Progression To Dementia In Patients Research Articles

Can the dietary inorganic nitrate supplementation mitigate the vascular dysfunction in elderly with Alzheimer’s disease?

Aging and Alzheimer disease (AD) are both characterized by progressive reduction in nitric oxide bioavailability and endothelial function impairment. Promising studies on young healthy individuals underly the positive effect of dietary nitrate supplementation on endothelial function. However, the pharmacokinetics of the plasma nitrate and nitrite (PN) and the accompanying endothelial responsiveness following the oral nitrate ingestion in healthy elderly (HE) and patients with AD is not clear. Our hypothesis was that due to the reduction of nitric oxide bioavailability during aging and AD, an equal dose of oral nitrate (ON) would ameliorate the endothelial responsiveness more in the HE and even more in patients with AD in comparison to healthy young subjects (HY). Therefore, with the aim of investigating the pharmacokinetics of PN and the time-course endothelial responsiveness in response to a single dose ON, 10 HY (25±4 YRS), 10 HE (72±8 YRS) and 13 AD (73±7 YRS) were recruited. PN levels and endothelial responsiveness (single-passive leg movement (ΔPLM)) were measured in the recruited individuals prior to (T0) and hourly for 4 hours (T1, T2, T3, and T4) after: a) a single dose of ON; and b) a single dose of placebo. As expected at T0 both PN and ΔPLM were significantly reduced in the HE and even more reduced in the AD in comparison to the HY (all p<0.001). No changes in PN nor ΔPLM were detected in any group following placebo intake. PN increased significantly in all three groups at T1 (p<0.001) and constantly increased up to T4, but no differences were detected between time points T1 to T4 in any group. ΔPLM increased significantly in all three groups at T2, reaching highest values at T4 (p<0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to HY (p<0.0001) and HE (p<0.001). Significant correlation between PN and ΔPLM was found (p<0.001, R2=0.1654). Contrary to our hypothesis, the results of this study suggest that the PN pharmacokinetics following a single dose of ON is similar in HY, HE and AD. Moreover, the expected time-course amelioration of the endothelial responsiveness was reduced in the HE and even more reduced in the AD, suggesting that other factors, rather than the nitric oxide bioavailability, are playing a role in the age- and AD-related vascular dysfunction. Ricerca di Base 2017 - RBVR17XRSA - Effectiveness of exercise and nitrate supplementation on progression of dementia in patients with Alzheimer’s disease. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Utility of Cortical Atrophy in Functional Networks as a Predictor of Progression in bvFTD

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous neurodegenerative disorder with variable rates of disease progression. Predictors of disease progression in bvFTD are significantly lacking, limiting the ability of clinical care planning. We recently showed that cortical atrophy in the frontoparietal control network (FPN) at baseline predicts the conversion to dementia in patients with Primary Progressive Aphasia (PPA). Leveraging this methodology, we hypothesized that FPN atrophy would predict progression of dementia in patients diagnosed with bvFTD.MethodWe analyzed data from 48 bvFTD patients (mean age 59.9 years, 20 Female) with very mild or mild dementia from our Frontotemporal Disorders Unit cohort and the Frontotemporal Lobar Degeneration Neuroimaging Initiative. Our primary outcome measure was change in the Clinical Dementia Rating‐FTLD Sum‐of‐Boxes (SoB) at baseline and at least one year later. Each participant underwent baseline MRI scanning for cortical thickness estimates. We ran a Pearson correlation analysis between the annualized change of CDR‐FTLD SoB from baseline to last observation, and baseline cortical network atrophy (quantified as network‐wise W scores). Vertex‐wise GLM analyses and network‐wise bivariate correlation analyses were also used to assess the relationship between network cortical atrophy and annualized CDR changes.ResultOf the 7 networks investigated, only FPN atrophy predicted annualized change in CDR‐FTLD SoB scores (r = ‐0.31, p = 0.03). That is, in bvFTD patients at the very mild/mild dementia stage, the greater the baseline FPN atrophy, the more rapid the clinical decline. Vertex‐wise GLM maps did not show that atrophy across the entire FPN predicted clinical decline. Rather, baseline atrophy in the dorsal precuneus and supramarginal gyrus nodes of the FPN was most predictive of clinical disease progression.ConclusionCortical atrophy in the FPN, and particularly in posterior regions of this network, is predictive of the rate of clinical decline in bvFTD patients, possibly due to the critical roles this network serves in executive function and affective regulation. This work could promote the use of structural imaging biomarkers to guide prognostication for bvFTD patients and their families, and to inform the design of clinical trials.

The Multifaceted Neurotoxicity of Astrocytes in Ageing and Age-Related Neurodegenerative Diseases: A Translational Perspective.

In a healthy physiological context, astrocytes are multitasking cells contributing to central nervous system (CNS) homeostasis, defense, and immunity. In cell culture or rodent models of age-related neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), numerous studies have shown that astrocytes can adopt neurotoxic phenotypes that could enhance disease progression. Chronic inflammatory responses, oxidative stress, unbalanced phagocytosis, or alteration of their core physiological roles are the main manifestations of their detrimental states. However, if astrocytes are directly involved in brain deterioration by exerting neurotoxic functions in patients with NDDs is still controversial. The large spectrum of NDDs, with often overlapping pathologies, and the technical challenges associated with the study of human brain samples complexify the analysis of astrocyte involvement in specific neurodegenerative cascades. With this review, we aim to provide a translational overview about the multi-facets of astrocyte neurotoxicity ranging from in vitro findings over mouse and human cell-based studies to rodent NDDs research and finally evidence from patient-related research. We also discuss the role of ageing in astrocytes encompassing changes in physiology and response to pathologic stimuli and how this may prime detrimental responses in NDDs. To conclude, we discuss how potentially therapeutic strategies could be adopted to alleviate or reverse astrocytic toxicity and their potential to impact neurodegeneration and dementia progression in patients.

Analysis of genetic variants associated with the removal of the pathological Abeta form in patients with Alzheimer's disease.

Alzheimer's disease (AD) is a dementia disease with a pathomechanism that is not fully understood. There are currently over 20 known genes associated with AD. These genes are involved in metabolism, the removal of abnormal products, including Aβ. Exosomes may be involved in removing abnormal proteins in AD. It is believed that the APOE, RAB11A and TSG101 genes may influence the functioning of exosomes. APOE E4 gene reduces ability to clear Aβ by affecting microglia function. TREM2, acts as a receptor for the Aβ oligomers and mediates its degradation by microglia. Both the CD33 and MS4A4A genes are also responsible for maintaining the efficiency of the immune system. So far, the correlation between these genes has not been studied in AD. The aim of the study was to analyze of genetic variants RAB11A (exon 2), TSG101 (exons 8, 9), CD33 (rs3865444), MS4A4A (rs6591561), TREM2 (rs75932628 and rs143332484) in AD patients, control subjects related to AD cases (CR), and controls subjects without family history of AD (CU). The studies were conducted on 170 individuals (AD and controls). The APOE genotype was determined by real-time PCR. The RAB11A, TSG101, CD33, MS4A4A, TREM2 genetic variants were determined by HRM and sequencing. The C/T variant of the TREM2 rs143332484 was a probable risk factor for AD. People carrying the pathogenic TREM2 rs143332484-C/T variant tended to have earlier onset of symptoms and faster progression of AD (p<0.05). Variant C/A CD33 rs3865444 was more frequent in patients with AD. The CD33 gene, a very rare polymorphism was detected: rs562148996-C/T. The C/A + C/T CD33 gene tended to occur more frequently in controls. The presence of the CD33 rs3865444-A/A might have indicated a protective effect in AD. The MS4A4A rs6591561-A variant was probably associated with the progression of dementia in patients with AD. Dementia tended to develop faster in A/A homozygotes, and slower in patients with the G/G genotype. Conversely, mutations in the RAB11A and TSG101 genes did not appear to affect the onset of AD. Genes associated with removal of pathogenic Aβ deposits seem to be involved in the pathogenesis of AD.

671-P: Liraglutide Possibly Prevents Progression of Dementia in Patients with Type 2 Diabetes

Purpose: The purpose of this study is to assess the usefulness of liraglutide in elderly patients with type 2 diabetes to prevent progression of dementia. Methods: We retrospectively reviewed 31 outpatients with 65 years of age or older, who have been treated with liraglutide for 6 years (Group G; 12 males/19 females, 73.1 ± 8.6 years-old, HbA1c 7.5 ± 0.4%, 9 patients with cerebrovascular diseases, 8 patients with cardiovascular diseases, 16 patients with insulin therapy). Daily dose of liraglutide was 0.9 mg except 2 patients (0.6 mg). We examined Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) on MRI, max-IMT measured by carotid artery ultrasonography, visceral fat area, concentrations of HbA1c and FPG, serum levels of CRP, HDL/LDL cholesterol, and TG, both before and after the treatment. Age, HbA1c, and VSRAD values-matched 16 patients who were treated with linagliptin were analyzed as a control (Group D). Results: After 6 years, VSRAD was significantly deteriorated in Group D (1.06±0.98→1.39±1.05 (p&amp;lt;0.01)) but not in Group G (1.28±0.80→1.39±1.1 (NS)). Max IMT and visceral fat are was significantly improved in Group G (2.41±1.50→2.09±0.84 (p&amp;lt;0.05), 141.1±57.2→127.2±52.9 (p&amp;lt;0.01)), but not in group D (2.04±1.01→1.99±0.68 (NS), 102.4±66.5→106.6±62.7cm2 (NS)). CRP was decreased in Group G (0.12±0.11→0.09±0.12mg/dl (p&amp;lt;0.01)). HbA1c (7.5±0.4 → 7.0±0.5 vs. 7.3±0.3 → 6.8±0.4%), FPG (137±19 → 121±11 vs. 129±12→110±15mg/dl), were significantly improved in both groups (p&amp;lt;0.01). No hypoglycemia requiring medical intervention was observed. Only TG in Group G (167±53→147±34mg/dl (p &amp;lt;0.01)) was improved in lipid parameters. During the 6 years, antidementia drugs were prescribed for 2 patients in both groups. A stroke event was found in a patient of Group D. Conclusion: Liraglutide possibly prevent progression of dementia. The reduction of visceral obesity may contribute to this beneficial effect through anti-arteriosclerosis. Disclosure M. Yoshida: None. A. Yoshida: None. E. Oh: None. N. Yamamoto: None. E. Sasaki: None. S. Yoshida: None. N. Ohsawa: None. M. Sugino: None. I. Koyama: None.

The Effect of Cognitive Training in a Day Care Center in Patients with Early Alzheimer's Disease Dementia: A Retrospective Study.

ObjectiveThis study aimed to evaluate the effect of cognitive training programs on the progression of dementia in patients with early stage Alzheimer’s disease dementia (ADD) at the day care center. MethodsFrom January 2015 to December 2018, a total of 119 patients with early ADD were evaluated. All subjects were classified into two groups according to participate in cognitive training program in addition to usual standard clinical care. Changes in scores for minimental status examination-dementia screening (MMSE-DS) and clinical dementia rating-sum of boxes (CDR-SOB) during the 12 months were compared between two groups. Multivariable logistic regression analyses were performed. ResultsAs compared to case-subjects (n=43), the MMSE-DS and CDR-SOB scores were significantly worse at 12 months in the control-subjects (n=76). A statistically significant difference between the two groups was observed due to changes in MMSE-DS (p=0.012) and CDR-SOB (p<0.001) scores. Multivariable logistic regression analysis showed that the cognitive training program (odds ratio and 95% confidence interval: 0.225, 0.070–0.725) was independently associated with less progression of ADD. ConclusionThe cognitive training program was associated with benefits in maintaining cognitive function for patients with early-stage ADD that were receiving medical treatment.

Verubecestat fails to slow progression of disease in prodromal Alzheimer's

Verubecestat reduces amyloid‐beta levels in the brain in healthy individuals and in patients with Alzheimer's disease, but a placebo‐controlled trial has found that the drug did not slow progression of dementia in patients who were at a prodromal stage of Alzheimer's disease. The research team terminated the trial for futility after finding more adverse outcomes in the medication group than in the placebo group. Study results were published April 11 in The New England Journal of Medicine.

A 'Comprehensive Visual Rating Scale' for predicting progression to dementia in patients with mild cognitive impairment.

BackgroundNumerous efforts have been made to identify biomarkers for predicting the progression of dementia in patients with mild cognitive impairment (MCI), and recently, a comprehensive visual rating scale (CVRS) based on magnetic resonance imaging (MRI) has been validated to assess structural changes in the brain of elderly patients. Based on this, the present study investigated the use of CVRS for predicting dementia and elucidated its association with cognitive change in patients with MCI over a three-year follow-up.MethodsWe included 340 patients with MCI with more than one follow-up visit. Data were obtained from the Alzheimer’s disease Neuroimaging Initiative study. We assessed all the patients using CVRS and determined their progression to dementia during a follow-up period of over 3 years. The cox proportional hazards model was used to analyze hazard ratios (HRs) of CVRS for disease progression. Further, multiple cognitive measures of the patients over time were fitted using the random effect model to assess the effect of initial CVRS score on subsequent cognitive changes.ResultsOf 340 patients, 69 (20.2%) progressed to dementia and the median baseline score (interquartile range) of CVRS significantly differed between stable MCI and progressive MCI (9 (5–13) vs 13 (8–17), p<0.001). The initial CVRS score was independently associated with an increased risk of progression to dementia (HR 1.123, 95% confidence interval [CI] 1.059–1.192). From 12 to 24 months, the effect of the interaction between CVRS and interval of follow-up visit on cognitive performance achieved significance (p<0.001).ConclusionsBaseline CVRS predicted the progression to dementia in patients with MCI, and was independently associated with longitudinal cognitive decline.

Possibility of Liraglutide for Prevention of Dementia Progression in Patients with Type 2 Diabetes

Purpose: The aim of this study was to assess the efficacy of liraglutide on prevention of dementia in elderly patients with type 2 diabetes (T2DM). Subjects and methods: We studied 34 (male 8/female 26) outpatients with 65 years or older, whose HbA1c was over 7.0% by other antidiabetic treatment. We administrated liraglutide 0.3mg before breakfast for the first week, 0.6mg for the second week, and 0.9mg after the third week. 34 subjects in the liraglutide group (G group) [8 males/ 26 females, 75.7±7.8 years old, HbA1c 7.5 ± 0.38%] were followed-up for 3 years. We examined Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) on MRI, max-IMT measured by carotid artery echo, visceral fat area, HbA1c, FPG, serum HDL/LDL level, and TG, both before and after the treatment.10 patients in the linagliptin group (D group) in which ages, HbA1c, visceral fat, and VSRAD were matched with G group were used as controls. Result: After 3 years, VSRAD was not changed in G group and was significantly deteriorated in D group (G group: 1.22±0.73→1.19±0.73 (NS) vs. G group: 1.36±0.87→1.53±0.99 (p = 0.022)). Max IMT was significantly improved in G group (2.42±1.65→2.14±1.40 (p =0.035) vs. 2.25±1.19→2.19±1.01(NS)). Visceral fat was significantly reduced in G group (137.1±54.0→128.0±59.3 (p &amp;lt;0.01) vs. 114.3±55.8 → 116.5±66.2 (NS)). HbA1c (7.5±0.38 → 6.8±0.46 vs. 7.3±0.55 → 6.9±0.42%), FPG (137±19 → 121±11 vs. 135 ±21 → 118±16 mg/dl), were significantly improved in both groups (p&amp;lt;0.01). No hypoglycemia requiring medical intervention was observed. Lipid was significantly improved only in TG in G group (TG: 162±53→145±34 (p &amp;lt;0.01) vs. 185±45→159±48 mg/dl (NS)). There was no onset of dementia. Conclusion: Liraglutide improved the glycemic control, lipid profile, and visceral obesity of elderly patients with T2DM for 3 years. In addition, the hippocampal atrophy and arteriosclerosis were not deteriorated, suggesting the possibility of being effective for prevention of dementia. Disclosure M. Yoshida: None. T. Morimoto: None. E. Oh: None. N. Yamamoto: None. K. Nagata: None. A. Saeki: None. E. Sasaki: None. S. Yoshida: None. T. Kuzuya: None. N. Ohsawa: None. M. Sugino: None.

Validation of prognostic biomarker scores for predicting progression of dementia in patients with amnestic mild cognitive impairment.

ObjectiveThe objective of this study was to develop and validate a practical computerized prognostic model that uses baseline psychometric and imaging data, including results of PET imaging of amyloid deposition, to predict the progression to dementia in patients at risk for Alzheimer’s disease (AD).Patients and methodsData from patients in a phase II trial of [18F]flutemetamol for PET imaging of brain amyloid and from the Alzheimer’s Disease Neuroimaging Initiative were used to train the prognostic model to yield a disease state index (DSI), a measure of the similarity of an individual patient’s data to data from patients in specific diagnostic groups. Inputs to the model included amyloid PET results, MRI measurements of hippocampal volume, and the results of psychometric tests. The model was subsequently validated by using data from a prospective study of an independent cohort of patients with mild cognitive impairment.ResultsIn total, data from 223 patients of the 233 enroled were suitable for analysis. The DSI predicted by the model and the risk of progression to AD dementia within 3 years were higher for patients with amyloid deposition and neurodegeneration than for patients with amyloid deposition without neurodegeneration. Rates of non-AD dementia among patients with neurodegeneration at baseline were consistent with the results of other studies. The results were consistent with the Jack model of AD progression.ConclusionThe DSI from the model that included psychometric, MRI, and PET amyloid data provides useful prognostic information in cases of mild cognitive impairment.

Hawaii Dementia Prevention Trial: A Randomized Trial Evaluating a Multifaceted Nutritional Intervention to Slow Cognitive Decline in Mild Cognitive Impairment Patients

Introduction: Alzheimer's disease (AD) has no effective treatment, nor does its “precursor” mild cognitive impairment (MCI). Methods: This is a nine-month, randomized, open, pilot trial. We are using four dietary changes and twelve supplements to slow progression of dementia in patients with MCI. Patients were randomly assigned to the diet-plus-supplement intervention group (1) or to the supplement intervention group (2). Supplementary cobalamin, folate, and S-adenosylmethionine (SAM) may reduce secretase/amyloid production. Antioxidants coenzyme Q10, ascorbates, gamma-tocopherol, and extracts of ginkgo biloba and centella asiatica were used. Zinc, copper, manganese, and selenium support endogenous antioxidant enzymes. Dietary interventions include berries, walnuts, decreasing dietary advanced glycation endproduct intake, and limiting saturated fatty acids to seven percent of calories. Results: In this small pilot study, it was surprising that participants in the supplement-only group improved more than in the supplement-plus-diet group. The Mini Mental State Examination (MMSE) was administered at baseline and every 3 months. While 9.6% of MCI patients normally degenerate to dementia each year, over nine months, participants in the supplement-only group had an average improvement in the MMSE of 10 points (out of 30 points). At the end of the intervention, average score was 29 out of 30 points, indicating a normal cognitive state. In the food-plus-supplement group no degeneration was seen, although improvement was also not seen. Conclusions: This multifaceted nutritional intervention had a positive impact by slowing the progression of dementia and reducing the risk of Alzheimer’s disease. A larger, multicenter trial is needed to confirm these results.

BODY MASS INDEX AND PROGRESSION TO DEMENTIA IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT

BODY MASS INDEX AND PROGRESSION TO DEMENTIA IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT

The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer's disease

To analyze the activity of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and neprilysin (NEP) in the blood serum in elderly people with different types of cognitive impairment and evaluate the effect of ceraxon on the biochemical parameters. Three groups of patients: without cognitive disorders (controls--CG), with amnestic mild cognitive impairment (а-MCI) and with Alzheimer's disease (AD were studied). The activity of AChE, BChE and NEP was reduced in the blood serum of patients with a-MCI and, to the greater extent, in patients with AD compared to CG and correlated with the level of cognitive dysfunction evaluated by MMSE, ADAS-cog, and other tests. For the first time, it has been shown that treatment of a-MCI patients with ceraxon (citicolin) results in an increase of the activity of blood serum AChE, BChE and NEP to the values observed in the CG. Thus, the activities of blood serum AChE, BChE and NEP reflect the level of cognitive dysfunction and can be used as prognostic biomarkers of the level of dementia progression in patients with impaired memory.

Protective effects of astragalosides on dexamethasone and Aβ25–35 induced learning and memory impairments due to decrease amyloid precursor protein expression in 12-month male rats

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder of the elderly characterized by learning and memory impairment. Stress level glucocorticoids (GCs) and β-amyloid (Aβ) peptide deposition are found to be correlated with dementia progression in patients with AD. The astragalosides (AST) was extracted from traditional Chinese herb Astragalus membranaceous. In this study, 12months male rats were treated with Aβ25–35 (10μg/rat, hippocampal CA1 injection) and dexamethasone (DEX, 1.5mg/kg, ig) and AST (8, 16 and 32mg/kg, ig) or ginsenoside Rg1 (Rg1, 5mg/kg, ig) for 14days. We investigated the protective effect of AST against DEX+Aβ25–35 injury in rats and its mechanisms of action. Our results indicate that DEX+Aβ25–35 can induce learning and memory impairments and increase APP and Aβ1–40 expression. AST (16, 32mg/kg) or Rg1 (5mg/kg) treatment significantly improve learning and memory, down-regulate the mRNA levels of APP and β-secretase, decrease expression of APP and Aβ1–40 in hippocampus. The results indicated that DEX might increase hippocampal vulnerability to Aβ25–35 and highlight the potential neuronal protection of AST.

Dexamethasone and Aβ 25–35 accelerate learning and memory impairments due to elevate amyloid precursor protein expression and neuronal apoptosis in 12-month male rats

Alzheimer's disease (AD) is an irreversible, progressive brain disorder of the elderly characterized by learning and memory impairment. Stress level glucocorticoids (GCs) and β-amyloid (Aβ) peptides deposition are found to be correlated with dementia progression in patients with AD. However, little is known about the simultaneous effects of glucocorticoids and Aβ on learning and memory impairment and its mechanism. In this study, 12-month-old male rats were chronically treated with Aβ 25–35 (10 μg/rat, hippocampal CA1 injection) and dexamethasone (DEX, 1.5 mg/kg) for 14 days to investigate the effects of DEX and Aβ 25–35 treatment on learning and memory impairments, pathological changes, neuronal ultrastructure, amyloid precursor protein (APP) processing and neuronal cell apoptosis. Our results showed that DEX or Aβ 25–35 treatment alone for 14 days had caused slight damage on learning and memory impairments and hippocampal neurons, but damages were significantly increased with DEX + Aβ 25–35 treatment. And the mRNA levels of the APP, β-secretase and caspase 3 were significantly increased after DEX + Aβ 25–35 treatment. The immunohistochemistry demonstrated that APP, Aβ 1–40, caspase 3 and cytochrome c in hippocampus CA1 were significantly increased. Furthermore, Hoechst 33258 staining and Aβ 1–40 ELISA results showed that DEX + Aβ 25–35 treatment induced hippocampus CA1 neuron apoptosis and increased the level of Aβ 1–40. The results suggest that the simultaneous effects of GCs and Aβ may have important roles in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy may increase the toxicity of Aβ and have cumulative impacts on the course of AD development and progression.

Protective Effect of Extract of Astragalus on Learning and Memory Impairments and Neurons Apoptosis Induced by Glucocorticoids in 12‐Month Male Mice

Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stress-level glucocorticoids are correlated with dementia progression in patients with AD. In this study, 12-month male mice were chronically treated with stress-level dexamethasone (DEX, 5 mg/kg) and extract of Astragalus (EA, 10, 20, and 40 mg/kg) or Ginsenoside Rg1 (Rg1, 6.5 mg/kg) for 21 days. We investigated the protective effect of EA against DEX injury in mice and its action mechanism. Our results indicate that DEX can induce learning and memory impairments and neuronal cell apoptosis. The mRNA levels of caspase-3 are selectively increased after DEX administration. The results of immunohistochemistry demonstrate that caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex are significantly increased. Furthermore, DEX treatment increased the activity of caspase-9 and caspase-3. Treatment groups with EA (20 and 40 mg/kg) or Rg1 (6.5 mg/kg) significantly improve learning and memory, downregulate the mRNA level of caspase-3, decrease expression of caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex, and inhibit activity of caspase-9 and caspase-3. The present findings highlight a possible mechanism by which stress level of DEX accelerates learning and memory impairments and increases neuronal apoptosis and the potential neuronal protection of EA.

Cognitive Impairment and Dementia in Parkinson′s DiseaseCognitive Impairment and Dementia in Parkinson′s DiseaseEmreMurat 288 pp., Oxford University Press, 2010, $110

Cognitive Impairment and Dementia in Parkinson′s Disease Murat Emre 288 pp., Oxford University Press, 2010, $110 This is an excellent book covering the neurophysiologic and neuropsychological features of dementia in Parkinson disease (PD-D). Risk factors for the development and progression of dementia in patients with PD are covered. A strong point of the book consists of the several chapters that are devoted …

Influence of White Matter Hyperintensities on the Cognition of Patients With Parkinson Disease

White matter hyperintensities (WMH) have been associated with cognitive impairment in elderly persons and in patients with Alzheimer disease. However, the role of WMH in Parkinson disease (PD) dementia remains to be elucidated. The cohort for this study comprised 71 consecutive patients with PD, all of whom completed a clinical assessment, neuropsychologic investigation, and magnetic resonance imaging of brain. WMH were rated using the semiquantitative visual rating system proposed by Scheltens et al. The PD dementia group had significantly more WMH than the PD without dementia group in the evaluated brain regions except for the infratentorial area. The WMH showed a significant correlation with age, Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination, sum of the box of Clinical Dementia Rating, and many of the cognitive domains. The linear regression model showed that the WMH was independently associated with cognitive impairment in patients with PD, regardless of age, sex, duration or severity of PD symptoms, and vascular risk factors. These findings confirm that WMH might be associated with cognitive decline in patients with PD, regardless of age, sex, education status, duration or severity of PD symptoms, and vascular risk factors. This result suggests that other nonvascular factors contribute to the progression of dementia in patients with PD.

Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice

Alzheimer's disease is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stress level glucocorticoids are correlated with dementia progression in patients with Alzheimer's disease. In this study, twelve month old male mice were chronically treated for 21 days with stress-level dexamethasone (5 mg/kg) . We investigated the pathological consequences of dexamethasone administration on learning and memory impairments, amyloid precursor protein processing and neuronal cell apoptosis in 12-month old male mice. Our results indicate that dexamethasone can induce learning and memory impairments, neuronal cell apoptosis, and mRNA levels of the amyloid precursor protein, β-secretase and caspase-3 are selectively increased after dexamethasone administration. Immunohistochemistry demonstrated that amyloid precursor protein, caspase-3 and cytochrome c in the cortex and CA1, CA3 regions of the hippocampus are significantly increased in 12-month old male mice. Furthermore, dexamethasone treatment induced cortex and hippocampus neuron apoptosis as well as increasing the activity of caspase-9 and caspase-3. These findings suggest that high levels of glucocorticoids, found in Alzheimer's disease, are not merely a consequence of the disease process but rather play a central role in the development and progression of Alzheimer's disease. Stress management or pharmacological reduction of glucocorticoids warrant additional consideration of the regimen used in Alzheimer's disease therapies.

Vascular Care in Patients with Alzheimer's Disease with Cerebrovascular Lesions—A Randomized Clinical Trial

To investigate whether vascular care slows dementia progression in patients with Alzheimer's disease with cerebrovascular lesions on neuroimaging. Multicenter randomized controlled clinical trial with 2-year follow-up. Neurological and geriatric outpatient clinics in 10 Dutch hospitals: three academic, five teaching, and two midsize community hospitals. One hundred thirty community-dwelling patients with mild dementia fulfilling clinical criteria for Alzheimer's disease with cerebrovascular lesions on neuroimaging. Patients randomized to vascular care were treated according to strict guidelines for hypercholesterolemia and hypertension. Acetylsalicylic acid, folic acid, and pyridoxine were prescribed. During visits every 3 months special attention was paid to smoking cessation, losing weight, and stimulating physical exercise. Primary outcome was disability, measured according to the Interview for Deterioration in Daily activities in Dementia (IDDD). Secondary outcomes were changes on the Mini-Mental State Examination (MMSE), the Revised Memory and Behavioural Problems Checklist (RMBPC), a composite measure of "poor outcome" (death, institutionalization, or severe clinical decline), and costs. Patients in the vascular and standard care condition declined equally on the IDDD (13.7 vs 11.0 points; difference 2.7, 95% confidence interval = -3.1-8.6). There was no treatment effect on the MMSE or RMBPC. There were no differences in institutionalization rate, "poor outcome" (41.4% vs 35.4%, P=.50), or costs. In the intervention group, there were three intracerebral hemorrhages and one gastrointestinal hemorrhage, versus none in the control group. Multicomponent vascular care, combining pharmacological and nonpharmacological interventions, does not slow decline in patients with Alzheimer's disease with cerebrovascular lesions.