Cognition In Alzheimer's Disease Patients Research Articles

Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.

DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. To characterize how AD impacts adaptive DNA breaks at nervous system genes. We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains. Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.

DECREASE: Decrease Cognitive Decline in Alzheimer’s Disease Through Occupational Therapy: A Randomized Controlled Phase III Trial Protocol

Introduction: Alzheimer’s disease (AD) accounts for more than 80% of dementia cases worldwide and imposes a significant economic burden on the healthcare system. Currently, there is no cure for AD, and pharmacological treatments alleviate AD symptoms but fail to decrease cognitive decline. Occupational Therapy (OT) for AD patients targets symptoms without the side effects of drugs and may even play a disease-modifying role by preserving cognitive functions. The DECREASE trial aims to assess the effectiveness of a cognitive-based OT intervention amongst AD patients. Methods: The DECREASE Trial is a randomized, controlled, multicentric, phase III, superiority trial comparing the effect of OT and standard of care versus standard of care alone on cognition in AD patients. OT will entail a five-week group cognitive rehabilitation program with remote maintenance sessions until six months of follow-up. We will include 278 mild AD patients aged between 65 and 80. Changes in cognitive function between groups will be measured and compared by the ADAS-cog after six months. Discussion: The strengths of this OT program are that it is non-invasive, safe, highly standardized, and accessible to occupational therapists and caretakers worldwide. There is broad evidence of the benefits of functionality. Nevertheless, there needs to be more literature on its effect on cognitive function. AD is a public health emergency that needs to be promptly addressed. This trial will finally determine if an OT-based intervention can decrease cognitive decline and whether it should be included in the standard of care for AD.

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer's disease.

Introduction: Hyperphosphorylation of tau is an important event in Alzheimer's disease (AD) pathogenesis, leading to the generation of "neurofibrillary tangles," a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics. Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4-GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT. Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250ns demonstrated the stability and conformational dynamics of the MARK4-GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC50 = 5.87µM). Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT's inhibition of MARK4 provides newer insights into the mechanism of GLT's action, which is already used to improve cognition in AD patients.

Microglia Impairs Proliferation and Induces Senescence In-Vitro in NGF Releasing Cells Used in Encapsulated Cell Biodelivery for Alzheimer's Disease Therapy.

There is no cure yet available for Alzheimer’s disease (AD). We recently optimized encapsulated cell biodelivery (ECB) devices releasing human mature nerve growth factor (hmNGF), termed ECB-NGF, to the basal forebrain of AD patients. The ECB-NGF delivery resulted in increased CSF cholinergic markers, improved glucose metabolism, and positive effects on cognition in AD patients. However, some ECB-NGF implants showed altered hmNGF release post-explantation. To optimize the ECB-NGF platform for future therapeutic purposes, we initiated in-vitro optimization studies by exposing ECB-NGF devices to physiological factors present within the AD brain. We report here that microglia cells can impair hmNGF release from ECB-NGF devices in-vitro, which can be reversed by transferring the devices to fresh culture medium. Further, we exposed the hmNGF secreting human ARPE-19 cell line (NGC0211) to microglia (HMC3) conditioned medium (MCM; untreated or treated with IL-1β/IFNγ/Aβ40/Aβ42), and evaluated biochemical stress markers (ROS, GSH, ΔΨm, and Alamar Blue assay), cell death indicators (Annexin-V/PI), cell proliferation (CFSE retention and Ki67) and senescence markers (SA-β-gal) in NGC0211 cells. MCMs from activated microglia reduced cell proliferation and induced cell senescence in NGC0211 cells, which otherwise resist biochemical alterations and cell death. These data indicate a critical but reversible impact of activated microglia on NGC0211 cells.

Effects of Tianeptine Treatment on Depression and Cognitive Function in Patients with Alzheimer's Disease: A 12-Month Retrospective Observational Study.

Background:Depression is a common manifestation in Alzheimer’s disease (AD). In clinical practice, antidepressant medication is often used for depression in AD.Objective:We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting.Methods:We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received: tianeptine group (n = 38) or other antidepressant group (n = 88). Drug effects on depression, cognition, behavior, and functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores.Results:Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test.Conclusion:Our results suggest that tianeptine reduces depressive symptoms and improves cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients.

Physical Activity Improves Cognition and Activities of Daily Living in Adults with Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective: The purpose of this meta-analysis was to examine the effects of physical activity (PA) on cognition and activities of daily living in adults with Alzheimer’s Disease (AD). Methods: Six electronic databases (MEDLINE, CINAHL, PsycArticles, SPORTDiscus, EMBASE and CNKI) were used to search for potential studies from inception until October 2021. Randomized controlled trials (RCTs) investigating the effect of physical activity (PA) on cognition and activities of daily living in AD patients compared to a control condition were included. The effect sizes were synthesized using a random effects model with a 95% confidence interval (CI). Results: Sixteen articles including 945 participants (aged 70 to 88 years, 34.6% male) met the inclusion criteria. The pooled effect sizes demonstrated that PA intervention was associated with significant improvements in global cognition (Standard Mean Difference (SMD) = 0.41, 95% CI [0.24, 0.58], p < 0.01) and activities of daily living (SMD = 0.56, 95% CI [0.32, 0.79], p < 0.01) in AD patients. Subgroup analyses suggested that PA for 3–4 times per week for 30–45 min for more than 12 weeks had a relatively strong effect on improving global cognition in AD patients. The sensitivity analysis showed robust results. Conclusions: The findings from the current meta-analysis suggested that AD patients can improve their global cognition and Activities of Daily Living (ADL) through engaging in aerobic and mixed exercise (aerobic and anaerobic exercise).

Effect of Age, Cognitive Impairment Severity, and Duration of Disease on Efficacy of Masupirdine in Moderate Alzheimer's Disease Patients: A Post Hoc Analysis of a Phase-2 Randomized Placebo Controlled Study Results

Alzheimer's disease (AD) is an age-related progressive neurodegenerative brain disorder with cognitive symptoms as a hallmark phenotype of the disease. Masupirdine, a pure serotonin 6 (5-HT6) receptor antagonist is being developed for the treatment of cognitive deficits in AD. The objective of the current study is the post hoc analysis of a multicenter, randomized, double-blind, parallel group, 26-week, placebo-controlled phase-2 study (NCT02580305) that evaluated the effects of masupirdine on cognition in patients with moderate AD. Methods: Masupirdine phase 2 study included AD patients of 50 to 85 years age, mini-mental state examination (MMSE) score of 12 to 20 and diagnosis of probable AD at least 1 year prior to the screening visit. The impact of age, cognitive impairment severity, and duration of disease since diagnosis on efficacy of masupirdine as assessed by 11-item version of the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog 11) was evaluated. Treatment effects were assessed by Cohen’s d effect size. Results: Cohen’s d effect size for change in ADAS-Cog 11 scores from baseline to week 26 ranged between ~0.2 and 0.4 for the subgroup of population with age ≤ 70 years, MMSE range of 18 to 20, and duration of disease over 4 years (since diagnosis). Conclusions: Considering the linear relationship between age and cognitive decline, masupirdine effects across the subgroups could be attributed to “slowing of cognitive decline”. The study provides important findings for design of future clinical trials. Further research is warranted to confirm the potential beneficial effects of masupirdine on cognition in AD patients.

Sleep apnoea and cognitive impairment: myth or reality?

A growing number of studies in animal models have highlighted the link between sleep disorders and Alzheimer's disease (AD). In the absence of curative treatment, it is therefore important to consider any comorbidities that may influence the course of AD such as obstructive sleep apnoea-hypnoea (OSAH) and its syndrome (OSAHS), which appear to be potentially interesting because it occurs frequently, it is treatable and it is often associated with cognitive impairment. The association between OSAH/OSAHS and cognition is variable across studies, but OSAH/OSAHS is more common in older patients with AD than in cognitively normal individuals. OSAH/OSAHS is often associated with the subsequent development of mild cognitive impairment and AD. Although there is no evidence that treatment of OSAH/OSAHS in AD would have a major impact on the course of the disease, treatment would appear to improve cognition in AD patients with OSAH/OSAHS. Finally, the literature suggests a link between OSAH/OSAHS and AD biomarkers. Taken together, these data highlight the importance of detecting and treating OSAHS in this population.

Brain Renin-Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer's Disease.

The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer’s disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.

Sleep apnea and cognitive impairment: Myth or reality?

A growing number of studies in animal models have highlighted the link between sleep disorders and Alzheimer's disease (AD). In the absence of curative treatment, it is therefore important to consider any comorbidities that may influence the course of AD such as Obstructive sleep apnea-hyponea (OSAH) and its syndrome (OSAHS), which appear to be potentially interesting because it is frequent, treatable and often associated with cognitive impairment. The association between OSAH/OSAHS and cognition is variable across studies, but OSAH/OSAHS is more common in older patients with AD than in cognitively normal individuals. OSAH/OSAHS is often associated with the subsequent development of mild cognitive impairment and AD. Although there is no evidence that treatment of OSAH/OSAHS in AD would have a major impact on the course of the disease, treatment would appear to improve cognition in AD patients with OSAH/OSAHS. Finally, the literature suggests a link between OSAH/OSAHS and AD biomarkers. Together, these data highlight the importance of detecting and treating OSAHS in this population.

1731-P: The Mechanism of the Protective Effect of GLP-1 on the Amelioration of Alzheimer’s Disease by Enhancing Brain Insulin Production

Background: Growing evidence supported that type 2 diabetes mellitus (T2DM) patients had a greater risk of developing Alzheimer’s disease (AD). Insulin secreted by “β cells” in brain played a critical role in T2DM patients and in AD patients. GLP-1 could improve cognition in AD patients via enhancing brain insulin signaling. We hypothesize the therapeutic effect of GLP-1 in T2DM might be due to promoting the insulin secretion of “β cells” in the nervous system. However, the molecular mechanism is unclear. Methods: The hippocampus cell- HT-22 cell line and T2DM rats were used in this study. The genes of insulin syntheses, animals’ cognitive function and the phosphorylation of tau protein in hippocampus of T2DM brain were examined. Results: Firstly, HT22 cell line was intervened by GLP-1 or high glucose or GLP-1+ high glucose. When stimulated by GLP-1 combined with high glucose, IRS1/PI3K/AKT located in insulin signal pathway could be activated and the expression of neurod-1 and ngn3 (insulin synthesis genes) were notably increased. These results indicated that neuronal cell could secrete insulin under a certain condition. Secondly, RAAV-sh- neurod-1 and RAAV-sh-ngn3 were icv to the T2DM rats to prevent the production of brain insulin. The Barnes Maze test indicated the T2DM rats with peripheral GLP-1 and icv RAAV-sh-nc injection had a more intelligence than those with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3. Thirdly, the T2DM rats with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3 had a significantly hyperphsphorylation of tau protein than those rats with peripheral GLP-1 and icv RAAV-sh-nc injection. This result showed that brain insulin could improve cognition by GLP-1 in T2DM rats. Conclusions: These results suggested that neuronal cells might synthesis and secrete insulin under the condition of high glucose and GLP-1. And GLP-1 could not improve cognitive ability in T2DM when brain insulin synthesized was prevented. Disclosure J. Huang: None. Y. Yang: None. Funding National Natural Science Foundation of China (81670754)

Dietary interventions and cognition of Alzheimer's disease patients: a systematic review of randomized controlled trial.

ABSTRACT.It is estimated that by 2030 there will be 82 million people in the world with dementia.Objective: To evaluate the effect of dietary interventions on the cognitive performance of individuals with Alzheimer’s disease (AD).Methods: A systematic review of randomized controlled trials (RCT) was conducted in the Scopus, PubMed, and Cochrane databases. Thirty-two RCT were included.Results: Omega-3 fatty acid showed positive effects at different doses. Fortasyn Connect seemed to be effective in the early stages of the disease. Probiotic, Ginseng, Inositol and specialized nutritional formulas seemed to have a positive effect on cognition. Most of the primary studies presented poor methodological quality, included patients with mild AD, small samples, and did not obtain significative results for all the cognitive outcomes.Conclusions: The effect of most dietary interventions on cognition in AD patients remains inconclusive, however, several nutrients, isolated or not, show potential to improve cognitive function in AD, especially in its early stages.

Repetitive transcranial magnetic stimulation for cognitive impairment in Alzheimer's disease: a meta-analysis of randomized controlled trials.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique for Alzheimer's disease (AD). rTMS, with high- or low-frequency, is thought to enhance or inhibit the cortical activities, respectively. This meta-analysis of randomized controlled trials (RCTs) was to summarize the efficacy of the rTMS on the cognition of AD patients and to identify its potential influential factors. Literature from the Pubmed, Embase, Cochrane Library and Web of Science were searched and screened to identify eligible studies. Standardized mean difference (SMD) and 95% confidence interval were used to evaluate the therapeutic effects of rTMS. Subgroup analyses were performed to investigate the influential factors. Ten studies with 15 trials involving 240 patients were included. Compared with sham stimulation, rTMS could significantly improve cognition in AD (SMD, 0.42; 95% CI 0.18-0.67; P = 0.0006). Subgroup analysis suggested significant cognitive enhancement in participants receiving rTMS on multiple sites rather than on single site, and in patients receiving rTMS of more than 10 sessions, but not ≤ 10 sessions. Compared with rTMS as the single therapeutic method, rTMS with concurrent cognitive training seemed to produce greater improvement. Moreover, 20Hz rTMS, seemed to be more effective than 10Hz or 1Hz rTMS. Furthermore, patients with higher education, or with mild-to-moderate AD were more likely to benefit from rTMS than patients with lower education, or with severe dementia, respectively. Based on the current evidence, rTMS was an effective therapy for cognitive impairment in AD. Large RCTs are warranted to further validate the results of our subgroup analyses.

The Alzheimer's disease THErapy with NEuroaid (ATHENE) study protocol: Assessing the safety and efficacy of Neuroaid II (MLC901) in patients with mild-to-moderate Alzheimer's disease stable on cholinesterase inhibitors or memantine—A randomized, double-blind, placebo-controlled trial

BackgroundDementia is a large and growing health care burden globally, and its major cause is Alzheimer's disease (AD). MLC901 (Neuroaid II) is a simplified form of MLC601 (Neuroaid), a Traditional Chinese Medicine with neuroprotective and neuroproliferative properties in cellular and animal models of brain injury. MLC601 has been shown to modulate amyloid precursor protein (APP) processing in human neuroblastoma cell cultures and increase the levels of soluble APPα. In addition, MLC901 has been shown to reduce tau phosphorylation in vitro. Hence, MLC901 may have possible multimodal actions and a disease-modifying effect in AD. In previous clinical studies, MLC601 has shown promising effects in AD. ObjectiveTo investigate the safety and efficacy of MLC901 add-on therapy to standard treatment in mild-to-moderate probable AD patients stable on standard treatment and to evaluate if MLC901 has a disease-modifying effect in AD. MethodsThis is a 6-month randomized, double-blind, placebo-controlled trial in mild-to-moderate probable AD where MLC901 will be given as an add-on therapy to standard AD treatment, followed by an extension study for another 6 months, where all subjects will be treated with open-label MLC901 in addition to standard treatment. The primary outcome is safety as measured by adverse events, vital signs, electrocardiogram, laboratory tests, and physical and neurological examinations. Secondary outcomes evaluating cognition, behavior, and activities of daily living at various time points include the Alzheimer's Disease Assessment Scale–cognitive subscale, Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change, Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Mini–Mental State Examination. ConclusionMLC901 has the potential to improve cognition in AD patients. It may also have a role in delaying disease progression. This study will be the first to provide safety and efficacy data for MLC901 in mild-to-moderate probable AD patients already receiving standard therapy.

Cognitive Training in Patients with Alzheimer's Disease: Findings of a 12-month Randomized Controlled Trial.

Cognitive training (CT) is a non-pharmacological intervention based on a set of tasks that reflect specific cognitive functions. CT is aimed at improving cognition in patients with cognitive impairment, though no definitive conclusions have yet been drawn on its efficacy in Alzheimer's disease (AD). To assess the effectiveness of a CT program designed to improve cognition in AD patients. This is a randomized, controlled, single-blind, longitudinal trial with a no-treatment control condition in mild-to-moderate AD. Treated patients received in-group CT twice a week for six months, whereas controls did not. CT consisted of tasks ranging from paper-and-pencil to verbal-learning exercises. Participants' cognitive levels were assessed at baseline, post-intervention and 6 months later by means of a complete neuropsychological test battery. Repeated measures ANOVA was used to analyze the effect of time on the outcome measures, as well as to compare treated and untreated patients over time, with demographic data considered as covariates. Of the 140 patients enrolled, 45 in the treated group and 85 controls concluded the study. The CT significantly improved treated subjects' cognitive functions immediately after the CT. Six months later, some test scores remained stable when compared with those obtained at baseline. The control group performed significantly worse than the treated group at each time-point, displaying a progressive cognitive decline over time. Our results suggest that CT may improve cognitive functions in patients with AD and may help to temporarily slow their cognitive decline.

Aerobic exercise effects upon cognition in Alzheimer's Disease: A systematic review of randomized controlled trials.

Previous reviews and meta-analysis have shown that physical activity has positive effects on cognition in healthy elderly as well as in patients with Mild Cognitive Impairment, even if with a minor effect whereas less is known about the effectiveness of aerobic exercise in patients with Alzheimer's Disease (AD). The aim of the present study was to systematically review the evidence from randomized controlled trials (RCTs) designed to evaluate aerobic exercise effects upon cognition in AD patients. PubMed, Cochrane, Web of Science and DARE databases were analytically searched for RCTs including aerobic exercise interventions for AD patients. There is scarce evidence that aerobic exercise improves cognition in AD patients. Overall, the included studies reported only positive effects for patients'global cognition after intervention, mainly due to a lack of accurate neuropsychological assessment of each cognitive domain. Whether the bene ts of exercise are evident in all stages of AD pathology remain also uncertain. Standardized protocols, larger and more rigorous RCTs with long-term follow-ups may provide better insight into the effects of aerobic exercise on cognitive deterioration characterizing people with AD.

Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease

While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.

Intranasal Insulin Ameliorates Cerebral Hypometabolism, Neuronal Loss, and Astrogliosis in Streptozotocin-Induced Alzheimer’s Rat Model

Intracerebroventricular injection of streptozotocin (ICV-STZ) in rodents leads to cognitive impairments and several pathological changes like Alzheimer's disease (AD). However, there is hardly any research about the effect of ICV-STZ on regional cerebral glucose metabolism in rodents. Previous studies have demonstrated that intranasal insulin improves cognition in AD patients. However, the underlying mechanism remains elusive. Here, we treated the ICV-STZ rats with daily intranasal delivery of insulin (2U/day) for 6 consecutive weeks, then monitored 18F-fluorodeoxyglucose (18F-FDG) uptake using a high-resolution small-animal positron emission tomography (microPET) and studied the expression of neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) using immunohistochemical staining. We observed that 18F-FDG uptake decreased significantly at the prefrontal cortex, cingulate cortex, striatum, hippocampus, and entorhinal cortex in ICV-STZ rats as compared with the control rats. Intranasal insulin restores the cerebral glucose metabolism in prefrontal and cingulate cortex and attenuates astroglia activation and neuronal loss in the hippocampus of ICV-STZ rats. These findings provide the mechanistic basis for treating AD patients with intranasal insulin.

The Relation of Circulating Levels of Leptin with Cognition in Patients with Alzheimer's Disease.

To investigate the relation of circulating levels of leptin with cognition in Alzheimer's disease (AD) patients. Thirty patients meeting the clinical diagnostic criteria for AD, and twenty-five healthy controls were enrolled into the study. At baseline, all patients underwent standing height, weight measurements, and waist circumference (in centimeters) using a standard scale. Body mass index (BMI) was then calculated as weight (in kilograms). A single 5-ml fasting blood sample was obtained from each patient. All subjects were evaluated by Turkish version of Mini Mental State Examination (MMSE), Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS). The mean age of patients and controls were 72.33±10.11 and 67.20±8.95, respectively. There was not any significant difference between age of the patients and the controls (p=0.054). Both patient and control groups consisted of mostly women (60% and 56% respectively). The mean waist circumferences (WC) of patients and controls were 95.46±10.87 and 97.76±10.07, respectively and was not statistically different (p=0.424). The mean serum leptin levels in patients and controls were 5.49±4.06 ng/dL 5.71±4.45 ng/dL, respectively. Leptin levels were not statistically different between patients and controls (p=0.84). The mean MMSE scores of AD patients and controls were 17±6.54 and 27.32±2.15 respectively, and AD patients had significantly lower MMSE scores than the controls (p=0.000). The mean BMI of patients and controls were 25.72±3.98 and 27.92±3.08 respectively. The BMI of controls were higher than patients and there was statistically significant difference between two groups (p=0.029). In the patient group, there were no correlations between leptin levels and age (p=0.067), BMI (p=0.098), WC (p=0.113), MMSE (p=0.203), CDR (p=0.519) and GDS (p=0.587). Similarly in control group leptin levels were not correlated with BMI (p=0.718), WC (p=0.755) and MMSE (p=0.859). In the present study, we could not find any relation between blood leptin levels and cognition in AD patients.

CONTINUOUS MONITORING OF TURNING MOBILITY IN PATIENTS WITH ALZHEIMER’S DISEASE: A PILOT STUDY

Patients with Alzheimer's Disease (AD) frequently have impairments with spatial orientation and navigation. These deficits in spatial cognition are thought to contribute to the increased risk of falls and wandering in AD, which are highly morbid conditions for these patients. Recent studies using continuous activity monitoring in cognitively-normal older adults observed that reduced spatial cognitive skills was associated with poorer turning mobility. The goal of this study was to investigate the preliminary feasibility of continuous monitoring of turning mobility in AD patients, with the broader goal of developing an objective measure of spatial cognitive skills in AD patients. We recruited four AD patients into the study. The patients wore an Opal sensor (APDM, Portland, OR) on a belt on the lower back during normal daily activity and were instructed to wear the device for 4 consecutive days. An algorithm identified periods of walking from the 3D accelerations (>10 sec) and calculated the following turning metrics that occurred while walking: 1) number of turns occurring in each 30 min period, 2) turn angle amplitudes, 3) turn durations, 4) turn velocities (mean and peak). We were able to successfully record from all 4 patients (mean age 77.3 years, 75% male, MMSE range 13–24). The number of days of use ranged from 2–5 days, and the number of hours of use ranged from 16.5–45.5 hours. Data on turning mobility were generated for all 4 patients. The only quantity that differed substantially between data from healthy older adults and the AD patients was mean turn angle which was higher in the older adults (96° vs. 75°). In this pilot study, AD patients (even with an MMSE of 13) tolerated the Opal continuous monitoring device and provided evaluable data on turning mobility. We determined that 4 days of monitoring (yielding at least 36 hours of data) would be needed to provide sufficient data for estimation of turning mobility parameters. The next steps of this study are to complete recruitment of a total of 25 patients, and evaluate whether turning mobility is associated with MMSE and spatial cognition in AD patients.