Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease.

BACKGROUND AND PURPOSE: A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. METHODS: Thirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). RESULTS: Statistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = -0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. CONCLUSION: This cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline.

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants. Using this information, polygenic risk scores (PRSs) can be calculated to quantify an individual's relative disease risk due to genetic factors. The Amish are a founder population descended from German and Swiss Anabaptist immigrants. They experienced a genetic bottleneck after arrival in the United States, making their genetic architecture different from the broader European ancestry population. Prior work has demonstrated the lack of transferability of PRSs across populations. Here, we compared the performance of PRSs derived from genome-wide association studies (GWASs) of Amish individuals to those derived from a large European ancestry GWAS. Participants were screened for cognitive impairment with further evaluation for AD. Genotype data were imputed after collection via Illumina genotyping arrays. The Amish individuals were split into two groups based on the primary site of recruitment. For each group, GWAS was conducted with account for relatedness and adjustment for covariates. PRSs were then calculated using weights from the other Amish group. PRS models were evaluated with and without covariates. The Amish-derived PRSs distinguished between dementia status better than the European-derived PRS in our Amish populations and demonstrated performance improvements despite a smaller training sample size. This work highlighted considerations for AD PRS usage in populations that cannot be adequately described by basic race/ethnicity or ancestry classifications.

Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.

Visuospatial and Verbal Memory Differences in Amish Individuals With Alzheimer Disease and Related Dementias.

BACKGROUND: Verbal and visuospatial memory impairments are common to Alzheimer disease and Related Dementias (ADRD), but the patterns of decline in these domains may reflect genetic and lifestyle influences. The latter may be pertinent to populations such as the Amish who have unique lifestyle experiences. METHODS: Our data set included 420 Amish and 401 CERAD individuals. Sex-adjusted, age-adjusted, and education-adjusted Z-scores were calculated for the recall portions of the Constructional Praxis Delay (CPD) and Word List Delay (WLD). ANOVAs were then used to examine the main and interaction effects of cohort (Amish, CERAD), cognitive status (case, control), and sex on CPD and WLD Z-scores. RESULTS: The Amish performed better on the CPD than the CERAD cohort. In addition, the difference between cases and controls on the CPD and WLD were smaller in the Amish and Amish female cases performed better on the WLD than the CERAD female cases. DISCUSSION: The Amish performed better on the CPD task, and ADRD-related declines in CPD and WLD were less severe in the Amish. In addition, Amish females with ADRD may have preferential preservation of WLD. This study provides evidence that the Amish exhibit distinct patterns of verbal and visuospatial memory loss associated with aging and ADRD.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial.

OBJECTIVE: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. DESIGN: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. SETTING: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. PARTICIPANTS: Alzheimer's disease patients with clinically significant apathy. MEASUREMENTS: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). RESULTS: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. CONCLUSION: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.

Computerized Block Games for Automated Cognitive Assessment: Development and Evaluation Study.

BACKGROUND: Cognitive assessment using tangible objects can measure fine motor and hand-eye coordination skills along with other cognitive domains. Administering such tests is often expensive, labor-intensive, and error prone owing to manual recording and potential subjectivity. Automating the administration and scoring processes can address these difficulties while reducing time and cost. e-Cube is a new vision-based, computerized cognitive assessment tool that integrates computational measures of play complexity and item generators to enable automated and adaptive testing. The e-Cube games use a set of cubes, and the system tracks the movements and locations of these cubes as manipulated by the player. OBJECTIVE: The primary objectives of the study were to validate the play complexity measures that form the basis of developing the adaptive assessment system and evaluate the preliminary utility and usability of the e-Cube system as an automated cognitive assessment tool. METHODS: This study used 6 e-Cube games, namely, Assembly, Shape-Matching, Sequence-Memory, Spatial-Memory, Path-Tracking, and Maze, each targeting different cognitive domains. In total, 2 versions of the games, the fixed version with predetermined sets of items and the adaptive version using the autonomous item generators, were prepared for comparative evaluation. Enrolled participants (N=80; aged 18-60 years) were divided into 2 groups: 48% (38/80) of the participants in the fixed group and 52% (42/80) in the adaptive group. Each was administered the 6 e-Cube games; 3 subtests of the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV; Block Design, Digit Span, and Matrix Reasoning); and the System Usability Scale (SUS). Statistical analyses at the 95% significance level were applied. RESULTS: The play complexity values were correlated with the performance indicators (ie, correctness and completion time). The adaptive e-Cube games were correlated with the WAIS-IV subtests (r=0.49, 95% CI 0.21-0.70; P<.001 for Assembly and Block Design; r=0.34, 95% CI 0.03-0.59; P=.03 for Shape-Matching and Matrix Reasoning; r=0.51, 95% CI 0.24-0.72; P<.001 for Spatial-Memory and Digit Span; r=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Block Design; and r=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Matrix Reasoning). The fixed version showed weaker correlations with the WAIS-IV subtests. The e-Cube system showed a low false detection rate (6/5990, 0.1%) and was determined to be usable, with an average SUS score of 86.01 (SD 8.75). CONCLUSIONS: The correlations between the play complexity values and performance indicators supported the validity of the play complexity measures. Correlations between the adaptive e-Cube games and the WAIS-IV subtests demonstrated the potential utility of the e-Cube games for cognitive assessment, but a further validation study is needed to confirm this. The low false detection rate and high SUS scores indicated that e-Cube is technically reliable and usable.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

BACKGROUND: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. METHODS: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. RESULTS: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). DISCUSSION: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Psychometric approaches to defining cognitive phenotypes in the Old Order Amish.

OBJECTIVE: Memory and cognitive problems are central to the diagnosis of Alzheimer's disease (AD). Psychometric approaches to defining phenotypes can aid in identify genetic variants associated with AD. However, these approaches have mostly been limited to affected individuals. Defining phenotypes of both affected and unaffected individuals may help identify genetic variants associated with both AD and healthy aging. This study compares psychometric methods for developing cognitive phenotypes that are more granular than clinical classifications. METHODS: 682 older Old Order Amish individuals were included in the analysis. Adjusted Z-scores of cognitive tests were used to create four models including (1) global threshold scores or (2) memory threshold scores, and (3) global clusters and (4) memory clusters. An ordinal regression examined the coherence of the models with clinical classifications (cognitively impaired [CI], mildly impaired [MI], cognitively unimpaired), APOE-e4, sex, and age. An ANOVA examined the best model phenotypes for differences in clinical classification, APOE-e4, domain Z-scores (memory, language, executive function, and processing speed), sex, and age. RESULTS: The memory cluster identified four phenotypes and had the best fit (χ2  = 491.66). Individuals in the worse performing phenotypes were more likely to be classified as CI or MI and to have APOE-e4. Additionally, all four phenotypes performed significantly differently from one another on the domains of memory, language, and executive functioning. CONCLUSIONS: Memory cluster stratification identified the cognitive phenotypes that best aligned with clinical classifications, APOE-e4, and cognitive performance We predict these phenotypes will prove useful in searching for protective genetic variants.

Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets.

INTRODUCTION: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI. METHODS: A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed-effects models examined association between age and single nucleotide variants (SNVs). RESULTS: Three SNVs were significantly associated (P < 5 × 10-8 ) with AAO on chromosomes 6 (rs14538074; hazard ratio [HR] = 3.35), 9 (rs534551495; HR = 2.82), and 17 (rs146729640; HR = 6.38). The chromosome 17 association was replicated in the independent National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease dataset. DISCUSSION: The replicated genome-wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease.

Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2.

INTRODUCTION: Alzheimer disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age. METHODS: Genome-wide association and linkage analyses were performed on 946 examined and sampled Amish individuals, aged 76-95, who were either cognitively unimpaired (CU) or impaired (CI). RESULTS: 12 SNPs demonstrated suggestive association (P≤5×10-4) with cognitive preservation. Genetic linkage analyses identified >100 significant (LOD≥3.3) SNPs, some which overlapped with the association results. Only one locus on chromosome 2 retained significance across multiple analyses. DISCUSSION: A novel significant result for cognitive preservation on chromosome 2 includes the genes LRRTM4 and CTNNA2. Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulates LRRTM4 and CTNNA2.

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease.

BACKGROUND: Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer's disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects.  METHODS: This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. RESULTS: In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. CONCLUSIONS: Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug's effects on AD biomarkers and clinical symptomatology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03706885.

Biocomponents Based on Hydroxiapatite: Influence of Sterilization on the Mechanical Resistance.

Objective This study aimed to evaluate the influence of sterilization on the compressive and flexural mechanical strength of hydroxyapatite-based biocomponents obtained through freeze-dried bovine bone, and its association with chitosan. Methods Freeze-dried bovine bone was processed into 100 µm particles and mixed with 50% of its weight in chitosan. The mixture was packed in metallic molds for preparing the specimens, and sterilized at 127°C using an autoclave for subsequent experimentation. The specimens were subjected to compression and flexion tests following norm 5833 of the International Organization for Standardization (ISO), with 6 × 12 mm cylindrical blocks (for compression tests) and 75 × 10 × 3.3 mm plates (for flexion tests) as samples. The samples were divided into four groups of 20 specimens each, with 10 for compression and 10 for flexion tests. Three groups were sterilized (autoclave, gamma rays, and ethylene oxide), whereas the fourth group (control) was not. The mechanical tests obtained from the different sterilization processes were compared using analysis of variance (ANOVA, p < 0.05), followed by the Tukey multiple comparison test of means, with a 95% confidence interval. Results The specimens presented mean compressive strengths of 10.25 MPa for the control group and 3.67 MPa, 9.65 MPa, and 9.16 MPa after ethylene oxide, gamma ray, and autoclave sterilization, respectively. Flexion test results showed an average resistance of 0.40 MPa in the control group, and 0.15 MPa, 0.17 MPa, and 0.30 MPa after ethylene oxide, gamma ray, and autoclave sterilization, respectively. There were statistically significant differences observed in the maximum compression of the ethylene oxide-sterilized group compared with that of the control group ( p = 0 . 0002), gamma ray-sterilized ( p = 0.0003), and the autoclaved ( p = 0.0006) groups. There was a statistically significant difference in maximum flexion of the specimens sterilized by gamma rays when compared with the control group ( p = 0.0245). However, low flexural strengths were observed in all specimens. Conclusion The autoclave sterilization group did not result in statistically significant differences in either compression or flexion strength tests. Thus, the autoclave proved to be the best sterilization option for the hydroxyapatite-based biocomponents in this study.

Biocomponents Based on Hydroxiapatite: Influence of Sterilization on the Mechanical Resistance / Biocomponentes à base de hidroxiapatita: Influência da esterilização na resistência mecânica

Abstract Objective This study aimed to evaluate the influence of sterilization on the compressive and flexural mechanical strength of hydroxyapatite-based biocomponents obtained through freeze-dried bovine bone, and its association with chitosan. Methods Freeze-dried bovine bone was processed into 100 μm particles and mixed with 50% of its weight in chitosan. The mixture was packed in metallic molds for preparing the specimens, and sterilized at 127°C using an autoclave for subsequent experimentation. The specimens were subjected to compression and flexion tests following norm 5833 of the International Organization for Standardization (ISO), with 6 × 12 mm cylindrical blocks (for compression tests) and 75 × 10 × 3.3 mm plates (for flexion tests) as samples. The samples were divided into four groups of 20 specimens each, with 10 for compression and 10 for flexion tests. Three groups were sterilized (autoclave, gamma rays, and ethylene oxide), whereas the fourth group (control) was not. The mechanical tests obtained from the different sterilization processes were compared using analysis of variance (ANOVA, p< 0.05), followed by the Tukey multiple comparison test of means, with a 95% confidence interval. Results The specimens presented mean compressive strengths of 10.25 MPa for the control group and 3.67 MPa, 9.65 MPa, and 9.16 MPa after ethylene oxide, gamma ray, and autoclave sterilization, respectively. Flexion test results showed an average resistance of 0.40 MPa in the control group, and 0.15 MPa, 0.17 MPa, and 0.30 MPa after ethylene oxide, gamma ray, and autoclave sterilization, respectively. There were statistically significant differences observed in the maximum compression of the ethylene oxide-sterilized group compared with that of the control group (p= 0.0002), gamma ray-sterilized (p= 0.0003), and the autoclaved (p= 0.0006) groups. There was a statistically significant difference in maximum flexion of the specimens sterilized by gamma rays when compared with the control group (p= 0.0245). However, low flexural strengths were observed in all specimens. Conclusion The autoclave sterilization group did not result in statistically significant differences in either compression or flexion strength tests. Thus, the autoclave proved to be the best sterilization option for the hydroxyapatite-based biocomponents in this study.

Resumo Objetivo O objetivo deste estudo foi avaliar a influência da esterilização na resistência mecânica à compressão e flexão de biocomponentes à base de hidroxiapatita obtida a partir de osso bovino liofilizado e sua associação com quitosana. Métodos O osso bovino liofilizado foi processado em partículas de 100 μm e misturado à quitosana em proporção de 50% de seu peso. A mistura foi acondicionada em moldes metálicos para preparo dos espécimes e esterilizada a 127°C em autoclave para posterior experimentação. Os espécimes foram submetidos a ensaios de compressão e flexão seguindo a norma 5833 da International Organization for Standardization (ISO); os espécimes eram blocos cilíndricos de 6 × 12 mm (para ensaios de compressão) e placas de 75 × 10 × 3,3 mm (para ensaios de flexão). As amostras foram divididas em quatro grupos de 20 espécimes cada, sendo 10 para ensaios de compressão e 10 para ensaios de flexão. Três grupos foram esterilizados (por autoclavagem, raios gama e óxido de etileno), enquanto o quarto grupo (controle) não foi. Os testes mecânicos obtidos nos diferentes processos de esterilização foram comparados por análise de variância (ANOVA, p< 0,05) seguido pelo teste de comparação múltipla de médias de Tukey, com intervalo de confiança de 95%. Resultados Os espécimes apresentaram resistências médias à compressão de 10,25 MPa para o grupo de controle e 3,67 MPa, 9,65 MPa e 9,16 MPa após esterilização com óxido de etileno, raios gama e autoclavagem, respectivamente. Os resultados do teste de flexão mostraram uma resistência média de 0,40 MPa no grupo de controle, e 0,15 MPa, 0,17 MPa e 0,30 MPa após esterilização com óxido de etileno, raios gama e autoclavagem, respectivamente. A compressão máxima observada no grupo esterilizado com óxido de etileno foi estatisticamente diferente à obtida no grupo de controle (p= 0,0002), esterilizado com raios gama (p= 0,0003) e autoclavado (p= 0,0006). A flexão máxima dos espécimes esterilizados com raios gama foi estatisticamente diferente à observada no grupo de controle (p= 0,0245). No entanto, a resistência à flexão foi baixa em todos os espécimes. Conclusão A esterilização em autoclave não foi associada a diferenças estatisticamente significativas nos testes de compressão ou flexão. Assim, a autoclave foi a melhor opção de esterilização para os biocomponentes à base de hidroxiapatita neste estudo.

Effects of Hypertension on Alzheimer's Disease and Related Disorders.

PURPOSE OF REVIEW: To review the pathophysiology of hypertension in Alzheimer's disease and related dementias and explore the current landscape of clinical trials involving treatment of hypertension to improve cognition. RECENT FINDINGS: Hypertension is increasingly recognized as a contributor to cognitive impairment. Clinical trials that explore blood pressure reductions with cognitive outcomes have been promising. Various antihypertensives have been evaluated in clinical trials, with growing interest in those agents that impact the renin-angiotensin-aldosterone system due to its own association with cognitive impairment. No antihypertensive agent has been found to be superior to others in reducing cognitive impairment risk or conferring neuroprotective benefits. In this review, the pathophysiology of and clinical trial data involving hypertension and dementia will be explored. Hypertension is a significant risk factor for the development of neurodegenerative dementias, and clinical trials have been overall favorable in improving cognition by reductions in blood pressure using antihypertensive agents.

Cognition/Psychological Burden and Resilience in Cutaneous T-Cell Lymphoma and Psoriasis Patients: Real-Life Data and Implications for the Treatment.

Background: Psoriasis and cutaneous T-cell lymphoma (CTCL) expose patients to chronic inflammation as well as physical and psychological disabilities, but the impact of such alterations on cognitive function is unknown. Objective: This study is aimed at determining if CTCL and psoriasis impact cognitive functioning in relation to psychological and health-related quality of life (HR-QOL) status. Methods: A cross-sectional study was performed in an outpatient dermatology clinic of a university teaching hospital. Thirty-nine subjects with CTCL (N = 20) or psoriasis (N = 19) who met eligibility criteria were included. The cognitive domains of memory, attention and processing speed, and executive function were assessed with standard neuropsychological tests. Subjects were assessed for depression, anxiety, and HR-QOL (using the SKINDEX-29 questionnaire). Results: Study participants were CTCL and psoriasis subjects; cognitive impairment was found in the domain of memory in 17.9% subjects with CTCL or psoriasis. Lower scores on executive function tests were predicted by higher (worse HR-QOL) SKINDEX-29 functioning scores (p = 0.01). A higher estimated baseline intellectual functioning predicted lower scores (better HR-QOL) on the symptoms and functioning domains of SKINDEX-29 (p = 0.01 and 0.02, respectively) and a statistical trend (p = 0.07) for the emotion domain. Memory and acute anxiety were adversely impacted by shorter disease duration (p = 0.01 for both). Conclusions: Memory impairment may be associated comorbidity in CTCL and psoriasis. Subjects with stronger cognitive resources appear to cope better with health-related quality of life (HR-QOL) challenges.

Graph Theory Analysis of Semantic Fluency in Russian-English Bilinguals.

BACKGROUND: Semantic category fluency is a widely used task involving language, memory, and executive function. Previous studies of bilingual semantic fluency have shown only small differences between languages. Graph theory analyzes complex relationships in networks, including node and edge number, clustering coefficient, average path length, average number of direct neighbors, and scale-free and small-world properties. OBJECTIVE: To shed light on whether the underlying neural processes involved in semantic category fluency testing yield substantially different networks in different languages. METHOD: We compared languages and methods using both network analysis and conventional analysis of word production. We administered the animal naming task to 51 Russian-English bilinguals in each language. We constructed network graphs using three methods: (a) simple association of unique co-occurring neighbors, (b) corrected associations between consecutive words occurring beyond chance, and (c) a network community approach using planar maximally filtered graphs. We compared the resultant network analytics as well as their scale-free and small-world properties. RESULTS: Participants produced more words in Russian than in English. Small-worldness metrics were variable between Russian and English but were consistent across the three graph theory analytical methods. CONCLUSION: The networks had similar graph theory properties in both languages. The optimal methodology for creating networks from semantic category fluency remains to be determined.

Biomarkers and Mindfulness: A Way Forward.

After years of anticipation, non-invasive tests for detecting cerebral amyloidosis and Alzheimer's disease (AD) are entering clinical care. The PrecivityADtrademark test from C2N is a plasma-based test yielding an Amyloid Probability score with high sensitivity and specificity for brain amyloid accumulation, but some samples may have inconclusive results. The AGREEDementia consortium raised concerns that the field needs study of how best to use and communicate results of PrecivityADtrademark. Continued attention and mindfulness should be applied to the whole class of dementia biomarker tests and directed in light of FDA biomarker context of use framework. Unintended uses of biomarkers tests may have unintended consequences, such as mislabeling patients. AD biomarker tests may efficiently stratify AD risk but will inevitably be included in electronic medical records and be subject to interpretation by medical personnel lacking proper knowledge or context to interpret results appropriately. Another way forward is mindful discussion and consensus among all stakeholders about the uses and limits of each specific test.

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Although APOE ε4 remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. As a founder population that typically practices endogamy, variants that are rare in the general population may be of a higher frequency in the Amish population. Since the Amish have a slightly lower incidence and later age of onset of disease, they represent an excellent and unique population for research on protective genetic variants. We compared AD risk in the Amish and to a non-Amish population through APOE genotype, a non-APOE genetic risk score of genome-wide significant variants, and a non-APOE polygenic risk score considering all of the variants. Our results highlight the lesser relative impact of APOE and differing genetic architecture of AD risk in the Amish compared to a non-Amish, general European ancestry population.

C19orf12 ablation causes ferroptosis in mitochondrial membrane protein-associated with neurodegeneration.

Mitochondrial membrane protein-associated with neurodegeneration (MPAN) is a rare genetic disease characterized by aggressive neurodegeneration and massive iron accumulation in patients' brains. Genetics studies identified defects in C19orf12 locus being associated with MPAN which likely caused loss of function although underlying pathogenic mechanism(s) remain elusive. In the present study, we investigated C19orf12 knockout (KO) M17 neuronal cells and primary skin fibroblasts from MPAN patients with C19orf12 homozygous G58S or heterozygous C19orf12 p99fs*102 mutations as cellular models of MPAN. C19orf12 KO cells and MPAN fibroblast cells demonstrated mitochondrial fragmentation and dysfunction, iron overload and increased oxidative damage. Antioxidant NAC and iron chelator DFO rescued both oxidative stress and mitochondrial deficits. Moreover, C19orf12 KO cells and MPAN fibroblast cells were susceptible to erastin- or RSL3-induced ferroptosis which could be almost completely prevented by pretreatment of iron chelator DFO. Importantly, we also found mitochondrial fragmentation and increased ferroptosis related oxidative damage in neurons in the biopsied cortical tissues from an MPAN patient. Collectively, these results supported the notion that iron overload and ferroptosis likely play an important role in the pathogenesis of MPAN.

Distinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer's disease.

Although genetic factors play a main role in determining the risk of developing Alzheimer's disease (AD), they do not explain extensive spectrum of clinicopathological phenotypes. Deposits of aggregated TAU proteins are one of the main predictors of cognitive decline in AD. We investigated the hypothesis that variabilities in AD progression could be due to diverse structural assemblies (strains) of TAU protein. Using sensitive biophysical methods in 40 patients with AD and markedly different disease durations, we identified populations of distinct TAU particles that differed in size, structural organization, and replication rate in vitro and in cell assay. The rapidly replicating, distinctly misfolded TAU conformers found in rapidly progressive AD were composed of ~80% misfolded four-repeat (4R) TAU and ~20% of misfolded 3R TAU isoform with the same conformational signatures. These biophysical observations suggest that distinctly misfolded population of 4R TAU conformers drive the rapid decline in AD and imply that effective therapeutic strategies might need to consider not a singular species but a cloud of differently misfolded TAU conformers.