Function In Alzheimer's Disease Patients Research Articles

The relationship between differentially expressed miR-19b-3p and cognitive function in patients with Alzheimer's disease

Objective To explore the relationship between differentially expressed miR-19b-3p and cognitive function in patients with Alzheimer's disease(AD). Methods The miRNA expression profiles of patients with AD(AD group, n=30) or healthy elderly people (NC group, n=30) were analyzed by Illumina/Solexa high-throughput sequencing technique. The miRNA lentiviral plasmids were constructed and injected into the model of AD rats. The cognitive function of rats was analyzed with water maze test. The mimics and inhibitors were synthesized and transfected into SH-SY5Y cell lines. The protein expression of β-amyloid precursor protein cleavage enzyme 1(BACE1) was detected by western blot. Results Compared with the NC group, the expression of miR-146a-5p(log2AD/Control=2.3), miR-195-5p(log2AD/Control=10.2), miR-20b-5p(log2AD/Control=15.1) in serum of AD group was up-regulated and the expression of miR-19b-3p(log2AD/Control=-8.0) and miR-125b-3p(log2AD/Control=-15.3) was down-regulated(P<0.05). Compared with the rats in the AD group((26.50±3.12)s), the rats in the AD+ miR-19b-3p group ((15.33±2.78)s) showed significantly shorter escape latencies(P<0.05). Compared with the NC group, the protein expression of BACE1 in miR-19b-3p mimetic group was decreased and the protein expression of BACE1 in inhibitor group was increased. Conclusion miR-19b-3p may improve the cognitive function of AD patients via regulating the expression of BACE1. Key words: Alzheimer's disease; Serum; miR-19b-3p; β-amyloid precursor protein cleavage enzyme 1

Repressive Coping Does Not Contribute to Anosognosia in First-Diagnosis Patients With Alzheimer Disease.

Anosognosia is common in patients with Alzheimer disease (AD) even in early stages. Although neural correlates and the impact of cognitive dysfunctions have been described, possible psychodynamic processes such as a repressive coping style as described in other illnesses, have not been examined. Our study aimed to examine possible psychological influence factors on illness perception embracing a repressive coping style and cognitive functions in AD patients in the diagnostic process. Fifty-four subjects with mild AD diagnosed in our memory clinic were enrolled. Anosognosia was evaluated using a patient-caregiver discrepancy rating. All patients underwent comprehensive neuropsychological testing. In addition, characteristics of a repressive coping style were assessed. In total, 79.6% of our patients showed a lack of awareness at least to some degree. 33.3% of the patients were classified as repressors. Repressors and nonrepressors did not differ in cognition, or the unawareness score. Multivariate regression analysis showed that repressive coping style did not significantly contribute to anosognosia, but that verbal memory and naming ability had a strong influence. Although our data indicate that a high proportion of patients with mild AD show characteristics of repressive coping, this possible defense mechanism had no influence on the awareness of illness-related deficits measured by caregiver patient discrepancy.

Therapeutics of Neurotransmitters in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by the loss of memory, multiple cognitive impairments and changes in the personality and behavior. Several decades of intense research have revealed that multiple cellular changes are involved in disease process, including synaptic damage, mitochondrial abnormalities and inflammatory responses, in addition to formation and accumulation of amyloid-β (Aβ) and phosphorylated tau. Although tremendous progress has been made in understanding the impact of neurotransmitters in the progression and pathogenesis of AD, we still do not have a drug molecule associated with neurotransmitter(s) that can delay disease process in elderly individuals and/or restore cognitive functions in AD patients. The purpose of our article is to assess the latest developments in neurotransmitters research using cell and mouse models of AD. We also updated the current status of clinical trials using neurotransmitters' agonists/antagonists in AD.

Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice

Amyloid-β (Aβ) peptide overproduction is one of the pathomechanisms contributing to Alzheimer's disease (AD). Agonists of α7 nicotinic acetylcholine receptors (α7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that α7 nAChR agonists may improve cognitive functions in AD patients. However, interactions between Aβ and α7 nAChRs have been observed, implying that high levels of Aβ may modify the effects of α7 nAChR agonists. Therefore, we tested the α7 nAChR agonist FRM-17874, an analogue of encenicline, in 8-month-old Aβ overproducing 5xFAD mice in an in vivo neurophysiological assay with a high construct and predictive validity for testing procognitive drugs. By recording changes in brainstem-stimulation–elicited hippocampal oscillations, we identified previously undescribed neurophysiological impairments in 5xFAD mice, including significantly decreased power of theta and gamma oscillations and theta-phase–gamma-amplitude coupling. Compared with their saline controls, systemically administered FRM-17874 significantly increased stimulation-induced theta power by 30% in both 5xFAD and wild-type mice. However, FRM-17874 did not impact gamma oscillation or theta-phase–gamma-amplitude coupling in either wild type or 5xFAD mice, and it did not eliminate the significant differences in these parameters between the 2 groups.

Cognitive and Functional Correlates of NPI-Q Scores and Symptom Clusters in Mildly Demented Alzheimer Patients.

Previous research has demonstrated an association between the emotional and behavioral symptoms of dementia, known as neuropsychiatric symptoms, and cognitive and functional decline among patients with Alzheimer disease (AD). The present study aimed to identify associations between neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and cognitive and functional performance. Participants were 256 AD patients enrolled in the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine. An exploratory factor analysis of the NPI-Q indicated a 2-factor structure consisting of Negative/Oppositional and Anxiety/Restlessness factors. Regression analyses revealed significant associations between greater total severity of neuropsychiatric symptoms and poorer performance on basic and Instrumental Activities of Daily Living. Greater severity of Anxiety/Restlessness symptoms was associated with poor performance on measures of visuospatial functioning and basic and instrumental activities of daily living. The Negative/Oppositional factor was not related to cognition or functioning. In summary, neuropsychiatric symptoms (particularly Anxiety/Restlessness symptoms) were related to cognition and everyday functioning. Proper assessment and treatment of these symptoms is essential for improving cognition and functioning in AD patients.

Elevated fecal calprotectin in patients with Alzheimer's dementia indicates leaky gut.

Fecal concentrations of calprotectin were examined in 22 patients with Alzheimer's disease (AD) and compared with serum concentrations of aromatic amino acids. Calprotectin concentrations were mean ± SEM 140 ± 31.9 mg/kg, 16 patients (73%) presented with concentrations outside normal (>50 mg/kg). Concentrations correlated inversely with serum levels of tryptophan, tyrosine and phenylalanine (all p < 0.05). Increased concentrations of fecal calprotectin indicate a disturbed intestinal barrier function in AD patients which could be of relevance for the lowering of essential aromatic amino acids concentrations in the blood.

Effect of hypertension on the resting-state functional connectivity in patients with Alzheimer's disease (AD)

Background/ObjectivesAlthough hypertension is known to be a risk factor for AD, the effects of hypertension on brain function in AD patients are not well understood. We investigated alterations in resting-state functional connectivity according to the presence of hypertension in AD patients by using a method of correlation analysis based on a seed region in the posterior cingulate cortex (PCC). We also determined whether differences in resting-state connectivity were associated with gray matter atrophy. MethodsThirty-seven AD patients (18 patients with hypertension and 19 patients without hypertension) underwent the resting-state functional magnetic resonance imaging. We obtained the PCC maps by a temporal correlation method, to identify alterations in the functional connectivity of the PCC in hypertensive group relative to non-hypertensive group. Voxel-based morphometry analysis was also applied to adjust the confounding effect of gray matter atrophy. ResultsWe detected a decreased connectivity to the PCC in the regions of subgenual anterior cingulated cortex (ACC) in hypertensive group relative to non-hypertensive group. However, we observed a pattern of increased connectivity between the PCC and the left inferior parietal cortex in hypertensive group. After correction for gray matter atrophy, all detected regions still remained significant. ConclusionsAltered connectivity in AD patients with hypertension suggests the possibility that hypertension impairs resting-state functional connectivity of the AD brain, inducing a compensational process outside the impaired networks or disequilibrium in brain connectivity. This finding may account for an additional contribution of hypertension to the pathophysiology of AD.

SAR studies on carboxylic acid series M(1) selective positive allosteric modulators (PAMs).

There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M1 muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M2 to M5 sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M1 is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M1 PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.

Mini-Mental State Examination subscores indicate visuomotor deficits in Alzheimer's disease patients: A cross-sectional study in a Dutch population

In diagnostics of Alzheimer's disease (AD), the Mini-Mental State Examination (MMSE) questionnaire is frequently used to test cognitive decline. The final subtest of the MMSE, in which patients have to copy two interlocking pentagons, tests a variety of visuomotor functions. Recent imaging studies suggest that visuomotor function could decline in early stage AD, as a result of degeneration of the brain networks involved. The goal of the present study was to compare memory and visuomotor function in AD patients, reflected by the MMSE subscores for orientation, recall and interlocking pentagons. The MMSE subscores for orientation, recall and interlocking pentagons of 125 AD patients was extracted from their medical history. Patients were divided into three groups based on disease duration. Using related-samples Wilcoxon signed-rank tests, the performance between subtests using normalized subscores was compared within each group. In all three groups, the subscores of recall and interlocking pentagons were significantly lower than orientation. No differences were found between the subscores of recall and interlocking pentagons. The presented data suggest that memory function and visuomotor function are equally impaired in the present study population. This could indicate that visuomotor dysfunction might be a more important clinical feature of AD than is currently assumed. This knowledge can be used to develop new tests and markers for AD reflecting deficits in visuomotor functions, such as quantification of eye and hand movements.

Detecting signs of dysphagia in patients with Alzheimer's disease with oral feeding in daily life

It is important to understand dysphagia in patients with dementia, as it is associated with malnutrition and aspiration pneumonia. Particularly in patients with Alzheimer's disease (AD), mortality from pneumonia is high and accounts for 70% of the causes of death. However, the standard swallowing tests are often difficult to use for patients with dementia, and methods to assess daily swallowing function are required. Therefore, the purpose of the present study was to identify signs of dysphagia in AD patients in daily life. A total of 155 AD patients underwent evaluation of their swallowing function (modified water swallowing test), oral status (residual teeth, occlusal contacts), oral functions (lips function, tongue function, rinsing and gargling ability), vital functions (Barthel Index, Vitality Index), nutritional status (serum albumin, body mass index), cognitive function and neurological signs (Mini-Mental State Examination, Clinical Dementia Rating, limb contractures), and diet-related assessments (storing food in the mouth, stuffing food into the mouth, appetite, caloric intake). The severity of AD was significantly associated with swallowing function (P < 0.001). According to logistic regression analysis, the factor most significantly associated with dysphagia was "rinsing ability" (P = 0.001, odds ratio 4.8, 95% confidence interval 1.9-12.1). The factors that affect swallowing function in AD patients were examined. The swallowing function of severe AD patients was poor, and an association between AD and dysphagia was shown. Defective rinsing ability was identified as a risk factor for dysphagia. Therefore, observation of daily rinsing ability appears to be useful to identify signs of dysphagia in AD patients.

Platelet a disintegrin and metallopeptidase 10 expression correlates with clock drawing test scores in Alzheimer's disease

Earlier studies have demonstrated that a disintegrin and metallopeptidase 10 (ADAM10) levels are reduced in Alzheimer's disease (AD) patients compared with healthy subjects. The objective of this study was to evaluate whether platelet ADAM10 levels correlates with the clock drawing test (CDT) scores, which is a simple and a reliable measure of visuospatial ability and executive function in AD patients. Thirty elderly patients with probable AD and 25 healthy patients forming the control group, matched by age, gender, and educational level, were evaluated. Platelet proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, and ADAM10 was identified by western blotting. The Spearman's correlation coefficient between ADAM10 and CDT was obtained for each group. The areas under the curves were used to compare the receiver operating characteristic curves. The CDT scores and platelet ADAM10 expression were significantly different between patients with AD and controls and also along the disease's progression. In AD patients, there was a positive correlation between ADAM10 expression and CDT scores. Among non-AD subjects, no correlation was found. The combination of ADAM10 and CDT was significantly better to confirm the AD diagnosis than the AUCs of ADAM10 and CDT separately. The association of blood-based biomarkers, such as ADAM10, and cognitive tests may be helpful for a more reliable AD diagnosis.

Efficacy and Tolerability of MlC601 in Patients with Mild to Moderate Alzheimer Disease who were Unable to Tolerate or Failed to Benefit from Treatment with Rivastigmine

Aim: To evaluate the efficacy and tolerability of MLC601 in patients with mild to moderate Alzheimer disease (AD). Study Design: This is an open-label pilot study. Place and Duration of Study: It was conducted at three university referral centres in Iran from September 2009 until November 2011. Methodology: One-hundred and twenty four outpatients with mild to moderate AD who had previously failed to tolerate or benefit from treatment with Rivastigmine for 6 months at a dose of 2 to 12 mg per day were switched to a MLC601 regimen of one capsule three times per day for up to 18 months. Outcome measures included adverse events (AEs), withdrawal rate, and changes in the Mini-Mental State Examination (MMSE) and the cognitive subscale of the AD Assessment Scale (ADAS-cog) relative to baseline measurements. Research Article British Journal of Medicine & Medical Research, 3(2): 341-350, 2013 342 Results: Two patients were lost to follow up, and 122 patients completed the 18-month trial. The mean age of the participants was 65.3±6.4 years (range 54-82), and 77 (63.1%) of the participants were female. Improved cognitive function was observed in the first 6 months of the regimen (ADAS-cog=-3.1±10.1; MMSE=1.2±3.0), and the stabilisation of cognitive decline was observed over the remaining 12 months (ADAScog=-1.6±7.6; MMSE=0.8±4.2). AEs were predominantly gastrointestinal and occurred in 7.3% of patients. Conclusions: MLC601 showed good tolerability and promising effects on cognitive function in AD patients during 18 months of treatment.

Strategy sequential difficulty effects in Alzheimer patients: A study in arithmetic

Objective: Consistent with Uittenhove and Lemaire (2012), we expected that strategy execution would be slower following execution of a difficult strategy than after an easy strategy (strategy sequential difficulty, SSD, effects). Moreover, we expected larger SSD effects in older adults than in young adults, and especially in Alzheimer's disease (AD) patients, a population with marked cognitive impairments. Method: A total of 25 young and older (41 AD and 25 healthy) adults were asked to execute rounding strategies to solve arithmetic problems (e.g., solving 43 + 68 by rounding operands down or up, e.g., 40 + 70 = 110). We measured solution latencies and percentage errors with a strategy as a function of the difficulty of the just-executed strategy. Results: Solution latencies were significantly shorter following the easier rounding-down strategy than following the harder rounding-up strategy, F(2, 156) = 35.8. Moreover, this effect was significantly larger in AD patients, F(1, 78) = 117.4. Conclusions: We found comparable SSD effects in young and healthy older adults but dramatically increased SSD effects in AD patients. This has implications to further our understanding of strategic aspects underlying decreased cognitive functioning in AD patients.

Human Neural Stem Cells Genetically Modified to Express Human Nerve Growth Factor (NGF) Gene Restore Cognition in the Mouse with Ibotenic Acid-Induced Cognitive Dysfunction

Alzheimer's disease (AD) is characterized by degeneration and loss of neurons and synapses throughout the brain, causing the progressive decline in cognitive function leading to dementia. No effective treatment is currently available. Nerve growth factor (NGF) therapy has been proposed as a potential treatment of preventing degeneration of basal forebrain cholinergic neurons in AD. In a previous study, AD patient's own fibroblasts genetically modified to produce NGF were transplanted directly into the brain and protected cholinergic neurons from degeneration and improved cognitive function in AD patients. In the present study, human neural stem cells (NSCs) are used in place of fibroblasts to deliver NGF in ibotenic acid-induced learning-deficit rats. Intrahippocampal injection of ibotenic acid caused severe neuronal loss, resulting in learning and memory deficit. NGF protein released by F3.NGF human NSCs in culture medium is 10-fold over the control F3 naive NSCs at 1.2 µg/10(6) cells/day. Overexpression of NGF in F3.NGF cells induced improved survival of NSCs from cytotoxic agents H2O2, Aβ, or ibotenic acid in vitro. Intrahippocampal transplantation of F3.NGF cells was found to express NGF and fully improved the learning and memory function of ibotenic acid-challenged animals. Transplanted F3.NGF cells were found all over the brain and differentiated into neurons and astrocytes. The present study demonstrates that human NSCs overexpressing NGF improve cognitive function of learning-deficit model mice.

Neuropsychological correlates of the P300 in patients with Alzheimer's disease

The P300 is a useful psychophysiological index that reflects cognitive functions; however, the relationship between P300 indices and neuropsychological tests in Alzheimer's disease (AD) patients is unclear. Thirty-one AD patients and 31 elderly normal control (NC) subjects were recruited. Age and education level were matched between the two groups. The relationship between the P300 and the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K) assessment packet (including 11 neuropsychological tests) was examined in AD patients. Compared to the NC subjects, the AD patients exhibited significantly decreased P300 amplitudes; however, there was no significant difference between the two groups in terms of P300 latency. After a permutation-based correction for multiple tests, P300 amplitudes at the Cz and Pz electrodes were significantly correlated with performance on the word list recognition, constructional praxis, and word fluency neuropsychological tests in the AD patients. Additionally, P300 latencies at the Pz and C6 electrodes were also significantly correlated with performance on the Mini-Mental State Examination, CERAD-K version (MMSE-K), and Trail Making Test part A (TMT-A) neuropsychological tests in the AD patients. The results suggest that the P300 is responsive to the deterioration of language, memory, and executive functions observed in AD patients. Although there was no significant difference between the AD patients and NC subjects in the P300 latency, P300 latency has been shown to reflect impaired global cognition and attention deficits associated with AD. Our results suggest that P300 indices could be used as biological markers that indicate impaired neuropsychological functions in AD patients.

Novel Chelators Targeting Cell Cycle Arrest, Acetylcholinesterase, and Monoamine Oxidase for Alzheimer's Therapy

The recent finding that acetylcholinesterase (AChE) colocalizes with β-amyloid (Aβ), promotes and accelerates Aβ aggregation has renewed an intense interest in developing new multitarget AChE inhibitors as potential disease-modifying drugs for Alzheimer's therapy. In this review, we first briefly discuss the linkage and complex interplay among the three characteristic hallmarks of Alzheimer's disease (AD): amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and cholinergic hypofunction. We then review the recent studies on the four marketed cholinesterase inhibitors in term of their multiple activities, potential disease-modifying effects, and the underlying mechanisms of these actions. We finally focus on a new emerging strategy or multitarget AChE inhibitors as effective drugs for AD therapy. We explore some examples of multitarget ChE inhibitors developed in our own and other laboratories, which were purposely designed to address multiple AD etiological targets. These new AChE inhibitors hold great promise for improving cognitive functions in AD patients, slowing down the disease progression, as well as treating behavior problems related to AD.

Medial temporal lobe atrophy relates to executive dysfunction in Alzheimer's disease

White matter hyperintensities (WMH) have frequently been associated with lower executive function performance. Little is known, however, about the effects of hippocampal atrophy on executive control in Alzheimer's disease (AD). The present study focused on the association of hippocampal atrophy with executive function in AD patients and examined whether a threshold effect is present, indicating that a certain amount of brain damage must be present before cognitive function becomes impaired. Finally, we examined the combined effect of hippocampal atrophy and WMH on cognitive task performance. We retrospectively collected neuropsychological and neuroimaging data of 94 AD patients. These patients completed tasks of general cognitive function, executive function, memory, and processing speed. With magnetic resonance imaging (MRI), hippocampal atrophy was rated as medial temporal lobe atrophy (MTA) and cerebrovascular disease was rated as WMH using validated visual rating scales. Medial temporal lobe atrophy (MTA) was associated with lower executive function, general cognitive function, and episodic memory performance. A threshold effect was present, indicating that severe to very severe, but not moderate, MTA was associated with lower executive function. WMH were significantly associated with a single executive test only, whereas the interaction between WMH and MTA was not significantly related to any of the cognitive tasks. Our findings suggest that AD neuropathology in itself may be responsible for executive dysfunction. Potential explanations for these findings are discussed, focusing on the role of the hippocampus in executive function tests and reduced frontal-posterior connectivity in this patient sample.

The Role of Phytochemicals in the Treatment and Prevention of Dementia

Dementia pathologies such as Alzheimer's disease (AD) are reaching epidemic proportions, yet they are not successfully managed by effective symptomatic treatments. Only five drugs have been developed to alleviate cognitive symptoms, and more effective and safe treatments are needed for both the cognitive symptoms and behavioural and psychological symptoms of dementia (BPSD). As two of these licensed drugs (cholinesterase inhibitors [ChEIs]) are naturally derived (galantamine and rivastigmine), the potential for plants to yield new therapeutic agents has stimulated extensive research to discover new ChEIs together with plant extracts, phytochemicals and their derivatives with other mechanistic effects relevant to dementia treatment. This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence. Those phytochemicals discussed include the alkaloid physostigmine, a ChEI from the calabar bean (Physostigma venenosum), which has been used as a template for the development of synthetic derivatives that inhibit acetylcholinesterase, including the drug rivastigmine. Also discussed are other ChEI alkaloids including huperzine A, from Huperzia serrata, and galantamine, originally from the snowdrop (Galanthus woronowii); both alkaloids improve cognitive functions in AD patients. Other phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression. The review also discusses plant extracts, and their known constituents, that have shown relevant mechanistic effects for dementia and promising clinical data, but require more evidence for their clinical efficacy and safety. Such plants include Ginkgo biloba, which has been extensively studied in numerous clinical trials, with most outcomes showing positive effects on cognitive functions in dementia patients; however, more reliable and consistent clinical data are needed to confirm efficacy. Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required. Other plants that are used in traditional practices of medicine have been suggested to improve cognitive functions (e.g. Polygala tenuifolia) or have been associated with alleviation of BPSD (e.g. the traditional prescription yokukansan); such remedies are often prescribed as complex mixtures of different plants, which complicates interpretation of pharmacological and clinical data and introduces additional challenges for quality control. Evidence for the role of natural products in disease prevention, the primary but considerably challenging aim with respect to dementia, is limited, but the available epidemiological and clinical evidence is discussed, with most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba. Challenges for the development of phytochemicals as drugs and for quality control of standardized plant extracts are also considered.

The relationship between motor cortex excitability and severity of Alzheimer's disease: A transcranial magnetic stimulation study

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have been limited to test motor cortical excitability. The aim of this study was to investigate the inhibitory circuits of the motor cortex and to relate these to measures of cognitive function in AD patients. Results were compared with those of a control group of healthy subjects matched for age, sex and education. Forty-five AD patients and 37 healthy volunteers were included in the study. Each participant received a neurological evaluation, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR). Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), motor evoked potential (MEP), cortical silent period (CSP), and transcallosal inhibition (TI). AD patients showed significantly reduced rMT, aMT and shorter MEP onset latency; in addition there was a prolongation of both CSP and TI. There was a significant positive correlation between the MMSE and CDR, on the one hand, and aMT and rMT, on the other hand, whereas the correlation was negative with CSP and TI durations. AD is associated with hyperexcitability of the motor cortex, which supports the hypothesis that changes in GABAb and glutamate function are important factors in cognitive impairment.

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.