Cognitive Function In Alzheimer's Disease Patients Research Articles

Methylene Blue Reduces Aβ Levels and Rescues Early Cognitive Deficit by Increasing Proteasome Activity

Promising results have emerged from a phase II clinical trial testing methylene blue (MB) as a potential therapeutic for Alzheimer disease (AD), where improvements in cognitive functions of AD patients after 6 months of MB administration have been reported. Despite these reports, no preclinical testing of MB in mammals has been published, and thus its mechanism of action in relation to AD pathology remains unknown. In order to elucidate the effects of MB on AD pathology and to determine its mechanism of action, we used a mouse model (3xTg-AD) that develops age-dependent accumulation of Aβ and tau and cognitive decline. Here, we report that chronic dietary MB treatment reduces Aβ levels and improves learning and memory deficits in the 3xTg-AD mice. The mechanisms underlying the effects of MB on Aβ pathology appears to be mediated by an increase in Aβ clearance as we show that MB increases the chymotrypsin- and trypsin-like activities of the proteasome in the brain. To our knowledge, this is the first report showing that MB increases proteasome function and ameliorates AD-like pathology in vivo. Overall, the data presented here support the use of MB for the treatment of AD and offer a possible mechanism of action.

Impacts of Hyper-Homocysteinemia and White Matter Hyper-Intensity in Alzheimers Disease Patients with Normal Creatinine: An MRI-Based Study with Longitudinal Follow-up

White matter hyper-intensities (WMHs) on magnetic resonance imaging (MRI) are commonly found in Alzheimer's disease (AD). Cerebro-vascular risk factors including plasma total homocysteine (tHcy) may result in WMHs. This study examined the association between tHcy and WMHs, and their effects on cognitive functions in AD patients over a two-year follow-up period. One hundred and fifty-seven AD patients with a clinical dementia rating of 1 or 2 were enrolled and follow-up for two years. tHcy, biochemistry tests, and mini-mental state examination (MMSE) scores were collected. WMHs were visually rated on brain MRI and classified as deep white matter hyper-intensities (DWMHs) or peri-ventricular white matter hyper-intensities (PWMHs). MMSEs were performed every six months to survey cognitive decline. In the cross sectional study, tHcy was significantly associated with total WMHs especially in DWMHs even after adjusting for age and other cerebrovascular risk factors. Initial MMSE was inversely correlated with WMH severity but not with tHcy level. In the longitudinal analysis, no differences were found either in tHcy or WMHs score in the two AD groups defined by the cognitive decline rate. tHcy is an independent risk factor for developing moderate to severe DWMHs in AD but shows non-significant effect on cognitive performance. The close association between high WMH score and poor initial MMSE suggests an additive impact in AD. The long-term effect of elevated tHcy on cognitive decline was not conclusive in the two-year follow-up period.

Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease

Elderly patients with Alzheimer's disease (AD) take more medicines, other than those for anti-dementia agents, than healthy people and are sensitive to anticholinergic medications. There are only a few reports, however, on the relationship between cognitive function and anticholinergic activity in AD patients, which is caused by taking prescribed medication. We measured serum anticholinergic activity (SAA) in 76 AD patients referred to a Psychogeriatric Unit and separated them into SAA positive group (n= 26, SAA (+) group) and SAA negative group (n= 50, SAA (-) group). The difference in demographic data and cognitive functions were compared between the two groups. The total scores of the Mini-Mental State Examination (MMSE), the score of MMSE domain of registration and recall were significantly lower (P < 0.05) and the Functional Assessment Staging (FAST) score, the number of different kinds of prescribed psychotropic medications (the number of prescribed psychotropic medications) were significantly higher (P < 0.05) in the SAA (+) group than in the SAA (-). These results suggest that a higher number of psychotropic medications prescribed leads to a tendency for SAA to be positive and that anticholinergic activity accelerates Alzheimer's pathology and decreases cognitive function, especially memory in AD patients. We should more prudently prescribe psychotropic medications to AD patients, because the prescribed psychotropic medications are one of the important causes of decline in cognitive function of AD patients by way of anticholinergic activity.

P4-016: Effect of blood pressure and physical activity on cognitive decline in patients with Alzheimer's disease

Sri Lanka has a national prevalence rate of 18% for hypertension and 36% for obesity. With a rapidly aging population where the percentage of those over 60 years is expected to reach 21% within the next ten years, Sri Lanka has a dementia prevalence rate similar to that reported from the West. Systolic hypertension and low physical activity have been identified as risk factors for the progression of cognitive impairment in patients with Alzheimer's disease (AD). Forty-three patients with mild-moderate AD attending a memory clinic are being studied prospectively. All subjects underwent detailed lifestyle and significant event history, physical examination, cognitive assessment with MMSE, and blood pressure assessment after informed consent. Diagnosis of AD was made according to established criteria. Patients with severe dementia, motor impairment, and other dementias were excluded. Regular exercise was defined as physical activity ≥30 minutes for ≥3 days per week. All subjects were assessed at baseline (enrolment in 2005), and annually for two years. Advice on physical activity and treatment for hypertension where indicated were given by the principal investigator. All subjects were on specific drug treatment for AD. The average age of subjects was 71 years and there were 24 males (55.8%) in the study cohort. The average MMSE scores at baseline (n=43), one year (n=40), and two years (n=39) were 19.9, 19.2, and 18.5 respectively. The MMSE score at one year had a significant association with the baseline MMSE and systolic blood pressure (SBP). The mean MMSE at one year was 1.8 points lower among hypertensive subjects. After adjusting for baseline MMSE and SBP, the two-year MMSE score had a significant association with regular exercise. The mean MMSE at two years was 2.6 points higher among those who exercised regularly for ≥30 min for ≥3 days per week. This cohort will be followed up prospectively. Regular physical activity and control of blood pressure have positive effects on cognitive function in AD patients. In the absence of disease modifying drug therapy, lifestyle interventions and control of vascular risk factors are important to delay cognitive decline in AD.

The new approach in development of anti-Alzheimer's disease drugs via the cholinergic hypothesis

A wide range of evidences show that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure–activity relationship (SAR) study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Recently, acetylcholinesterase inhibitors (AChEIs) have been studied for other mechanisms of action, such as neuroprotective action and lowering of beta-amyloid (β-amyloid). Donepezil also reduced beta-amyloid plaque in in vitro. The amyloid hypothesis is believed to be the most promising approach in the development of anti-AD drugs. We speculate the mechanism of lowering beta-amyloid by donepezil implicate alpha-secretase (α-secretase) enhancer.

Angiotensin-Converting Enzyme Gene in Alzheimer's Disease

Dementia has been increasing exponentially in recent years, especially in Asia. This increasing prevalence calls for the necessity of antecedent biomarkers. The angiotensin-converting enzyme (ACE) gene, located on chromosome 17q23, has been regarded as a candidate susceptibility gene for Alzheimer's disease (AD), because ACE could degrade beta-amyloid, the pathological hallmark of AD, thereby inhibiting its aggregation. The level and activity of ACE, in part, may be modulated by the insertion or deletion (indel) polymorphism of ACE gene. The indel polymorphism, consisting of the presence or absence of a 287-bp DNA fragment, has been considered the biomarker of AD, although its validity varies with race. In the Japanese, seemingly different results have been reported. One report shows significant association of insertion homozygote with AD, whereas other shows no association of indel polymorphism with AD. In the Taiwanese, the significant association of deletion homozygote with AD was found. Moreover, clinical studies have shown that using ACE inhibitors could slow the deterioration of cognitive function in AD patients, despite that ACE can degrade beta-amyloid. These heterogeneous results on the association of ACE gene with AD and clinical significance of using ACE inhibitor in AD highlight the necessity of exploring detailed mechanisms from the ACE gene to the development of AD. These detailed mechanisms and findings may serve as the basis for further study.

Effectiveness of treatment with donepezil hydrochloride and changes in regional cerebral blood flow in patients with Alzheimer's disease

The objective of this study was to elucidate the relationship between the effects of donepezil hydrochloride (donepezil) and cerebral blood flow, and to evaluate the usefulness of cerebral blood flow imaging in assessing and predicting treatment effectiveness. The subjects were 29 outpatients (12 men and 17 women; age 50-82 years; mean age 69.2 years), who had received a diagnosis of Alzheimer's disease (AD). Efficacy was evaluated before donepezil administration; after 1 month, 3 months, and 6 months of drug administration; and at 1 year after completion of administration using the Japanese version of the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog), as a measure of cognitive function. The ADAS-cog has been frequently used to evaluate cognitive function in AD patients. Patients whose ADAS-cog scores improved by 3 or more points during the observation period were classified as responders, and those with no improvement were classified as nonresponders. (123)I-IMP was used for single photon emission computed tomography cerebral blood flow scintigraphy. On the basis of ADAS-cog score improvement, 22 of the 29 patients were responders (7 men and 15 women; age 50-82 years; mean age 69.0 years) and seven were nonresponders (5 men and 2 women; age 61-80 years; mean age 70.0 years). The results indicate that a difference in cerebral blood flow responsiveness after 1 month of treatment distinguishes responders from nonresponders. After 1 month, blood flow was significantly decreased in all regions of nonresponders, whereas significant increases in blood flow were seen in the anterior frontal lobe and parietal lobe of responders. At that time point, blood flow in the basal ganglion differed significantly between the two groups, indicating that this difference in responsiveness after 1 month of treatment may distinguish responders from nonresponders. In cognitive function testing, the group that exhibited a complete response showed improvement primarily in parameters reflecting frontal lobe function. Complete responders also showed significantly greater blood flow increases in the basal ganglion and thalamus early during the treatment period. This indicates that the drug responsiveness of the basal ganglion and thalamus affects frontal lobe function and distinguishes complete responders from patients who do not exhibit such a response.

Melatonin in Alzheimer's disease and other neurodegenerative disorders

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.

Cholinesterase inhibitors: new roles and therapeutic alternatives

An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in Alzheimer disease (AD) patients. While AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15 fold from 5 to 75 nM concentrations with little cholinergic side effects in the animal. Based on these data and on clinical data showing a relation between CSF BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolyzing brain acetylcholine. Based on the changes of ChE activity in the brain of AD patients, a rational indication of selective BuChEI (or of mixed double function inhibitors) is the treatment of advanced cases. A second novel aspect of ChEI therapy is the emerging of new indications which include various forms of dementia such as dementia with Lewy Bodies, Down Syndrome, vascular dementia and Parkinson Dementia. Clinical results demonstrate examples of versatility of cholinergic enhancement.

Cholinesterase inhibitors: new roles and therapeutic alternatives

An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in Alzheimer disease (AD) patients. While AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15 fold from 5 to 75 nM concentrations with little cholinergic side effects in the animal. Based on these data and on clinical data showing a relation between CSF BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolyzing brain acetylcholine. Based on the changes of ChE activity in the brain of AD patients, a rational indication of selective BuChEI (or of mixed double function inhibitors) is the treatment of advanced cases. A second novel aspect of ChEI therapy is the emerging of new indications which include various forms of dementia such as dementia with Lewy Bodies, Down Syndrome, vascular dementia and Parkinson Dementia. Clinical results demonstrate examples of versatility of cholinergic enhancement.

Cholinesterases: new roles in brain function and in Alzheimer's disease.

The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission--experimental or pathological, such as in AD--leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on beta-amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine.

Advances and challenges in the prevention and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and accounts for one-half to three-fourths of all cases of dementia. In the United States, AD is the leading cause of a loss of independent living and subsequent institutionalization. Approximately 4 million Americans are currently diagnosed with Alzheimer's disease-which results in greater than $100 billion dollars in health care costs. This review provides a description of the cognitive and neuropathological features of AD and the challenge that aging populations around the globe pose to health care systems and to societies. A review of new and promising therapeutic strategies for the prevention of AD is discussed which includes estrogen replacement therapy and anti-inflammatory therapeutics. Pharmaceutical approaches that delay the progression of the disease, such as antioxidants, are discussed as well as therapeutic strategies for improvement of cognitive function in AD patients, including the new generation of compounds aimed at enhancing cholinergic function. This section is followed by a review of the current status on nerve growth factor trials. The final section addresses the issue of the genetic linkages of AD, the impact of transgenic and gene knockout mouse models of AD on research in the field and the potential use of gene therapy to treat AD.