Blink rate study in patients with Alzheimer's disease, Mild Cognitive Impairment and Subjective Cognitive Decline

Background: Blink rate (BR) is considered a marker of dopaminergic activity in humans. BR is increased in patients with Mild Cognitive Impairment (MCI), but no study has yet investigated whether BR changes with the progression of cognitive decline from MCI to Alzheimer’s disease (AD) and whether BR abnormalities are present in subjects with Subjective Cognitive Decline (SCD). Objective: The aim of our study was to assess BR in patients with AD, MCI, and SCD and to correlate BR with demographic and clinical features of cognitive decline. Methods: We enrolled 22 subjects with SCD, 23 with MCI, and 18 with AD and a group of 20 age-matched healthy controls (HCs). Cognitive function was assessed by testing global cognitive status and frontal, attentional, memory, verbal, and visuospatial functions. BR was measured by counting the number of blinks per minute. Results: MCI subjects had an increased BR (p<0.001), whereas AD subjects had a lower BR than HCs (p<0.05). Conversely, SCD subjects had a BR similar to HCs. No significant correlations emerged between neuropsychological scores and BR in SCD, MCI, and AD subjects. Conclusion: Increased BR in MCI likely reflects early compensatory mechanisms occurring before AD, whereas decreased BR in AD suggests dopaminergic system involvement in this condition.

White Matter Microstructure is Associated with Serum Clusterin and Everyday Functioning in a Sample of Nondemented Older Adults

Background: Although clusterin-a protein involved in lipid metabolism, amyloid beta clearance, and myelination-has been linked to gray matter atrophy within samples of older adults at risk for Alzheimer’s disease, research exploring associations with white matter (WM) micro- and macro- structural markers are largely limited. Objective:: The current study [1] explored associations between serum clusterin protein levels and WM micro- and macro- structural markers, and [2] clarified whether variations in WM fractional anisotropy (FA) were associated with functional abilities within in a racially homogenous sample of relatively well-educated older adults free of dementia. Methods: Participants underwent magnetic resonance imaging (MRI) brain exams and a blood draw and completed a performance-based measure of everyday functioning. Multiple linear regression adjusting for age, sex, APOE e4 positivity, and vascular risk were used to explore serum clusterin associations with WM metrics, as well clarify potential links between WM microstructure and everyday functioning. Results: Higher serum clusterin was associated with lower FA in several thalamocortical (anterior and posterior internal capsule, posterior thalamic radiation; ßs = -.32 to -.37, ps = .01 to .02) and association fiber tracts (external capsule, superior longitudinal fasciculus; ßs = -.32 to -.40, ps = .02). Serum clusterin was not associated with white matter hyperintensity volume (ß = .14, p = .28), but higher FA of several WM tracts was associated with better performance on the Independent Living Scale (ßs = .37 to .53, ps = .006 to .03). Conclusion: Serum clusterin is differentially associated with WM metrics, and WM microstructure is associated with everyday functioning.

Oxidative Damage of Proteins Precedes Loss of Cholinergic Phenotype in the Septal Neurons of Olfactory Bulbectomized Mice

Background: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer’s disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer’s disease. Objective: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. Methods: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. Results: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. Conclusion: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer’s disease.

Assessment of apolipoprotein E genotype for β-amyloid status prediction

Background: Apolipoprotein E (ApoE) is the major genetic risk factor for sporadic Alzheimer's Disease (AD). Some studies showed a relationship between ApoE4 genotype and the cerebrospinal fluid (CSF) biomarkers (β-amyloid42, p-Tau, t-Tau), as well as with cognitive status. In this sense, it could be interesting to develop an approach to establish amyloid status in a minimally invasive way. Methods: The present study assessed the ApoE genotype in different participant groups (mild cognitive impairment due to AD (MCI-AD), mild/moderate dementia due to AD, MCI not due to AD (MCI not AD), other neurological diseases, healthy participants) (n = 342). Results: As expected, the ApoE4 allele was more prevalent in AD patients, characterized by impairment in CSF β-amyloid42 levels (Aβ +), than in the other groups (Aβ -). In this sense, ApoE4-carrier subjects showed lower CSF levels for β-amyloid42 and higher CSF levels for t-Tau and p-Tau. From this, a multivariate model to predict Aβ status was developed by means of partial least square analysis (PLS) and predictive variables (ApoE genotype, cognitive score, sex, age). This model showed suitable AUC-ROC 0.792 (95% CI, 0.744-0.840) and predictive negative value (81.6%). Conclusion: ApoE genotype could be useful in detecting CSF β-amyloid42 impairment associated with early AD development.

Effects of the Co-occurrence of Diabetes Mellitus and Tooth Loss on Cognitive Function

Objective: Both diabetes mellitus (DM) and poor oral health are common chronic conditions and risk factors of Alzheimer’s disease and related dementia among older adults. This study assessed the effects of DM and complete tooth loss (TL) on cognitive function, accounting for their interactions. Methods: Longitudinal data were obtained from the 2006, 2012, and 2018 waves of the Health and Retirement Study. This cohort study included 7,805 respondents aged 65 years or older with 18,331 person-year observations. DM and complete TL were self-reported. Cognitive function was measured by the Telephone Interview for Cognitive Status. Random-effect regressions were used to test the associations, overall and stratified by sex. Results: Compared with older adults without neither DM nor complete TL, those with both conditions (b = -1.35, 95% confidence interval [CI]: -1.68, -1.02), with complete TL alone (b = -0.67, 95% CI: -0.88, -0.45), or with DM alone (b = -0.40, 95% CI: -0.59, -0.22), had lower cognitive scores. The impact of having both conditions was significantly greater than that of having DM alone (p < .001) or complete TL alone (p = 0.001). Sex-stratified analyses showed the effects were similar in males and females, except having DM alone was not significant in males. Conclusion: The co-occurrence of DM and complete TL poses an additive risk for cognition. Healthcare and family-care providers should pay attention to the cognitive health of patients with both DM and complete TL. Continued efforts are needed to improve older adults’ access to dental care, especially for individuals with DM.

Does the Global Postural Re-Education Affect the Psychological and Postural Aspects of Alzheimer Disease Patients? A Six Months Quasi-Experimental Study

Objective: To study the implementation of Global Postural Re-education as a rehabilitative alternative in residence facilities for seniors with Alzheimer, and to verify its effect on psychological and cognitive symptoms. Methods: A quasi-experimental design was employed using month-follow-up assessments at 1,3, and 6 months respectively. Ninety elderly people participated in the composition of the study sample: 69 women and 21 men aged from 67 to 89 years (80.2 ±5.5), grouped in two phases: mild and moderate, according to Alzheimer severity. Patients in both groups received the same treatment twice a week for consecutively 24 weeks. Three follow-up medium-long term assessments were performed at intervals of 1, 3, and 6 months. Outcome measures included Mini-Mental State Examination, Geriatric Depression Scale, Quality of Life in Alzheimer Disease, Barthel Index, and Tinetti Scale. Results: The severity of groups therapy interaction showed significant changes in four outcome measures as cognition [F(1,88)=60.26; p=.000; partial η2= 0.406], depression [F(1,88)=8.24; p=.005; partial η2= 0.086], life quality [F(1,88)= 10.45; p=.002; partial η2= 0.106] and equilibrium [F(1,88)= 6.96; p=.010; partial η2= 0.073]. No changes were found for autonomy [F(1,88)= 1.10; p=.297; partial η2= 0.012]. These changes between the two groups were observed at the sixth month follow-up assessment. Conclusion : Global postural reeducation could be useful as a complementary rehabilitation treatment in Alzheimer patients.

Control of β-Site Amyloid Precursor Protein-Cleaving Enzyme-1 Expression by Protein Kinase C-λ/ι and Nuclear Factor κ-B

Βackground: β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of Aβ-peptides that form Aβ-plaque in Alzheimer’s disease. Methods: Reportedly, acute insulin treatment in normal mice, and hyperinsulinemia in high-fat-fed (HFF) obese/diabetic mice, increase BACE1 activity and levels of Aβ-peptides and phospho- -thr-231-tau in the brain; moreover, these effects are blocked by PKC-λ/ι inhibitors. However, as chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to further examine PKC-λ/ι requirements. We found that total-body heterozygous PKC-λ knockout reduced acute stimulatory effects of insulin and chronic effects of hyperinsulinemia in HFF/obese/diabetic mice, on brain PKC-λ activity and production of Aβ1-40/42 and phospho-thr-231-tau. This protection in HFF mice may reflect that hepatic PKC-λ haploinsufficiency prevents the development of glucose intolerance and hyperinsulinemia. Results: On the other hand, heterozygous knockout of PKC-λ markedly reduced brain levels of BACE1 protein and mRNA, and this may reflect diminished activation of nuclear factor kappa-B (NFκB), which is activated by PKC-λ and increases BACE1 and proinflammatory cytokine transcription. Accordingly, whereas intravenous administration of aPKC inhibitor diminished aPKC activity and BACE1 levels by 50% in the brain and 90% in the liver, nasally-administered inhibitor reduced aPKC activity and BACE1 mRNA and protein levels by 50-70% in the brain while sparing the liver. Additionally, 24-hour insulin treatment in cultured human-derived neurons increased NFκB activity and BACE1 levels, and these effects were blocked by various PKC-λ/ι inhibitors. Conclusion: PKC-λ/ι controls NFκB activity and BACE1 expression; PKC-λ/ι inhibitors may be used nasally to target brain PKC-λ/ι or systemically to block both liver and brain PKC-λ/ι, to regulate NFκB-dependent BACE1 and proinflammatory cytokine expression.

Olfactory Function, Genetic Predisposition, and Cognitive Performance in Chinese adults

Objective: The objective of this study is to examine the association of olfactory function and genetic predisposition of Alzheimer’s disease (AD) with cognitive performance in adults. Methods: A total of 2049 Chinese adults from Rugao Longevity and Ageing Study (RuLAS, n=1460, mean age 78 years) and Central China Cohort (CCC, n=589, mean age 48 years) were included in this study. A standard interview-based survey, clinical information, and blood samples were collected in both cohorts. Olfactory function in terms of olfactory identification was measured by the brief version of the Chinese Smell Identification Test consisted of 18 full points. Cognitive performance was measured by the Chinese version of the Mini-mental State Examination. A genetic risk score (GRS) was calculated from 5 single nucleotide polymorphisms, which were robustly related to Alzheimer’s disease in Caucasians and cognitive performance in our Chinese population. Results: In the pooled analyses, participants at the lowest quartile of olfactory function had significantly higher odds of cognitive impairment (adjusted odds ratio [95% CI] =1.45 [1.00 to 2.09], Ptrend =0.005), and such association was stronger among participants with a stronger genetic predisposition of Alzheimer’s disease (β coefficient±SE, -0.06±0.03 in participants with a lower GRS vs. -0.19±0.05 in those with a higher GRS, respectively, Pinteraction=0.01). Similar associations were observed in RuLAS (P-trend=0.06) and in CCC (P-trend<0.001). Conclusion: In this study, a decreased olfactory function was associated with worse cognitive performance in adults, especially among participants with a higher genetic risk of Alzheimer’s disease. Further studies are warranted to evaluate the causal relationship between olfaction and cognitive performance.

Association of Dietary Prebiotic Consumption with Reduced Risk of Alzheimer’s Disease in a Multiethnic Population

Objective: This study aimed to investigate the association between dietary prebiotic intake and risk for Alzheimer’s disease (AD). Methods: This longitudinal study includes 1,837 elderly (≥65 years) participants of a multi-ethnic community-based cohort study who were dementia-free at baseline and had provided dietary information from food frequency questionnaires. Total daily intake of fructan, one of the best-known prebiotics, was calculated based on consumption frequency and fructan content per serving of 8 food items. The associations of daily fructan intake with AD risk were examined using a Cox proportional hazards model, adjusted for cohort recruitment wave, age, gender, race/ethnicity, education, daily caloric intake, and APOE genotype. Effect modification by race/ethnicity, APOE genotype, and gender was tested by including an interaction term into the Cox models, as well as by stratified analyses. Results: Among 1,837 participants (1,263 women [69%]; mean [SD] age = 76 [6.3] years), there were 391 incident AD cases during a mean follow-up of 7.5 years (13736 person-years). Each additional gram of fructan intake was associated with 24% lower risk for AD ((95% CI)=0.60-0.97; P =0.03). Additional adjusting for smoking, alcohol consumption, and comorbidity index did not change results materially. The associations were not modified by race/ethnicity, gender, and APOE genotype, although stratified analyses showed that fructan intake was significantly associated with reduced AD risk in Hispanics but not in non-Hispanic Blacks or Whites. Conclusion: Higher dietary fructan intake is associated with a reduced risk of clinical Alzheimer’s disease among older adults.

Theracurmin supplementation may be a therapeutic option for older patients with alzheimer’s disease: a 6-month retrospective follow-up study

Background: Alzheimer’s Disease (AD) is still a great global challenge and agents with various mechanisms represent a promising therapeutic opportunity. Theracurmin, a very highly absorbable curcumin formulation, was shown to improve memory and attention in non-demented people. Objective: To investigate the effect of Theracurmin on disease course in elderly patients with mild cognitive impairment (MCI) and AD. Methods: This follow-up study was performed retrospectively on 93 patients with MCI or AD. All patients underwent comprehensive geriatric assessment, including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), clock-drawing test, activities of daily living (ADL), at baseline and end of the 6th-month. 19 patients with AD and 17 with MCI were treated with Theracurmin 180 mg/day per oral. Results: MMSE, MOCA and instrumental ADL scores decreased in AD patients that were not treated with Theracurmin (p<0.001, p=0.011, and p=0.004, respectively), whereas these scores remained stable in those treated with Theracurmin. This stabilization in the instrumental ADL was also observed in MCI patients treated with Theracurmin. During the follow-up, three of MCI patients who did not receive Theracurmin progressed to AD, whereas only one patient progressed in those who received it. Conclusion: Theracurmin seems to be a therapeutic option for elderly patients with AD and MCI via providing stabilization of the disease course by preventing progressive loss in cognitive functions and ADLs.