AD) is a neurodegenerative disorder associated with behavioral and cognitive impairments. Unfortunately, the drugs the Food and Drug Administration...
Alzheimer's disease (AD) is a neurodegenerative disorder associated with behavioral and cognitive impairments. Unfortunately, the drugs the Food and Drug Administration currently approved for AD have shown low effectiveness in delaying the progression of the disease. The focus has shifted to non-pharmacological interventions (NPIs) because of the challenges associated with pharmacological treatments for AD. One such intervention is environmental enrichment (EE), which has been reported to restore cognitive decline associated with AD effectively. However, the therapeutic mechanisms by which EE improves symptoms associated with AD remain unclear. Therefore, this study aimed to reveal the mechanisms underlying the alleviating effects of EE on AD symptoms using histological, proteomic, and neurotransmitter-related analyses. Wild-type (WT) and 5XFAD mice were maintained in standard housing or EE conditions for 4 weeks. First, we confirmed the mitigating effects of EE on cognitive impairment in an AD animal model. Then, histological analysis revealed that EE reduced Aβ accumulation, neuroinflammation, neuronal death, and synaptic loss in the AD brain. Moreover, proteomic analysis by liquid chromatography-tandem mass spectrometry showed that EE enhanced synapse- and neurotransmitter-related networks and upregulated synapse- and neurotransmitter-related proteins in the AD brain. Furthermore, neurotransmitter-related analyses showed an increase in acetylcholine and serotonin concentrations as well as a decrease in polyamine concentration in the frontal cortex and hippocampus of 5XFAD mice raised under EE conditions. Our findings demonstrate that EE restores cognitive impairment by alleviating AD pathology and regulating synapse-related proteins and neurotransmitters. Our study provided neurological evidence for the application of NPIs in treating AD.
PubMed: 38952076
DOI: 10.1111/acel.14231 -
Alzheimer's Research & Therapy Jun 2024Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease...
BACKGROUND
Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups.
METHODS
Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older.
RESULTS
PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18).
CONCLUSIONS
The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.
Topics: Humans; Veterans; Stress Disorders, Post-Traumatic; Male; Female; Aged; Apolipoprotein E4; Dementia; Risk Factors; United States; Brain Injuries, Traumatic; Aged, 80 and over; Retrospective Studies
PubMed: 38951900
DOI: 10.1186/s13195-024-01512-w -
BMC Medicine Jul 2024Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on...
BACKGROUND
Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on neurodegeneration and dementia risk remain uncertain.
METHODS
We included 5443 cognitively healthy (MMSE ≥ 26) participants from the population-based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005-2008) was derived from pharmacy dispensing records, from which we determined drug type and cumulative dose. Benzodiazepine use was defined as prescription of anxiolytics (ATC-code: N05BA) or sedative-hypnotics (ATC-code: N05CD) between inception of pharmacy records and study baseline. Cumulative dose was calculated as the sum of the defined daily doses for all prescriptions. We determined the association with dementia risk until 2020 using Cox regression. Among 4836 participants with repeated brain MRI, we further determined the association of benzodiazepine use with changes in neuroimaging markers using linear mixed models.
RESULTS
Of all 5443 participants, 2697 (49.5%) had used benzodiazepines at any time in the 15 years preceding baseline, of whom 1263 (46.8%) used anxiolytics, 530 (19.7%) sedative-hypnotics, and 904 (33.5%) used both; 345 (12.8%) participants were still using at baseline assessment. During a mean follow-up of 11.2 years, 726 participants (13.3%) developed dementia. Overall, use of benzodiazepines was not associated with dementia risk compared to never use (HR [95% CI]: 1.06 [0.90-1.25]), irrespective of cumulative dose. Risk estimates were somewhat higher for any use of anxiolytics than for sedative-hypnotics (HR 1.17 [0.96-1.41] vs 0.92 [0.70-1.21]), with strongest associations for high cumulative dose of anxiolytics (HR [95% CI] 1.33 [1.04-1.71]). In imaging analyses, current use of benzodiazepine was associated cross-sectionally with lower brain volumes of the hippocampus, amygdala, and thalamus and longitudinally with accelerated volume loss of the hippocampus and to a lesser extent amygdala. However, imaging findings did not differ by type of benzodiazepines or cumulative dose.
CONCLUSIONS
In this population-based sample of cognitively healthy adults, overall use of benzodiazepines was not associated with increased dementia risk, but potential class-dependent adverse effects and associations with subclinical markers of neurodegeneration may warrant further investigation.
Topics: Humans; Female; Dementia; Male; Aged; Benzodiazepines; Middle Aged; Magnetic Resonance Imaging; Netherlands; Aged, 80 and over; Neuroimaging; Brain; Prospective Studies; Neurodegenerative Diseases; Hypnotics and Sedatives; Risk Factors
PubMed: 38951846
DOI: 10.1186/s12916-024-03437-5 -
Alzheimer's Research & Therapy Jun 2024The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the... (Review)
Review
The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the main constituent of amyloid plaques in Alzheimer's Disease (AD). The physiological functions of APP in the human adult brain are very diverse including intracellular signaling, synaptic and neuronal plasticity, and cell adhesion, among others. There is growing evidence that APP becomes dysfunctional in AD and that this dyshomeostasis may impact several APP functions beyond Aβ generation. The vast majority of current anti-amyloid approaches in AD have focused on reducing the synthesis of Aβ or increasing the clearance of brain Aβ aggregates following a paradigm in which Aβ plays a solo in APP dyshomeostasis. A wider view places APP at the center stage in which Aβ is an important, but not the only, factor involved in APP dyshomeostasis. Under this paradigm, APP dysfunction is universal in AD, but with some differences across different subtypes. Little is known about how to approach APP dysfunction therapeutically beyond anti-Aβ strategies. In this review, we will describe the role of APP dyshomeostasis in AD beyond Aβ and the potential therapeutic strategies targeting APP.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Amyloid beta-Peptides; Brain
PubMed: 38951839
DOI: 10.1186/s13195-024-01504-w -
Scientific Reports Jul 2024Overly restrictive clinical trial eligibility criteria can reduce generalizability, slow enrollment, and disproportionately exclude historically underrepresented...
Overly restrictive clinical trial eligibility criteria can reduce generalizability, slow enrollment, and disproportionately exclude historically underrepresented populations. The eligibility criteria for 196 Alzheimer's Disease and Related Dementias (AD/ADRD) trials funded by the National Institute on Aging were analyzed to identify common criteria and their potential to disproportionately exclude participants by race/ethnicity. The trials were categorized by type (48 Phase I/II pharmacological, 7 Phase III/IV pharmacological, 128 non-pharmacological, 7 diagnostic, and 6 neuropsychiatric) and target population (51 AD/ADRD, 58 Mild Cognitive Impairment, 25 at-risk, and 62 cognitively normal). Eligibility criteria were coded into the following categories: Medical, Neurologic, Psychiatric, and Procedural. A literature search was conducted to describe the prevalence of disparities for eligibility criteria for African Americans/Black (AA/B), Hispanic/Latino (H/L), American Indian/Alaska Native (AI/AN) and Native Hawaiian/Pacific Islander (NH/PI) populations. The trials had a median of 15 criteria. The most frequent criterion were age cutoffs (87% of trials), specified neurologic (65%), and psychiatric disorders (61%). Underrepresented groups could be disproportionately excluded by 16 eligibility categories; 42% of trials specified English-speakers only in their criteria. Most trials (82%) contain poorly operationalized criteria (i.e., criteria not well defined that can have multiple interpretations/means of implementation) and criteria that may reduce racial/ethnic enrollment diversity.
Topics: Humans; Alzheimer Disease; Clinical Trials as Topic; Cognitive Dysfunction; Dementia; Eligibility Determination; Ethnicity; National Institute on Aging (U.S.); Patient Selection; United States; Black or African American; Hispanic or Latino; American Indian or Alaska Native; Native Hawaiian or Other Pacific Islander
PubMed: 38951633
DOI: 10.1038/s41598-024-65767-x -
Experimental & Molecular Medicine Jul 2024The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying...
The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying mechanisms through which Aβ contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aβ induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aβ accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aβ-induced tau uptake in AD.
PubMed: 38951140
DOI: 10.1038/s12276-024-01274-3 -
ENeuro Jul 2024
Topics: Alzheimer Disease; Humans; Antibodies, Monoclonal, Humanized
PubMed: 38951040
DOI: 10.1523/ENEURO.0319-23.2024 -
BMJ Open Jul 2024This review identifies and examines theoretical approaches (components and objectives) to person-centred dementia care in order to obtain a better understanding of what... (Review)
Review
OBJECTIVES
This review identifies and examines theoretical approaches (components and objectives) to person-centred dementia care in order to obtain a better understanding of what is meant by the concept of person-centred dementia care.
DESIGN
Following the approach of Whittemore and Knafl, an integrative literature review was conducted to answer the following questions: (1) Which theoretical approaches to person-centred dementia care have been published? (2) What are the components of the theoretical approaches to person-centred dementia care thus identified, and which objectives can be identified?
DATA SOURCES
MEDLINE (via PubMed), CINAHL (via EBSCO) and PsycINFO (via EBSCO) were searched through to 26 April 2021.
ELIGIBILITY CRITERIA
We included any kind of published literature that describes theoretical approaches to person-centred dementia care and that was written in German or English.
DATA EXTRACTION AND SYNTHESIS
Two independent reviewers extracted data. Data were pooled using a data extraction form developed by the Joanna Briggs Institute. A qualitative content analysis was conducted.
RESULTS
The analysis revealed heterogeneous perspectives within the identified approaches to person-centred dementia care. Statements pertaining to the components and objectives could be assigned to three different subcategories (microlevel, macrolevel and application level). This analysis enabled an enhanced understanding of how person-centred dementia care is currently described and whether and how the theoretical approaches differ in terms of their orientations and their focus on the individual and/or on sociality, which allows conclusions regarding the underlying conceptual idea of personhood.
CONCLUSIONS
There is a clear challenge for future research to overcome the dominance of the focus on the individual and to consider aspects of sociality to be at least equally important. This is needed in order to understand dementia as a multifaceted phenomenon that demands a differentiated consideration of theoretical notions of how to understand personhood in this context.
Topics: Humans; Patient-Centered Care; Dementia
PubMed: 38951009
DOI: 10.1136/bmjopen-2024-085051 -
Proceedings of the National Academy of... Jul 2024While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to...
While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to noninvasively probe lactate in intracellular and extracellular spaces. Here, we show that, by measuring the diffusion of lactate with diffusion-weighted magnetic resonance (MR) spectroscopy in vivo and comparing it to the diffusion of purely intracellular metabolites, noninvasive quantification of extracellular and intracellular lactate fractions becomes possible. More specifically, we detect alterations of lactate diffusion in the APP/PS1 mouse model of Alzheimer's disease. Data modeling allows quantifying decreased extracellular lactate fraction in APP/PS1 mice as compared to controls, which is quantitatively confirmed with implanted enzyme-microelectrodes. The capability of diffusion-weighted MR spectroscopy to quantify extracellular-intracellular lactate fractions opens a window into brain metabolism, including in Alzheimer's disease.
Topics: Animals; Lactic Acid; Alzheimer Disease; Brain; Mice; Mice, Transgenic; Diffusion Magnetic Resonance Imaging; Extracellular Space; Disease Models, Animal; Magnetic Resonance Spectroscopy; Male; Amyloid beta-Protein Precursor
PubMed: 38950371
DOI: 10.1073/pnas.2403635121 -
BJPsych Bulletin Jul 2024Dementia in-patient units (DIU) are mental health wards that care for people living with dementia (PLWD) whose symptoms are causing severe distress or potential risk....
AIMS AND METHOD
Dementia in-patient units (DIU) are mental health wards that care for people living with dementia (PLWD) whose symptoms are causing severe distress or potential risk. DIUs look after some of the most vulnerable and unwell people in society, yet they are environments that are underresearched: a recent systematic review revealed only 36 articles worldwide relating to DIUs. To better understand research priorities in DIUs, we undertook a two-round online Delphi survey of PLWD with experience of DIUs, their carers and professionals who work in DIUs.
RESULTS
Ten research priorities were described and ranked. The top three were how to use non-pharmacological techniques to manage non-cognitive symptoms of dementia, supporting families and better understanding of how to discharge PLWD safely and healthily.
CLINICAL IMPLICATIONS
This is the first Delphi consensus to describe DIU research priorities. This paper will help researchers focus on the areas that matter most to people who use DIUs.
PubMed: 38949259
DOI: 10.1192/bjb.2024.42