Journal of Alzheimer's Disease Reports

It is inconclusive on how sex affects the risk of developing mild cognitive impairment (MCI) or dementia.

To investigate how sex affects the risk of developing MCI or dementia.

A secondary data analysis was performed on data collected from participants enrolled at Alzheimer’s Disease Research Centers funded by National Institute on Aging. There were two inclusion criteria: 1) participants were free of dementia at the baseline visit; 2) every participant must have at least one follow-up visit. A Cox proportional hazards model was used to investigate how sex affects the risk of developing cognitive impairments.

During a follow-up period of more than 10 years, male participants had a slightly higher incidence than female participants for either MCI or dementia. Not surprisingly, a higher prevalence was observed in male than female participants for either MCI or dementia. However, male participants had a higher mortality rate than their female counterparts.

The male sex is associated with a higher risk for developing cognitive impairments along the aging process.

Alzheimer’s disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-β (Aβ) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aβ or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aβ and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together.

We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aβ and tau aggregates through in vitro assessments.

We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aβ fibrils. Then, anti-cytotoxic, anti-Aβ, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis.

When HT22 cells were exposed to Aβ aggregates, the treatment of borrelidins alleviates the Aβ-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aβ aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aβ aggregates but also directly regulates tau aggregation.

Borrelidin dissociates insoluble Aβ and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aβ or anti-tau immunotherapy for clearance of both aggregates.

The present systematic review and meta-analysis of diagnostic test accuracy summarizes the last three decades in advances on diagnosis of Alzheimer’s disease (AD) in developed and developing countries.

To determine the accuracy of biomarkers in diagnostic tools in AD, for example, cerebrospinal fluid, positron emission tomography (PET), and magnetic resonance imaging (MRI), etc.

The authors searched PubMed for published studies from 1990 to April 2020 on AD diagnostic biomarkers. 84 published studies were pooled and analyzed in this meta-analysis and diagnostic accuracy was compared by summary receiver operating characteristic statistics.

Overall, 84 studies met the criteria and were included in a meta-analysis. For EEG, the sensitivity ranged from 67 to 98%, with a median of 80%, 95% CI [75, 91], tau-PET diagnosis sensitivity ranged from 76 to 97%, with a median of 94%, 95% CI [76, 97]; and MRI sensitivity ranged from 41 to 99%, with a median of 84%, 95% CI [81, 87]. Our results showed that tau-PET diagnosis had higher performance as compared to other diagnostic methods in this meta-analysis.

Our findings showed an important discrepancy in diagnostic data for AD between developed and developing countries, which can impact global prevalence estimation and management of AD. Also, our analysis found a better performance for the tau-PET diagnostic over other methods to diagnose AD patients, but the expense of tau-PET scan seems to be the limiting factor in the diagnosis of AD in developing countries such as those found in Asia, Africa, and Latin America.

As a result of caring for a person with dementia, caregivers of persons with Alzheimer’s disease (AD) may be uniquely aware of public stigma for persons with AD.

The purpose of this study was to compare self-identified caregivers and non-caregivers’ expectations of public stigma experienced by persons living with dementia.

Analysis of data from a survey of 910 adults (median age = 49 years) who read a vignette about a man with mild stage dementia. Multivariable ordered logistic regression was used to examine how AD caregiver status associated with responses on a modified Family Stigma in Alzheimer’s Disease Scale (FS-ADS).

9%(n = 82) of respondents self-identified as a current or former primary caregiver of a person with AD, about the same as the national estimate of informal caregivers (8.8%). Compared to non-caregivers, AD caregivers were more likely to report stronger reactions on all seven domains of the FS-ADS (all p <  0.05). As compared to AD caregivers with less factual knowledge about caregiving, AD caregivers with more knowledge expected the person with dementia to experience less social distance (p <  0.05). In addition, female AD caregivers reported fewer negative aesthetic attributions than male AD caregivers (p <  0.05).

Compared to non-caregivers, respondents who self-identified as an AD caregiver gave responses that suggest they perceived more stigma of dementia among members of the public. Their reactions were attenuated by AD knowledge and being female. The findings have key implications for interventions to reduce AD stigma.

The increasing prevalence of Alzheimer’s disease (AD) and lack of effective medications has led to a need to identify modifiable risk factors as targets for interventions.

In this cross-sectional study, we sought to determine whether worse sleep quality is associated with increased pathological tau, and whether this relationship is affected by amyloid pathology.

66 male participants underwent Florbetapir (AV45) positron emission tomography (PET) and Flortaucipir (FTP) PET and completed the Pittsburgh Sleep Quality Index questionnaire (PSQI) as part of the Department of Defense Alzheimer’s Disease Neuroimaging Initiative, a multicenter study collecting data from Vietnam War veterans, some of whom have a history of post-traumatic stress disorder, or non-penetrating traumatic brain injury. AV45 PET was used to determine the presence of significant amyloid pathology. We used regression models to determine the effects of amyloid pathology and PSQI on tau deposition in brain regions associated with Braak stages.

Among the 66 participants, 14 individuals were amyloid positive (21%) and 52 were amyloid negative (79%). In regions associated with Braak stages III-IV, there was a significant interaction of amyloid status on PSQI (β= 0.04, p = 0.003) with higher PSQI correlating with higher FTP SUVr in amyloid-positive individuals only (β= 0.031, p = 0.005).

Our study found that an AD profile of tau deposition was associated with an interaction between self-reported sleep quality and amyloid pathology such that worse self-reported sleep was related to higher tau in regions usually associated with AD progression, but only in individuals with high cerebral amyloid deposition.

Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline.

To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD.

Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an online test (UKB data field 20240).

We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4.

UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival.

Poor sleep is common among older adults at risk for dementia and may be due to circadian dysregulation. Light is the most important external stimulus to the circadian clock and bright light therapy (BLT) has been used for >20 years to help realign circadian rhythms. However, the ability of field methods (e.g., actigraphy) to accurately determine the type and intensity of light is unknown.

We examined the ability of the MotionWatch8 (MW8) light sensor to determine: 1) light versus dark, 2) electrical light versus daylight, and 3) device-based BLT versus light which was not BLT.

We tested the MW8 under 17 daily light scenarios. Light exposure data was collected for 5 minutes during each scenario. Concurrently, we measured light exposure using the LT40 Light Meter, a sensitive measure of light intensity. We then developed individual cut-points using receiver operator characteristics analyses to determine optimal MW8 cut-points for 1) light versus dark; 2) electrical light versus daylight; and 3) light from a BLT box versus light which was not BLT. Bland-Altman plots tested the precision of the MW8 compared to the LT40.

The MW8 accurately discriminated light versus dark (>32 lux), and electrical light versus daylight (<323 lux). However, the MW8 had poor accuracy for 1) discriminating BLT from light which was not BLT; and 2) low precision compared to the LT40.

The MW8 appears to be able to discern light versus dark and electrical light versus daylight; however, there remains a need for accurate field methods capable of measuring light exposure.

How the relationship between obesity and MRI-defined neural properties varies across distinct stages of cognitive impairment due to Alzheimer’s disease is unclear.

We used multimodal neuroimaging to clarify this relationship.

Scans were acquired from 47 patients clinically diagnosed with mild Alzheimer’s disease dementia, 68 patients with mild cognitive impairment, and 57 cognitively healthy individuals. Voxel-wise associations were run between maps of gray matter volume, white matter integrity, and cerebral blood flow, and global/visceral obesity.

Negative associations were found in cognitively healthy individuals between obesity and white matter integrity and cerebral blood flow of temporo-parietal regions. In mild cognitive impairment, negative associations emerged in frontal, temporal, and brainstem regions. In mild dementia, a positive association was found between obesity and gray matter volume around the right temporoparietal junction.

Obesity might contribute toward neural tissue vulnerability in cognitively healthy individuals and mild cognitive impairment, while a healthy weight in mild Alzheimer’s disease dementia could help preserve brain structure in the presence of age and disease-related weight loss.

Individuals with coronary artery disease (CAD) have worse executive function compared to the general population but the mechanisms are unknown.

To investigate the role of acute mental stress (MS) on the executive function of patients with CAD.

Participants with stable CAD underwent acute MS testing with simultaneous peripheral vascular function measurements and brain imaging using high resolution-positron emission tomography. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during MS/baseline was calculated as a measure of microvascular constriction during MS. Plasma levels of catecholamine and interleukin-6 were assessed at baseline and after MS. Executive function was assessed both at baseline and at 2 years follow-up using the Trail Making Test parts A and B.

We studied 389 individuals with brain data available for 148 participants. Of this population follow-up cognitive assessments were performed in 226 individuals (121 with brain imaging). After multivariable adjustment for baseline demographics, risk factors, and medication use, a lower sPAT, indicating greater vasoconstriction, a higher inferior frontal lobe activation with MS, and increases in norepinephrine and IL-6 levels with MS were all independently associated with greater time to complete Trail B test.-38.4pt

In response to acute MS, greater peripheral vasoconstriction, higher inferior frontal lobe brain activation, and increases in the levels of norepinephrine and IL-6 are associated with worse executive function.

Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer’s disease.

The aim of this study was to assess whether the association was present in cognitively normal older adults.

Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study.

No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020).

These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.

Alzheimer’s disease (AD) features perturbed brain glucose utilization, which could contribute to brain bioenergetic failure. This led some to consider using ketone bodies to enhance AD brain bioenergetics and treat AD.

We evaluated the rate at which brain homogenates from persons with Alzheimer’s disease (AD) metabolize D-β-hydroxybutyrate (BHB).

We homogenized pieces of temporal cortex from frozen autopsy brains obtained from recently deceased AD subjects (n = 4), and age-matched subjects that did not have clinical AD (n = 3). Measuring the rate of CO2 production that followed the introduction of radiolabeled BHB to the homogenates yielded a BHB utilization rate.

Compared to the control homogenates, the BHB-supported CO2 production rate was 66%lower in the AD homogenates (p < 0.05).

AD brains can utilize BHB, albeit less robustly than control brains. In conjunction with a previous study that demonstrated reduced glucose utilization in AD brain homogenates, our BHB data provide further evidence of AD brain mitochondrial dysfunction or altered mitochondrial biology.

There is a need for new practical tools to assess the cognitive impairment of small vessel disease (SVD) patients in the clinic.

This study aimed to examine cognitive functioning by administering the Virtual Supermarket (VST) in patients with SVD with cognitive impairment (SVD-CI, N = 32), cognitively normal SVD (SVD-CN, N = 37), and age-and education-matched healthy controls (HC, N = 30).

The tablet-based VST application and comprehensive traditional pencil-and-paper neuropsychological tests assessing memory, attention, executive function, visuospatial function, and language were administered to all participants.

A moderate correlation was found between the “Duration” and “Correct Quantities” variables of VST and visuospatial function and general cognitive status composite Z scores across SVD-CI patients. “Duration” and “Correct Money” variables were moderately related to memory, executive functions, and visuospatial function composite Z scores across SVD-CN patients. A combination of all VST variables discriminated SVD-CI and HC with a correct classification rate of 81%, a sensitivity of 78%, and a specificity of 84%.

This study is the first to evaluate cognitive functions employing the VST in SVD with and without cognitive impairment. It provides encouraging preliminary findings of the utility of the VST as a screening tool in the assessment of cognitive impairment and the differentiation of SVD patients from HC. In the future, validation studies of the VST with larger samples are needed.

Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. Although a significant proportion of the population with MCI experience reversion to normal cognition, it is still poorly understood.

This study was designed to extend the present evidence regarding the difference between stable and reverting MCI by including whole brain atrophy measures as possible parameters involved.

405 patients diagnosed with MCI at baseline were selected. After one-year follow-up period, 337 patients (83.2%) were categorized as stable MCI and 68 patients (16.8%) reverted to cognitively normal status (reversion group). Several baseline biomarkers including cerebrospinal fluid (CSF) biomarkers of AD, including Aβ₄₂, t-tau, and p-tau and MRI-based atrophy measurements were compared.

Participants with stable MCI demonstrated greater brain atrophy as well as lower Aβ and higher tau proteins in the CSF. The atrophy rate was found to be associated with CSF biomarkers merely in the stable group, after adjustment for confounding variables.

These findings provide novel evidence regarding the biological perspective of the reversion phenomenon in individuals with MCI.

Recent studies suggest meditation and music listening (ML) may improve cognitive and psychosocial outcomes in adults with subjective cognitive decline (SCD). However, lack of a usual care group has limited conclusions.

To assess the: 1) feasibility of incorporating an enhanced usual care (EUC) comparator in a trial of Kirtan Kriya meditation (KK) and ML for adults experiencing SCD; and 2) preliminary effects of active treatment (KK/ML) versus an EUC program.

Forty participants with SCD were randomized 1:1:2 to a 12-week KK, ML, or EUC program. KK and ML participants were asked to practice 12 minutes/day; EUC participants were given a comprehensive educational packet regarding healthy aging and strategies for improving/maintaining brain health and asked to record any activities or strategies used. Feasibility was assessed using measures of retention, adherence, treatment expectancies, and participant satisfaction, as well as information from exit questionnaires and daily practice/activity logs. Cognitive functioning, stress, mood, sleep-quality, and health-related quality of life (QOL) were measured pre- and post-intervention using well-validated instruments.

Thirty-two participants (80%) completed the 3-month study, with retention highest in the EUC group (p < 0.05). Active treatment participants averaged 6.0±0.4 practice sessions/week, and EUC participants, 7.5±0.6 brain health activities/week. Treatment expectancies were similar across groups. EUC participants indicated high satisfaction with the program and study. Despite limited study power, the active treatment group showed significantly greater gains in subjective memory functioning (ps≤0.025) and nonsignificant improvements in cognitive performance (TMT-B), perceived stress, QOL, and mood (ps≤0.08) compared to the EUC group.

Findings of this pilot feasibility trial suggest incorporation of an EUC program is feasible, and that participation in a simple 12-week relaxation program may be helpful for adults with SCD versus engagement in an EUC program.

Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer’s Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden.

To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD.

Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded.

The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r = –0.33 [95%CI –0.47 to –0.17], p < 0.0001.

In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI.

The prevalence of cognitive dysfunction increases in elderly due to cardiovascular disease related risk factors in rural communities like West Texas.

The purpose of this study was to find risk factors of cardiovascular disease (CVD) related to cognitive dysfunction and their impact on elderly adults in rural West Texans.

Statistical methods such as Pearson’s chi-squared and a multinomial logistic regression were utilized to analyze data. We used SPSS software to detect and understand the nature of the risk factors.

A summary of statistics was obtained by using Pearson’s chi-squared test for categorical variables. CVD, diabetes mellitus, and depression were significantly associated with cognitive dysfunction for both males and females (p = 0.0001), whereas anxiety was found to be significantly associated with cognitive dysfunction for females (p = 0.0001). Age group and race/ethnicity were significantly associated with cognitive dysfunction for both males and females (p = 0.0001). By performing a multinomial logistic regression method and controlling for confounders, the significant risk factors (p <  0.05)— age (65– 84 years), diabetes, and memory loss for age-associated cognitive impairment; diabetes for cognitive impairment no dementia; age (65– 84, ≥85 years), CVD, diabetes, depression, memory loss, non-Hispanic Whites, and Black/African-Americans for mild cognitive impairment; and age, memory loss, non-Hispanic Whites, Black/African-Americans, and male gender were found for dementia.

CVD related risk factors in developing cognitive dysfunction exist and integrating such risk variables may guide relevant policy interventions to reduce Alzheimer’s incidence or dementia in rural communities in West Texans.

Amyloid-β (Aβ), the key constituent of Alzheimer’s disease (AD) plaques, has antimicrobial properties.

To investigate the association between plasma Aβ and antibodies against the AD-related pathogens herpes simplex virus (HSV), cytomegalovirus (CMV), and C. pneumoniae.

Plasma from 339 AD cases, obtained on average 9.4 years (±4.00) before diagnosis, and their matched controls were analyzed for Aβ₄₀ and Aβ₄₂ concentrations with Luminex xMAP technology and INNOBIA plasma Aβ-form assays. Enzyme-linked immunosorbent assays were utilized for analyses of anti-HSV immunoglobulin (Ig) G, anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG. Follow-up samples were available for 150 of the cases.

Presence and levels of anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG did not correlate with concentrations of Aβ₄₂ or Aβ₄₀ in cases or controls.

Levels of plasma Aβ were not associated with antibodies against different AD-related pathogens.

Emerging evidence indicates that the misfolded tau protein can propagate aggregates between cells in a prion-like manner. This prion activity has been typically studied in brain extracts of patients with Alzheimer’s disease (AD), but not in the olfactory region that can be a potential biomarker in AD.

To investigate the prion seeding activity of tau in nasal mucosa tissues using a cell culture model of tau propagation.

Brain and nasal mucosa homogenates were added to HEK293T cells expressing three repeat or four-repeat domains of tau with the L266V, V337M (3RD^*VM) and P301L and V377M mutations (4RD^*LM) fused to the enhanced green fluorescence protein (EGFP) respectively. We also measured the level of phosphorylated tau (p-tau), total tau (t-tau), and p-tau/t-tau ratio and performed correlation analysis between tau prion activity and the level of tau.

We found that brain and nasal tissue homogenates from patients with AD significantly induced tau aggregation in HEK293T cells either expressing tau 3RD^*VM-EGFP or 4RD^*LM-EGFP compared with control brain and nasal tissue homogenates. The levels of p-tau and p-tau/t-tau ratio were significantly increased in the brain of patients with AD; however, no significant difference was found in nasal tissue compared with their respective control tissue homogenates.

These results suggest that the nasal tissues contain tau seeds, similar to the brain, albeit without changes in the levels of p-tau and t-tau. Therefore, a cellular bioassay using nasal tissues would have great potential as an AD biomarker because of the usefulness of nasal tissue biopsy.

The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE.

Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology.

DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology.

Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels.

APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

Familial Alzheimer’s disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD.

Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred.

Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method.

Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques.

These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo.

Parkinson’s disease (PD) is one of the most important neurodegenerative disorders in human in which recovery of functions could be achieved by improving the survival and function of residual dopaminergic neurons in the substantia nigra pars compacta. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the dopamine (DA) biosynthesis pathway.

Earlier our laboratory has shown that sodium benzoate (NaB), a metabolite of cinnamon and an FDA-approved drug against urea cycle disorders and glycine encephalopathy, increases neuroprotective molecules and protects dopaminergic neurons in a mouse model of PD. Here, we examined whether NaB could stimulate the production of DA in dopaminergic neurons.

We employed PCR, real-time PCR, western blot, immunostaining, and HPLC to study the signature function of dopaminergic neurons. Locomotor functions were monitored in mice by open-field.

NaB increased the mRNA and protein expression of TH to produce DA in mouse MN9D dopaminergic neuronal cells. Accordingly, oral feeding of NaB increased the expression of TH in the nigra, upregulated striatal DA, and improved locomotor activities in striatum of normal C57/BL6 and aged A53T-α-syn transgenic mice. Rapid induction of cAMP response element binding (CREB) activation by NaB in dopaminergic neuronal cells and the abrogation of NaB-induced expression of TH by siRNA knockdown of CREB suggest that NaB stimulates the transcription of TH in dopaminergic neurons via CREB.

These results indicate a new function of NaB in which it may be beneficial in PD via stimulation of DA production from residual dopaminergic neurons.

The presence of recurrent, complex visual hallucinations (VH) is among the core clinical features of dementia with Lewy bodies (DLB). It has been proposed that VH arise from a disrupted organization of functional brain networks. However, studies are still limited, especially investigating the resting-state functional brain features underpinning VH in patients with dementia.

The aim of the present pilot study was to investigate whether there were any alterations in functional connectivity associated with VH in DLB.

Seed-based analyses and independent component analysis (ICA) of resting-state fMRI scans were carried out to explore differences in functional connectivity between DLB patients with and without VH.

Seed-based analyses reported decreased connectivity of the lateral geniculate nucleus, the superior parietal lobule and the putamen with the medial frontal gyrus in DLB patients with VH. Visual areas showed a pattern of both decreased and increased functional connectivity. ICA revealed between-group differences in the default mode network (DMN).

Functional connectivity analyses suggest dysfunctional top-down and bottom-up processes and DMN-related alterations in DLB patients with VH. This impairment might foster the generation of false visual images that are misinterpreted, ultimately resulting in VH.

LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)_1–40 and Aβ_1–42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD).

To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia.

Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline.

A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo.

LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

While an association between atherosclerosis and dementia has been identified, few studies have assessed the longitudinal relationship between aortic valve calcification (AVC) and cognitive impairment (CI).

We sought to determine whether AVC derived from lung cancer screening CT (LCSCT) was associated with CI in a moderate-to-high atherosclerotic risk cohort.

This was a single site, retrospective analysis of 1401 U.S. veterans (65 years [IQI: 61, 68] years; 97%male) who underwent quantification of AVC from LCSCT indicated for smoking history. The primary outcome was new diagnosis of CI identified by objective testing (Mini-Mental Status Exam or Montreal Cognitive Assessment) or by ICD coding. Time-to-event analysis was carried out using AVC as a continuous variable.

Over 5 years, 110 patients (8%) were diagnosed with CI. AVC was associated with new diagnosis of CI using 3 Models for adjustment: 1) age (HR: 1.104; CI: 1.023–1.191; p = 0.011); 2) Model 1 plus hypertension, hyperlipidemia, diabetes, CKD stage 3 or higher (glomerular filtration rate < 60 mL/min) and CAD (HR: 1.097; CI: 1.014–1.186; p = 0.020); and 3) Model 2 plus CVA (HR: 1.094; CI: 1.011–1.182; p = 0.024). Sensitivity analysis demonstrated that the association between AVC and new diagnosis of CI remained significant upon exclusion of severe AVC (HR: 1.100 [1.013–1.194]; p = 0.023). Subgroup analysis demonstrated that this association remained significant when including education in the multivariate analysis (HR: 1.127 [1.030–1.233]; p = 0.009).

This is the first study demonstrating that among mostly male individuals who underwent LCSCT, quantified aortic valve calcification is associated with new diagnosis of CI.

Non-pharmacological therapies have been shown to be effective in managing challenging behavior in people with dementia. However, the efficacy of art therapy has yet to be determined.

In the present systematic review, we evaluate the efficacy of art therapy as a non-pharmacological intervention for dementia and examine whether art therapy improves wellbeing and quality of life while decreasing biological and psychological symptoms of dementia (BPSD).

Research undertaken between 2015 and 2020 was examined and a total of seventeen studies met the specified search criteria, with 853 participants (657 people with dementia, 180 formal and informal carers, and 16 volunteers) involved.

We identified four outcome domains: wellbeing, quality of life, BPSD, and cognitive function. One or more significant outcomes as having an impact on the efficacy of the intervention were reported in 88% (15/17) of the studies, whereas 17% (3/17) demonstrated significant outcomes across quality of life, wellbeing, and BPSD.

People with dementia benefit from art therapy. These interventions when incorporating elements of being ‘in the moment’ increase opportunities for communication between people with dementia and their caregiver(s) and facilitate person-centered therapeutic activities.

A 57-year-old right-handed man was admitted to the Treviso Memory Clinic due to the presence of memory forgetfulness, repetition of the same questions, episodes of confusion, initial difficulties in performing complex tasks and easy distraction over the past two years, as well as recurrent and never-happened-before car accidents.

We report a peculiar case of an early onset Alzheimer’s disease (AD) with an unusual symptomatology, apparently not fitting in any of the categorized atypical forms of AD nor being representative of a typical amnestic AD.

The patient underwent a neuropsychological, structural, and metabolic cerebral evaluation by MRI and ¹⁸F-FDG PET, together with the search for cerebral amyloid (amyloid PET), a genetic testing for dementia related genes and the dosage of CSF protein biomarkers of neurodegenerative conditions.

We observed a convergence of predominant frontal (dysexecutive, verbal disinhibition) and posterior (visuospatial) features of cognitive impairment. Structural MRI sequences showed subarachnoid spaces of the vault enlarged in the fronto-parietal region with anterior and posterior cortical atrophy. The hippocampus appeared preserved. The ¹⁸F-FDG PET scans showed hypometabolism in the prefrontal, lateral temporal, posterior parietal, and occipital regions bilaterally. The ¹⁸F-Flutemetamol scan showed a diffused uptake of the amyloid tracer at the cerebral cortex. CSF biomarkers were compatible with Alzheimer’s disease (AD).

This case report presented with clinical phenotypic aspects atypical of AD, both frontal and posterior, never described as concomitant in the most accredited criteria for atypical AD, and appeared therefore more atypical than each of the atypical AD phenotypes already reported.

Mutations in PRESENILIN 2 (PSEN2) cause early onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon—the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated.

To predict cellular functions affected by heterozygosity for a frameshift, or a reading frame-preserving mutation in zebrafish psen2 using bioinformatic techniques.

A frameshift mutation (psen2^N140fs) and a reading frame-preserving (in-frame) mutation (psen2^{T141 _ L142delinsMISLISV}) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analyzed.

The in-frame mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long-term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signaling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions.

A frameshift and an in-frame mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long-term potentiation and the cell cycle may promote EOfAD pathogenesis in humans.

Accumulating data suggest infectious agents are involved in Alzheimer’s disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression.

The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression.

Sixty-nine patients 60–85 years were treated with Apovir or placebo for 9 months and followed until 12 months after end of treatment. Cognitive tests, safety, biomarkers, drug plasma, and cerebrospinal fluid concentrations were assessed.

The tolerability of Apovir was compromised as demonstrated by the large drop-out rate and increased frequency and severity of adverse events. The primary endpoint, demonstrating a difference in change from baseline to 9 months between groups in ADAS-cog total score, was not met (p = 0.1809). However, there were observations indicating potential effects on both ADAS-cog and CDR-SB but these effects need to be verified. Also, there was a decrease in cerebrospinal fluid amyloid-β in Apovir at 9 months (p = 0.0330) but no change in placebo.

This was the first randomized, placebo controlled clinical trial exploring antiviral treatment on AD progression. The trial is considered inconclusive due to the large drop-out rate. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process.

Web-based educational interventions are emerging as a potential solution to improve caregiver dementia knowledge and overall well-being.

To assess the feasibility of delivering a web-based intervention for dementia caregivers by examining: 1) engagement with the online platform, 2) skill implementation, and 3) changes on outcome metrics over the 30-day study period.

Enrolled participants were onboarded by a trained research coordinator and provided 24/7 access to the platform over 30 days. At study onset and completion, caregivers completed assessments of care recipient dementia severity and neuropsychiatric symptoms along with instruments which measured dementia knowledge, caregiver burden, and carer experience.

Of 84 referrals, 60 caregivers met study inclusion criteria and 55 completed pre and post study measures. Caregivers completed an average of 8 hours of learning over the 30-day web-based intervention, with 84.4%of participants reporting using at least one skill they learned from the online platform. Eighty-nine percent of participants reported high satisfaction with the web-based educational intervention. There were small effect sizes for decreases in NPIQ neuropsychiatric symptom severity and caregiver distress scores from pre- to post-intervention. Small effect sizes were observed for changes in caregiver burden from pre- to post-intervention among caregivers who perceived their care recipient as having high global deterioration.

Findings show online educational programs are feasible for informal family caregivers of dementia and have perceived value. Future studies should address caregiver response to online education in less severe versus more severe care recipients, and explore the value of caregiver online platforms in diverse caregiver samples.

The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019).

Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation.

Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations.

AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression.

This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

Aerobic capacity is associated with metabolic, cardiovascular, and neurological health. Low-capacity runner (LCR) rats display low aerobic capacity, metabolic dysfuction, and spatial memory deficits. A heat treatment (HT) can improve metabolic dysfunction in LCR peripheral organs after high fat diet (HFD). Little is known about metabolic changes in the brains of these rats following HT.

Our objective was to examine the extent to which high or low aerobic capacity impacts Akt (a protein marker of metabolism) and heat shock protein 72 (HSP72, a marker of heat shock response) after HFD and HT in hippocampus.

We measured phosphorylated Akt (pAkt) in the striatum and hippocampus, and HSP72 in the hippocampus, of HFD-fed and chow-fed LCR and high-capacity runner (HCR) rats with and without HT.

pAkt was lower in the hippocampus of chow-fed LCR than HCR rats. HFD resulted in greater pAkt in LCR but not HCR rats, but HT resulted in lower pAkt in the LCR HFD group. HSP72 was greater in both HCR and LCR rat hippocampus after HT. The HFD blunted this effect in LCR compared to HCR hippocampus.

The abnormal phosphorylation of Akt and diminished HSP response in the hippocampus of young adult LCR rats might indicate early vulnerability to metabolic challenges in this key brain region associated with learning and memory.

Current understanding of amyloid-β protein (Aβ) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer’s disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides.

The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aβ_1–42 aggregating inhibition and Aβ clearance.

In the present study, in silico, in vitro, and in vivo studies were integrated for screening tri-peptides binding to Aβ, then evaluating its inhibition of aggregation of Aβ, and finally its rescuing cognitive deficit.

In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aβ_1–42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aβ_1–42 in vitro. In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aβ_1–42-induced cognitive deficit, reducing the Aβ_1–42 load and increasing the dendritic spines in the transgenic mouse model.

Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aβ_1–42 aggregation and treatment for Aβ-induced cognitive deficit.

Mobile Health (mHealth) apps can delay the cognitive decline of people with dementia (PwD), by providing both objective assessment and cognitive enhancement.

This patient involvement survey aims to explore human factors, needs and requirements of PwD, their caregivers, and Healthcare Professionals (HCPs) with respect to supportive and interactive mHealth apps, such as brain games, medication reminders, and geolocation trackers through a constructive questionnaire.

Following the principles of user-centered design to involve end-users in design we constructed a questionnaire, containing both open-ended and closed-ended questions as well as multiple choice and Likert scale, in order to investigate the specific requirements and preferences for mHealth apps. We recruited 48 participants including people with cognitive impairment (n = 15), caregivers (n = 16), and HCPs (n = 17) and administered the questionnaire.

All participants are likely to use mHealth apps, with the primary desired features being the improvement of memory and cognition, assistance on medication treatment, and perceived ease to use. HCPs, caregivers, and PwD consider brain games as an important technology-based, non-pharmaceutical intervention. Both caregivers and patients are willing to use a medication reminder app frequently. Finally, caregivers are worried about the patient wandering. Therefore, global positioning system tracking would be particularly important to them. On the other hand, patients are concerned about their privacy, but are still willing to use a geolocation app for cases of emergency.

This research contributes to mHealth app design and potential adoption. All three groups agree that mHealth services could facilitate care and ameliorate behavioral and cognitive disturbances of patients.

Behavioral disturbance (BD) is common in dementia patients, with no FDA approved medications for this condition. Little data exists on the real-world medication use in this population.

To describe real-world medications use in this population.

A cross-sectional study was conducted using the MarketScan database for outpatient medications and the Cerner database for inpatient medications. The study period was Oct 2015–Jun 2018. Patients with dementia and BD were identified through ICD-10-CM. We examined outpatient medications prescribed during 6-month before or after BD event date, and inpatient medications during inpatient visits, especially on central nervous systems (CNS) drugs including antidementia drugs, antidepressants, antipsychotics, anxiolytics, and anticonvulsants.

A total of 56,544 outpatients and 34,245 patient hospitalizations were assessed separately. Among outpatients, patients filled more medications after a BD event. The use of the five CNS drug classes generally increased after a BD event, and the largest increase was seen in antipsychotics (23%to 33%). Among inpatients, the median number of medications used in each hospitalization was 14. The use of antipsychotics was particularly high (64%), followed by anxiolytics (51%). A list of 60 unique medications were suggested to be the commonly used drugs in dementia patients with BD.

In dementia patients with BD, anti-dementia medications, antidepressants, anticonvulsants, hypnotics and antipsychotics were the most used drug classes. Antidepressants and antipsychotics use were more frequent after a BD event, which suggests a need for safe drugs targeting BD in dementia patients.

The multiple appearance phenotypes in Alzheimer’s disease (AD) are manifested in epidemiologic sexual dimorphism, variation in age of onset, progress, and severity of the disease.

In this study, we focused on sexual dimorphism, aiming to untie some of the complex interconnections in AD between sex, disease status, and gene expression profiles. Two strategic decisions guided our study: 1) to value transcriptomic multi-layered profiles over alterations in single genes expression; and 2) to embrace a sexual dimorphism centered approach, as we suspect that transcriptomic profiles may dramatically differ not only between healthy and sick individuals but between men and women as well.

Microarray dataset GSE15222, fulfilling our strict criteria, was retrieved from the GEO repository. We performed cluster analysis for each sex separately, comparing the proportion of healthy and AD individuals in each cluster.

We were able to identify a biased, female, AD-typified cluster. Furthermore, we showed that this female AD-typified cluster is highly similar to one of the male clusters. While the female cluster constitutes mostly sick individuals, the male cluster constitutes healthy and sick individuals in almost identical proportion.

Our results clearly indicate that similar transcriptomic profiles in the two sexes are “physiologically translated” in to a very different, dramatic outcome. Thus, our results suggest the need for a sex-based and transcriptomic profile-based study, for a better understanding of the onset and progression of AD.

Postmortem studies of brains with Alzheimer’s disease (AD) not only find amyloid-beta (Aβ) and neurofibrillary tangles (NFT) in the visual cortex, but also reveal temporally sequential changes in AD pathology from higher-order association areas to lower-order areas and then primary visual area (V1) with disease progression.

This study investigated the effect of AD severity on visual functional network.

Eight severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a resting-state fMRI (rs-fMRI) and a task fMRI of viewing face photos. A resting-state visual functional connectivity (FC) network and a face-evoked visual-processing network were identified for each group.

For the HS, the identified group-mean face-evoked visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, the resting-state visual FC network was mainly confined within the visual cortex. AD disrupted these two functional networks in a similar severity dependent manner: the more severe the cognitive impairment, the greater reduction in network connectivity. For the face-evoked visual-processing network, MAD disrupted and reduced activation mainly in the higher-order visual association areas, with SAD further disrupting and reducing activation in the lower-order areas.

These findings provide a functional corollary to the canonical view of the temporally sequential advancement of AD pathology through visual cortical areas. The association of the disruption of functional networks, especially the face-evoked visual-processing network, with AD severity suggests a potential predictor or biomarker of AD progression.

COVID-19 can be related to any diseases caused by microbial infection(s) because 1) co-infection with COVID-19-related virus and other microorganism(s) and 2) because metabolites produced by microorganisms such as bacteria, fungi, and protozoan can be involved in necrotizing pneumonia and other necrotizing medical conditions observed in COVID-19.

By way of illustration, the microbial metabolite of aromatic amino acid tryptophan, a biogenic amine tryptamine inducing neurodegeneration in cell and animal models, also induces necrosis.

This report includes analysis of COVID-19 positivity by zip codes in Florida and relation of the positivity to population density, possible effect of ecological and social factors on spread of COVID-19, autopsy analysis of COVID-19 cases from around the world, serum metabolomics analysis, and evaluation of autoantigenome related to COVID-19.

In the present estimations, COVID-19 positivity percent per zip code population varied in Florida from 4.65% to 44.3% (February 2021 data). COVID-19 analysis is partially included in my book Microbial Metabolism and Disease (2021). The autoantigenome related to COVID-19 is characterized by alterations in protein biosynthesis proteins including aminoacyl-tRNA synthetases. Protein biosynthesis alteration is a feature of Alzheimer’s disease. Serum metabolomics of COVID-19 positive patients show alteration in shikimate pathway metabolism, which is associated with the presence of Alzheimer’s disease-associated human gut bacteria.

Such alterations in microbial metabolism and protein biosynthesis can lead to toxicity and neurodegeneration as described earlier in my book Protein Biosynthesis Interference in Disease (2020).

Utilities of blood-based biomarkers in Alzheimer’s disease (AD) clinical trials remain unknown.

To evaluate the ability of plasma neurofilament light chain (NfL) to predict future declines in cognition and activities of daily living (ADL) outcomes in 26 older adults with mild-to-moderate AD dementia from the FIT-AD Trial.

Plasma NfL was measured at baseline and 3 and 6 months. Cognition and ADL were assessed using the AD Assessment Scale-Cognition (ADAS-Cog) and AD Uniform Dataset Instruments and Disability Assessment for Dementia (DAD), respectively, at baseline, 3, 6, 9, and 12 months. Linear mixed effects models were used to examine the associations between baseline or change in plasma NfL and changes in outcomes.

Higher baseline plasma NfL was associated with greater rate of decline in ADAS-Cog from baseline to 6 months (standardized estimate of 0.00462, p = 0.02853) and in ADL from baseline to 12 months (standardized estimate of –0.00284, p = 0.03338). Greater increase in plasma NfL in short term from baseline to 3 months was associated with greater rate of decline in memory and ADL from 3 to 6 months (standardized estimate of –0.04638 [0.003], p = 0.01635; standardized estimate of –0.03818, p = 0.0435) and greater rate of decline in ADL from 3 to 12 month (standardized estimate of –0.01492, p = 0.01082).

This study demonstrated that plasma NfL might have the potential to predict cognitive and function decline up to 12 months. However, future studies with bigger sample sizes need to confirm the findings.

Over- and potentially inappropriate prescribing of psychotropic medications is a major public health concern among people with dementia.

Describe the CHemical Restraints avOidance MEthodology (CHROME) criteria and evaluate its effects on psychotropic prescribing and quality of life (QoL).

Observational, prospective, two-wave study conducted in two nursing homes. A multicomponent program to eliminate chemical restraints and attain quality prescription of psychotropic medications was implemented. CHROME’s diagnostic criteria comprise constellations of behavioral and psychological symptoms of dementia under six primary syndromic diagnoses. Since pharmacologic treatment is aimed at only one syndrome, polypharmacy is avoided. Psychotropic prescription, QoL, neuropsychiatric symptoms (NPS), and other clinical measurements were collected before and one year after the intervention. Results are presented for all residents (n = 171) and for completer subjects (n = 115).

Mean age (SD) of the residents was 87.8 (5.7), 78.9% were women, and 68.5% suffered advanced dementia. Psychotropic prescriptions decreased from 1.9 (1.1) to 0.9 (1.0) (p < 0.0005). Substantive reduction in prescribing frequency was observed for antidepressants (76.9% pre-intervention, 33.8% post-intervention) and for atypical neuroleptics (38.8% pre-intervention, 15.1% post-intervention). There was improvement in patient’s response to surroundings (p < 0.0005) and total NPS (p < 0.01), but small worsening occurred in social interaction (p < 0.02, completer subjects). Safety measurements remained stable.

CHROME criteria appear to optimize psychotropic prescriptions, avoid chemical restraints, and allow external verification of quality prescriptions. Extensive use seems feasible, related to substantial reduction of prescriptions, and of benefit for people with dementia as de-prescriptions are not associated to increased NPS or QoL loss.

The study of reaction time (RT) and its intraindividual variability (IIV) in aging, cognitive impairment, and dementia typically fails to investigate the processing stages that contribute to an overall response. Applying “mental chronometry” techniques makes it possible to separately assess the role of processing components during environmental interaction.

To determine whether RT and IIV-decomposition techniques can shed light on the nature of underlying deficits in subcortical ischemic vascular cognitive impairment (VCI). Using a novel iPad task, we examined whether VCI deficits occur during both initiation and movement phases of a response, and whether they are equally reflected in both RT and IIV.

Touch cancellation RT and its IIV were measured in a group of younger adults (n = 22), cognitively healthy older adults (n = 21), and patients with VCI (n = 21) using an iPad task.

Whereas cognitively healthy aging affected the speed (RT) of response initiation and movement but not its variability (IIV), VCI resulted in both slowed RT and increased IIV for both response phases. Furthermore, there were group differences with respect to response phase.

These results indicate that IIV can be more sensitive than absolute RT in separating VCI from normal aging. Furthermore, compared to cognitively healthy aging, VCI was characterized by significant deficits in planning/initiating action as well as performing movements. Such deficits have important implications for real life actions such as driving safety, employment, and falls risk.

Therapeutic research into Alzheimer’s disease (AD) has been dominated by the amyloid cascade hypothesis (ACH) since the 1990s. However, targeting amyloid in AD patients has not yet resulted in highly significant disease-modifying effects. Furthermore, other promising theories of AD etiology exist.

We sought to directly investigate whether the ACH still dominates the opinions of researchers working on AD and explore the implications of this question for future directions of research.

During 2019, we undertook an international survey promoted with the help of the Alzheimer’s Association with questions on theories and treatments of AD. Further efforts to promote a similar study in 2021 did not recruit a significant number of participants.

173 researchers took part in the 2019 survey, 22% of which held “pro-ACH” opinions, tended to have more publications, were more likely to be male, and over 60. Thus, pro-ACH may now be a minority opinion in the field but is nevertheless the hypothesis on which the most clinical trials are based, suggestive of a representation bias. Popular vote of all 173 participants suggested that lifestyle treatments and anti-tau drugs were a source of more therapeutic optimism than anti-amyloid treatments.

We propose a more democratic research structure which increases the likelihood that promising theories are published and funded fairly, promotes a broader scientific view of AD, and reduces the larger community’s dependence on a fragile economic model.

Neuroinflammation is a recognized aspect of Alzheimer’s disease (AD) and other neurological illnesses. Interleukin 1 receptor antagonist (IL-1Ra) is an anti-inflammatory molecule, which inhibits inflammatory molecules in different cells including brain cells. However, mechanisms for upregulating IL-1Ra in brain cells are poorly understood.

Since aspirin is a widely available pain reliever that shows promise beyond its known pain-relieving capacity, we examined whether aspirin could upregulate the IL-1Ra in the brain.

We employed PCR, real-time PCR, western blot, immunostaining, chromatin immunoprecipitation (ChIP), and lentiviral transduction in glial cells. 5xFAD mice, an animal model of AD, were treated with aspirin orally via gavage.

Aspirin increased the expression of IL-1Ra mRNA and protein in primary mouse astrocytes and mouse BV-2 microglial cells. While investigating the mechanism, we found that the IL-1Ra gene promoter harbors peroxisome proliferator response element (PPRE) and that aspirin upregulated IL-1Ra in astrocytes isolated from peroxisome proliferator-activated receptor-beta knockout (PPARβ^–/–), but not PPARα^–/–, mice. Moreover, we observed that aspirin bound to tyrosine 314 residue of PPARα to stimulate IL-1Ra and that aspirin treatment also increased the recruitment of PPARα to the IL-1Ra promoter. Accordingly, aspirin increased IL-1Ra in vivo in the brain of wild type and PPARβ^–/–, but not in PPARα^–/– mice. Similarly, aspirin treatment also increased astroglial and microglial IL-1Ra in the cortex of 5xFAD, but not 5xFAD/PPARα^–/– mice.

Aspirin may reduce the severity of different neurological conditions by upregulating IL-1Ra and reducing the inflammation.

Dementia is a major global health problem and the search for improved therapies is ongoing. The study of young onset dementia (YOD)—with onset prior to 65 years—represents a challenge owing to the variety of clinical presentations, pathology, and gene mutations. The advantage of the investigation of YOD is the lack of comorbidities that complicate the clinical picture in older adults. Here we explore the origins of YOD.

To define the clinical diversity of YOD in terms of its demography, range of presentations, neurological examination findings, comorbidities, medical history, cognitive findings, imaging abnormalities both structural and functional, electroencephagraphic (EEG) data, neuropathology, and genetics.

A prospective 20-year study of 240 community-based patients referred to specialty neurology clinics established to elucidate the nature of YOD.

Alzheimer’s disease (AD; n = 139) and behavioral variant frontotemporal (bvFTD; n = 58) were the most common causes with a mean age of onset of 56.5 years for AD (±1 SD 5.45) and 57.1 years for bvFTD (±1 SD 5.66). Neuropathology showed a variety of diagnoses from multiple sclerosis, Lewy body disease, FTD-MND, TDP-43 proteinopathy, adult-onset leukoencephalopathy with axonal steroids and pigmented glia, corticobasal degeneration, unexplained small vessel disease, and autoimmune T-cell encephalitis. Non-amnestic forms of AD and alternative forms of FTD were discovered. Mutations were only found in 11 subjects (11/240 = 4.6%). APOE genotyping was not divergent between the two populations.

There are multiple kinds of YOD, and most are sporadic. These observations point to their stochastic origins.

Communication difficulties are one of the primary symptoms associated with dementia, and mobile applications have shown promise as tools for facilitating communication in patients with dementia (PwD). The literature regarding mobile health (mHealth) applications, especially communications-based mHealth applications, is limited.

This review aims to compile the existing literature on communications-based mobile applications regarding dementia and assess their opportunities and limitations. A PICO framework was applied with a Population consisting of PwD, Interventions consisting of communication technology, focusing primarily on mobile applications, Comparisons between patient well-being with and without technological intervention, and Outcomes that vary but can include usability of technology, quality of communication, and user acceptance.

Searches of PubMed, IEEE XPLORE, and ACM Digital Library databases were conducted to establish a comprehensive understanding of the current literature on dementia care as related to 1) mobile applications, 2) communication technology, and 3) communications-based mobile applications. Applying certain inclusion and exclusion criteria, yielded a set of articles (n = 11).

The literature suggests that mobile applications as tools for facilitating communication in PwD are promising. Mobile applications are not only feasible socially, logistically, and financially, but also produce meaningful communication improvements in PwD and their caregivers. However, the number of satisfactory communications-based mobile applications in the mHealth marketplace and their usability is still insufficient.

Despite favorable outcomes, more research involving PwD using these applications are imperative to shed further light on their communication needs and on the role of mHealth.

As the sixth-leading cause of death in the United States, Alzheimer’s disease (AD) entails deteriorating endothelial control of blood flow throughout the brain. In particular, reduced inward-rectifying K⁺ (K_IR) channel function in animal models of aging and AD compromises endothelial function and optimal perfusion of brain parenchyma. Deficient endothelial K_IR channels may result from aberrant interaction with plasma membrane cholesterol as a primary regulator of membrane fluidity and ion channels.

We tested the hypothesis that mild methyl-β-cyclodextrin (MβCD) treatment to reduce membrane cholesterol may restore endothelial K_IR channel function in brain endothelium of old AD mice.

Membrane potential was continuously measured in isolated endothelial tubes from posterior cerebral arteries of young (1 to 3 months) and old (16 to 19 months) female 3xTg-AD mice before and after mild treatment with the cholesterol-removing agent MβCD (1 mmol/L). Elevated extracellular potassium ([K⁺]_E; 15 mmol/L) and NS309 (1μmol/L) activated K_IR and Ca²⁺-activated K⁺ (SK_Ca/IK_Ca) channels respectively before and after MβCD treatment.

SK_Ca/IK_Ca channel function for producing hyperpolarization remained stable regardless of age group and MβCD treatment (ΔV_m: ∼–33 mV). However, as deficient during AD, K_IR channel function was restored (ΔV_m: –9±1 mV) versus pre-MβCD conditions (–5±1 mV); a progressive effect that reached –14±1 mV hyperpolarization at 60 min following MβCD washout.

In female animals, MβCD treatment of brain endothelium selectively restores K_IR versus SK_Ca/IK_Ca channel function during AD. Thus, the endothelial cholesterol-K_IR channel interface is a novel target for ameliorating perfusion of the AD brain.

Pharmacological treatment of Alzheimer’s disease (AD) involves symptomatic improvement of cognition using cholinesterase inhibitors (ChEIs) and memantine. The cost-effectiveness of these medications will guide decision-makers in making judicious use of scarce healthcare resources, particularly during the advanced disease stages.

To evaluate the cost-effectiveness of ChEIs, memantine, and ChEI-memantine combinations in persons with moderate-to-severe AD from the US healthcare perspective.

This pharmacoeconomic evaluation study used a state-transition Markov cohort model to simulate the costs and effectiveness of ChEI-memantine combinations compared with monotherapies of ChEI (donepezil, galantamine and rivastigmine) and memantine in persons with moderate-to-severe AD over a lifetime horizon with a 1-year cycle length. We estimated expected quality-adjusted life-years (QALYs), costs (in 2020 $US), net monetary benefits, and incremental cost-effectiveness ratios (ICERs). We discounted future costs and QALYs at the rate of 3%.

In this study, donepezil monotherapy, galantamine-memantine combination, and rivastigmine transdermal patch formed the cost-effectiveness frontier. Findings suggests that rivastigmine transdermal patch is the optimal treatment strategy at a willingness-to-pay (WTP) threshold of $150,000/QALY (ICER = $93,307/QALY [versus donepezil monotherapy]). Results across subgroups by age and sex also suggest that the rivastigmine transdermal patch is the optimal treatment strategy with the highest net benefit.

From the US healthcare perspective, we found that, for persons with moderate-to-severe AD at a WTP threshold of $150,000/QALY, the rivastigmine transdermal patch is the most cost-effective pharmacological treatment option. Given that the transdermal patch is a preferred route of administration for persons with AD and their caregivers due to its convenience, our findings provide additional incentives for its use.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that accounts for more than 50% of all dementia cases worldwide. There is wide consensus on the risk factors of AD; however, a clear etiology remains unknown. Evidence suggests that the inflammatory-mediated disease model, such as that found with periodontal disease due to Porphyromonas gingivalis (P. gingivalis), plays a role in AD progression.

This study aims to systematically review the literature on the association between P. gingivalis to AD, and to identify the homogeneity of the methods used across studies to measure P. gingivalis involvement in AD.

We systematically searched studies on Cochrane library, Ovid Medline, PubMed, Web of Science, WHOLIS, Google Scholar databases, and reference lists of identified studies.

6 studies out of 636 identified records fulfilled all eligibility criteria. Results showed no clear pathophysiology of AD due to P. gingivalis and its various virulence factors. No consensus was found in the literature pertaining to the method of measurement of AD or P. gingivalis and its virulence factors.

The included studies suggest that P. gingivalis bacteria play a role in the process of systemic inflammation which leads to cerebrospinal fluid inflammation and indirectly cause hastening of AD onset and progression. Our included studies revealed heterogeneity in the methodologies of measurement of AD and/or P. gingivalis and its virulence factors, which opens discussion about the benefits and weakness of possible standardization.

Although caregiver burden is common among carers of people with dementia, little is known about its prevalence and predictors among caregivers of patients attending memory clinics.

To examine carer and patient-specific characteristics associated with caregiver burden across the cognitive spectrum in a memory clinic population.

Consecutive patients referred to a university hospital geriatric memory clinic were included. Caregiver burden was scored using the Caregiver Burden Score (CBS), (modified Zarit), with scores≥15/30 suggesting burden. BPSD were measured with the dysfunctional behaviour rating instrument (DBRI). Cognition was screened using the Montreal Cognitive Assessment (MoCA) and Quick Mild Cognitive Impairment (Qmci) screen.

In all, 351 patients were included, median age 77 (±11) years; 65.5% were female. The prevalence of caregiver burden was 33.6% overall, increasing from 10.8% in subjective cognitive decline (SCD), to 15% in mild cognitive impairment (MCI) and 43% in dementia; CBS scores were significantly higher in dementia (p < 0.001). Caregivers with burden were significantly younger (p = 0.045) and were more likely to be adult children (p = 0.007). The CBS weakly correlated with the stage of cognitive impairment (r = 0.16) but had moderate correlation with MoCA (r = –0.54) and Qmci scores (r = –0.60). After adjustment for co-variates, DBRI scores alone independently predicted burden (odds ratio 1.23;1.11–1.35, p < 0.001).

Caregiver burden is associated with the stage of cognitive impairment, with higher prevalence proportions in those with dementia compared with MCI and SCD. Only the severity of neuropsychiatric symptoms independently predicted caregiver burden in this population and its presence should prompt assessment for burden.

Canine cognitive dysfunction (CCD) is a progressive syndrome recognized in mature to aged dogs with a variety of neuropathological changes similar to human Alzheimer’s disease (AD), for which it is thought to be a good natural model. However, the presence of hyperphosphorylated tau protein (p-Tau) in dogs with CCD has only been demonstrated infrequently.

The aim of the present study was to investigate the presence of p-Tau and amyloid-β oligomer (Aβo) in cerebral cortex and hippocampus of dogs with CCD, with focus on an epitope retrieval protocol to unmask p-Tau.

Immunohistochemical and immunofluorescence analysis of the cortical and hippocampal regions of five CCD-affected and two nondemented aged dogs using 4G8 anti-Aβp, anti-Aβ_1 - 42 nanobody (PrioAD13) and AT8 anti-p-Tau (Ser202, Thr205) antibody were used to demonstrate the presence of Aβ plaques (Aβp) and Aβ_1 - 42 oligomers and p-Tau deposits, respectively.

The extracellular Aβ senile plaques were of the diffuse type which lack the dense core normally seen in human AD. While p-Tau deposits displayed a widespread pattern and closely resembled the typical human neuropathology, they did not co-localize with the Aβp. Of considerable interest, however, widespread intraneuronal deposition of Aβ_1 - 42 oligomers were exhibited in the frontal cortex and hippocampal region that co-localized with p-Tau.

Taken together, these findings reveal further shared neuropathologic features of AD and CCD, supporting the case that aged dogs afflicted with CCD offer a relevant model for investigating human AD.

In Alzheimer’s disease (AD), cognitive impairment begins 10–15 years later than neurodegeneration in the brain. Plasma biomarkers are promising candidates for assessing neurodegeneration in people with normal cognition. It has been reported that subjects with the concentration of plasma amyloid-β 1-42×total tau protein higher than 455 pg²/ml² are assessed as having a high risk of amnesic mild impairment or AD, denoted as high risk of AD (HRAD).

The prevalence of high-risk for dementia in cognitively normal controls is explored by assaying plasma biomarkers.

422 subjects with normal cognition were enrolled around Taiwan. Plasma Aβ_1-40, Aβ_1-42, and T-Tau levels were assayed using immunomagnetic reduction to assess the risk of dementia.

The results showed that 4.6% of young adults (age: 20–44 years), 8.5% of middle-aged adults (age: 45–64 years), and 7.3% of elderly adults (age: 65–90 years) had HRAD. The percentage of individuals with HRAD dramatically increased in middle-aged and elderly adults compared to young adults.

The percentage of HRAD in cognitively normal subjects are approximately 10%, which reveals that the potentially public-health problem of AD in normal population. Although the subject having abnormal levels of Aβ or tau is not definitely going on to develop cognitive declines or AD, the risk of suffering cognitive impairment in future is relatively high. Suitable managements are suggested for these high-risk cognitively normal population. Worth noting, attention should be paid to preventing cognitive impairment due to AD, not only in elderly adults but also middle-aged adults.

The total number of people with dementia is projected to reach 82 million in 2030 and 152 in 2050. Early and accurate identification of the underlying causes of dementia, such as Alzheimer’s disease (AD) is of utmost importance. A large body of research has shown that imaging techniques are most promising technologies to improve subclinical and early diagnosis of dementia. Morphological changes, especially atrophy in various structures like cingulate gyri, caudate nucleus, hippocampus, frontotemporal lobe, etc., have been established as markers for AD. Being the largest white matter structure with a high demand of blood supply from several main arterial systems, anatomical alterations of the corpus callosum (CC) may serve as potential indication neurodegenerative disease.

To detect mild and moderate AD using brain magnetic resonance image (MRI) processing and machine learning techniques.

We have performed automatic detection and segmentation of the CC and calculated its morphological features to feed into a multivariate pattern analysis using support vector machine (SVM) learning techniques.

Our results using large patients’ cohort show CC atrophy-based features are capable of distinguishing healthy and mild/moderate AD patients. Our classifiers obtain more than 90%sensitivity and specificity in differentiating demented patients from healthy cohorts and importantly, achieved more than 90%sensitivity and > 80%specificity in detecting mild AD patients.

Results from this analysis are encouraging and advocate development of an image analysis software package to detect dementia from brain MRI using morphological alterations of the CC.

Alzheimer’s disease (AD) is a significant burden on patients and caregivers. How this burden increases as disease progresses has not been well researched.

To assess the association of caregiver burden and quality of life with Alzheimer’s disease severity and disease progression in community-dwelling patients in Germany, Spain, and the UK.

This was a prospective observational longitudinal study of mild-to-moderate AD patients (assessed by Mini-Mental State Examination, MMSE), and their caregivers. The humanistic burden was assessed using these instruments: [Rapid Assessment of Physical Activity (RAPA), EuroQoL-5-Dimension Level (EQ-5D-5L)] and caregiver-reported [Dependence Scale (DS), EQ-5D-5L, Zarit Burden Interview (ZBI)]. Caregiver-reported healthcare resource use was assessed using the Resource Use in Dementia (RUD) and ad-hoc questions.

Of 616 patients recruited, 338 and 99 were followed-up at 12 and 18 months, respectively. The caregiver-reported EQ-5D-5L scores of patients’ health-related quality of life (HRQoL) showed a negative trend over time (baseline: 0.76; 18 months: 0.67) while patient-reported HRQoL remained at 0.85. DS scores tended to worsen. Disease progression was an independent predictor of HRQoL and increased dependence.

Mean ZBI score increased over time reflecting an increase in caregiver burden; MMSE being an independent predictor for caregiver burden. Patient resource utilization and caregiver time for caregiving tended to increase over time.

We found significant association between disease progression and caregiver and patient burden. Independently, both disease-specific outcomes and disease burden measures increased over time, but as disease progresses, we also found incremental burden associated with it.

micro-RNAs (miRNAs) are stable, small, non-coding RNAs enriched in exosomes. Their variation in levels according to different disease etiologies have made them a promising diagnostic biomarker for neurodegenerative diseases such as Alzheimer’s disease (AD). Altered expression of miR-320a, miR-328-3p, and miR-204-5p have been reported in AD and frontotemporal dementia (FTD).

To determine their reliability, we aimed to examine the expression of three exosomal miRNAs isolated from cerebrospinal fluid (CSF) of patients with young-onset AD and FTD (< 65 years), correlating with core AD biomarkers and cognitive scores.

Exosomes were first isolated from CSF samples of 48 subjects (8 controls, 28 AD, and 12 FTD), followed by RNA extraction and quantitative PCR to measure the expression of miR-320a, miR-328-3p, and miR-204-5p.

Expression of all three markers (miR-320a (p = 0.005), miR-328-3p (p = 0.049), and miR-204-5p (p = 0.036)) were significantly lower in AD versus controls. miR-320a was reduced in FTD versus controls (p = 0.049) and miR-328-3p was lower in AD versus FTD (p = 0.054). Notably, lower miR-328-3p levels could differentiate AD from FTD and controls with an AUC of 0.702, 95% CI: 0.534– 0.870, and showed significant correlation with lower CSF Aβ₄₂ levels (r = 0.359, p = 0.029). Pathway enrichment analysis identified potential targets of miR-328-3p implicated in the AMPK signaling pathway linked to amyloid-β and tau metabolism in AD.

Overall, we demonstrated miR-320a and miR-204-5p as reliable biomarkers for AD and FTD and report miR-328-3p as a novel AD biomarker.

The study involved a female patient diagnosed with late-stage dementia, with chronic daytime somnolence (CDS) as a prominent symptom.

To explore whether her dementia resulted from Type 3 diabetes, and whether it could be reversed through ketosis therapy.

A ketogenic diet (KD) generating low-dose 100 μM Blood Ketone Levels (BKL) enhanced by a brief Ketone Mono Ester (KME) regimen with high-dose 2–4 mM BKLs was used.

Three sets of data describe relief (assessed by % days awake) from CDS: 1) incremental, slow, time-dependent KD plus KME-induced sigmoid curve responses which resulted in partial wakefulness (0–40% in 255 days) and complete wakefulness (40–85% in 50 days); 2) both levels of wakefulness were shown to be permanent; 3) initial permanent relief from CDS with low-dose ketosis from 6.7% to 40% took 87 days. Subsequent low-dose recovery from illness-induced CDS (6.9% to 40%) took 10 days. We deduce that the first restoration involved permanent repair, and the second energized the repaired circuits.

The results suggest a role for ketosis in the elimination of CDS with the permanent functional restoration of the awake neural circuits of the Sleep-Wake cycle. We discuss whether available evidence supports ketosis-induced bioenergetics alone or whether other mechanisms of functional renewal were the basis for the elimination of CDS. Given evidence for permanent repair, two direct links between ketosis and neurogenesis in the adult mammalian brain are discussed: Ketosis-induced 1) brain-derived neurotrophic factor, resulting in neural progenitor/stem cell proliferation, and 2) mitochondrial bioenergetics-induced stem cell biogenesis.

Behavioral and psychological symptoms of dementia (BPSD) exhibited by persons with dementia (PwD) in nursing home communal areas are generally managed by segregation and/or pharmacological interventions.

This study trialed MindfulGarden (MG), a novel digital calming device, in a Canadian nursing home.

Participants were 15 PwD (mean age = 87.67; 5m,10f; mean MMSE = 11.64±7.85). Each was observed by a research assistant (RA) for an average of 8–10 hours on two separate days. The RA followed them during time spent in communal areas of the nursing home including their unit’s dining space, lounges, and corridors and spaces shared with other units (e.g., gym and gift shop) and documented any BPSD exhibited. Day-1 provided baseline data; on Day-2, residents were exposed to MG if nursing staff considered their BPSD were sufficiently intense or sustained to warrant intervention. Staff rated the impact as positive, neutral, or negative.

On Day-1, 9 participants exhibited both aggressive and non-aggressive behaviors, 4 non-aggressive behaviors only, and 2 no BPSD. On Day-2, 7 exhibiting aggressive behaviors were exposed to MG. Staff reported MG as having distracting/calming effects and gave positive impact ratings to 6/13 exposures; there were no negative ratings. The most common aggressive BPSD on days of observation were pushing/shoving and screaming.

MG may have value as a “psychiatric crash cart” in de-escalating agitation and aggression in care home settings.

Tauopathies are a group of neurodegenerative diseases associated with the accumulation of misfolded tau protein. The mechanisms underpinning tau-dependent proteinopathy remain to be elucidated. A protein quality control pathway within the endoplasmic reticulum, the unfolded protein response (UPR), has been suggested as a possible pathway modulating cellular responses in a range of neurodegenerative diseases, including those associated with misfolded cytosolic tau.

In this study we investigated three different clinically defined tauopathies to establish whether these diseases are accompanied by the activation of UPR.

We used PCR and western blotting to probe for the modulation of several reliable UPR markers in mRNA and proteins extracted from three distinct tauopathies: 20 brain samples from Alzheimer’s disease patients, 11 from Pick’s disease, and 10 from progressive supranuclear palsy. In each disease samples from these patients were compared with equal numbers of age-matched non-demented controls.

Our investigation showed that different markers of UPR are not changed at the late stage of any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls.

These data from late-stage human cortical tissue report an activation of UPR markers within the aged brain across all cohorts investigated and further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a disease-associated activation of UPR.

Guidelines worldwide recommend restricted prescription of benzodiazepine receptor agonists (BZRAs), i.e., benzodiazepines and Z-drugs, for the treatment of dementia-associated behavioral and psychological symptoms and insomnia.

To assess the prevalence and appropriateness of BZRA use among nursing home residents with dementia.

This is a post-hoc analysis of BZRA prescriptions from two intervention studies on psychotropic drug use, conducted from 2016 to 2018. It includes 1,111 residents of dementia special care units from 24 Dutch long-term care organizations. We assessed the prevalence of use of continuous and as-needed BZRA prescriptions and their association with registered symptoms. Continuous BZRA prescriptions were evaluated for appropriateness, i.e., whether indication, dosage, duration, and evaluation accorded with guidelines for the treatment of challenging behavior in dementia and sleep disorders.

The prevalence of BZRA use is 39.2% (95% CI: 36.3%–42.0%): continuous 22.9%; only as-needed 16.3%. Combinations of preferred BZRAs and appropriate indications occur in 19.0% of continuous anxiolytic prescriptions and 44.8% of hypnotic prescriptions. Frequently registered inappropriate indications are aggression/agitation for anxiolytics (continuous: 75.7%; as-needed: 75.2%) and nighttime agitation for hypnotics (continuous: 40.3%; as-needed: 26.7%). None of the continuous prescriptions with appropriate indications were appropriate for all other items. For most of the prescriptions, duration and time to evaluation exceeded 4 weeks.

BZRA use in nursing home residents with dementia is highly frequent. A large proportion of prescriptions do not follow the guidelines with regard to indication, exceed the recommended duration and are not evaluated in a timely manner. The discrepancy between evidence-based guidelines and daily practice calls for an exploration of factors maintaining inappropriate use.

The role of neuroinflammation has become more evident in the pathogenesis of neurodegenerative diseases. Increased expression of microglial markers is widely reported in Alzheimer’s disease (AD), but much less is known about the role of monocytes in AD pathogenesis. In AD animal models, bone marrow-derived monocytes appear to infiltrate the parenchyma and contribute to the phagocytosis of amyloid-β depositions, but this infiltration has not been established in systematic studies of the human brain postmortem.

In addition to assessing the distribution of different subtypes of microglia by immunostaining for CD68, HLA-DR, CD163, and CD206, we focused on the involvement of C-chemokine receptor type2 (CCR2) positive monocytes during the AD course.

We used formalin-fixed and paraffin-embedded tissue from four vulnerable brain regions (hippocampus, occipital lobe, brainstem, and cerebellum) from neuropathologically characterized AD cases at different Braak stages and age-matched controls.

Only singular migrated CCR2-positive cells were found in all brain regions and stages. The brainstem showed the highest number of positive cells overall, followed by the hippocampus. This mechanism of recruitment seems to work less efficiently in the human brain at an advanced age, and the ingress of monocytes obviously takes place in much reduced numbers or not at all.

In contrast to studies on animal models, we observed only a quite low level of myeloid monocytes associated with AD pathology. Furthermore, we provide evidence associating early microglial reactions carried out in particular by pro-inflammatory cells with early effects on tangle- and plaque-positive vulnerable brain regions.