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1.  Medical Students' Perceptions of Dementia after Participation in Poetry Workshop with People with Dementia 
Purpose. Researchers assessed whether medical students' participation in a poetry workshop with people with Alzheimer's disease and related dementias (ADRD) affected their attitudes towards persons with ADRD. Objective. To add to the growing body of research summarizing the impact of nonclinical interventions on medical students' perspectives about people with ADRD. Design. Researchers used dementia attitudes scale (DAS) and interpretive phenomenological analysis (IPA) to analyze participants' attitudes. Setting. Osteopathic medical school and dementia care unit in the state of New Jersey. Participants. Eleven out of fourteen medical students completed the study. Measurements. Emerging themes were classified from the postintervention semistructured interviews and descriptive statistics were used to compare the preintervention to postintervention DAS. Results. Researchers found statistically significant differences between preintervention and postintervention DAS scores. Study participants scored a preintervention DAS mean, 107.09 (SD = 11.85), that changed positively and significantly to the postintervention DAS mean, 121.82 (SD = 10.38). DAS subdomains, “comfort” (P = 0.002) and “knowledge” (P = 0.01), and eleven of the twenty DAS items underwent a positive and statistically significant shift from preintervention to postintervention. IPA of the interviews yielded five primary and five secondary themes, supporting the measured statistical outcomes. Conclusion. Medical students' participation in a poetry workshop, with people with ADRD, positively impacts their attitudes.
doi:10.1155/2016/2785105
PMCID: PMC4763010  PMID: 26977333
2.  Driving Competence in Mild Dementia with Lewy Bodies: In Search of Cognitive Predictors Using Driving Simulation 
Driving is a multifactorial behaviour drawing on multiple cognitive, sensory, and physical systems. Dementia is a progressive and degenerative neurological condition that impacts the cognitive processes necessary for safe driving. While a number of studies have examined driving among individuals with Alzheimer's disease, less is known about the impact of Dementia with Lewy Bodies (DLB) on driving safety. The present study compared simulated driving performance of 15 older drivers with mild DLB with that of 21 neurologically healthy control drivers. DLB drivers showed poorer performance on all indicators of simulated driving including an increased number of collisions in the simulator and poorer composite indicators of overall driving performance. A measure of global cognitive function (i.e., the Mini Mental State Exam) was found to be related to the overall driving performance. In addition, measures of attention (i.e., Useful Field of View, UFOV) and space processing (Visual Object and Space Perception, VOSP, Test) correlated significantly with a rater's assessment of driving performance.
doi:10.1155/2015/806024
PMCID: PMC4680081  PMID: 26713169
3.  Alzheimer's Disease: Exploring the Role of Inflammation and Implications for Treatment 
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by both structural abnormalities and inflammation in the brain. While recent research has chiefly focused on the structural changes involved in AD, understanding the pathophysiology and associated inflammation of the AD brain helps to elucidate potential therapeutic and preventative options. By exploring the data supporting an inflammatory etiology of AD, we present a case for the use of existing evidence-based treatments addressing inflammation as promising options for treating and preventing AD. We present data demonstrating tumor necrosis factor alpha association with the inflammation of AD. We also discuss data supporting TNF alpha associated inflammation in traumatic brain injury, stroke, and spinal disc associated radiculopathy. We augment this previously unarticulated concept of a unifying pathophysiology of central nervous system disease, with reports of benefits of TNF alpha inhibition in many hundreds of patients with those diseases, including AD. We also assess the pathophysiologic and clinical trial evidence supporting the role of other inflammation resolving treatments in AD. In aggregate, the data from the several potentially effective therapeutic and preventative options contained within this report presents a clearer picture of next steps needed in research of treatment alternatives.
doi:10.1155/2015/515248
PMCID: PMC4664815  PMID: 26664821
4.  PET Imaging of Epigenetic Influences on Alzheimer's Disease 
The precise role of environment-gene interactions (epigenetics) in the development and progression of Alzheimer's disease (AD) is unclear. This review focuses on the premise that radiotracer-specific PET imaging allows clinicians to visualize epigenetically influenced events and that such imaging may provide new, valuable insights for preventing, diagnosing, and treating AD. Current understanding of the role of epigenetics in AD and the principles underlying the use of PET radiotracers for in vivo diagnosis are reviewed. The relative efficacies of various PET radiotracers for visualizing the epigenetic influences on AD and their use for diagnosis are discussed. For example, [18F]FAHA demonstrates sites of differential HDAC activity, [18F]FDG indirectly illuminates sites of neuronal hypomethylation, and the carbon-11 isotope-containing Pittsburgh compound B ([11C]PiB) images amyloid-beta plaque deposits. A definitive AD diagnosis is currently achievable only by postmortem histological observation of amyloid-beta plaques and tau neurofibrillary tangles. Therefore, reliable in vivo neuroimaging techniques could provide opportunities for early diagnosis and treatment of AD.
doi:10.1155/2015/575078
PMCID: PMC4633540  PMID: 26600964
5.  Vitamin D and Alzheimer's Disease: Neurocognition to Therapeutics 
Alzheimer's disease (AD), the major cause of dementia worldwide, is characterized by progressive loss of memory and cognition. The sporadic form of AD accounts for nearly 90% of the patients developing this disease. The last century has witnessed significant research to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzing postmortem AD brains and experimenting with animal and cell culture based models. However, the treatment strategies, as of now, are only symptomatic. Accumulating evidences suggested a significant association between vitamin D deficiency, dementia, and AD. This review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiological evidence of the high prevalence of hypovitaminosis D among aged and AD population. Moreover, disrupted signaling, altered utilization of vitamin D, and polymorphisms of several related genes including vitamin D receptor (VDR) also predispose to AD or AD-like neurodegeneration. This review explores the relationship between this gene-environmental influence and long term vitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials with vitamin D. It is, therefore, urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventing and halting progressive neurodegeneration in AD patients.
doi:10.1155/2015/192747
PMCID: PMC4553343  PMID: 26351614
6.  Evaluating Adult's Competency: Application of the Competency Assessment Process 
Competency assessment of adults with cognitive impairment or mental illness is a complex process that can have significant consequences for their rights. Some models put forth in the scientific literature have been proposed to guide health and social service professionals with this assessment process, but none of these appear to be complete. A new model, the Competency Assessment Process (CAP), was presented and validated in other studies. This paper adds to this corpus by presenting both the CAP model and the results of a survey given to health and social service professionals on its practical application in their clinical practice. The survey was administered to 35 participants trained in assessing competency following the CAP model. The results show that 40% of participants use the CAP to guide their assessment and the majority of those who do not yet use it plan to do so in the future. A large majority of participants consider this to be a relevant model and believe that all interdisciplinary teams should use it. These results support the relevance of the CAP model. Further research is planned to continue the study of the application of CAP in healthcare facilities.
doi:10.1155/2015/753873
PMCID: PMC4518146  PMID: 26257978
7.  Auditory and Visual Cues for Topic Maintenance with Persons Who Exhibit Dementia of Alzheimer's Type 
This study compared the effectiveness of auditory and visual redirections in facilitating topic coherence for persons with Dementia of Alzheimer's Type (DAT). Five persons with moderate stage DAT engaged in conversation with the first author. Three topics related to activities of daily living, recreational activities, food, and grooming, were broached. Each topic was presented three times to each participant: once as a baseline condition, once with auditory redirection to topic, and once with visual redirection to topic. Transcripts of the interactions were scored for overall coherence. Condition was a significant factor in that the DAT participants exhibited better topic maintenance under visual and auditory conditions as opposed to baseline. In general, the performance of the participants was not affected by the topic, except for significantly higher overall coherence ratings for the visually redirected interactions dealing with the topic of food.
doi:10.1155/2015/126064
PMCID: PMC4478409  PMID: 26171273
8.  Inhibitory Effects of Sodium Arsenite and Acacia Honey on Acetylcholinesterase in Rats 
This study was conducted to investigate the effect of sodium arsenite and Acacia honey on acetylcholinesterase (AChE) activity and electrolytes in the brain and serum of Wistar rats. Male Wistar albino rats in four groups of five rats each were treated with distilled water, sodium arsenite (5 mg/kg body weight), Acacia honey (20% v/v), and sodium arsenite and Acacia honey, daily for one week. The sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the brain with the combined treatment being more potent. Furthermore, sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the serum. Strong correlation was observed between the sodium and calcium ion levels with acetylcholinesterase activity in the brain and serum. The gas chromatography mass spectrometry analysis of Acacia honey revealed the presence of a number of bioactive compounds such as phenolics, sugar derivatives, and fatty acids. These findings suggest that sodium arsenite and/or Acacia honey modulates acetylcholinesterase activities which may be explored in the management of Alzheimer's diseases but this might be counteracted by the hepatotoxicity induced by arsenics.
doi:10.1155/2015/903603
PMCID: PMC4363587  PMID: 25821630
9.  Beneficial Effects of Teucrium polium and Metformin on Diabetes-Induced Memory Impairments and Brain Tissue Oxidative Damage in Rats 
Objective. The effects of hydroalcoholic extract of Teucrium polium and metformin on diabetes-induced memory impairment and brain tissues oxidative damage were investigated. Methods. The rats were divided into: (1) Control, (2) Diabetic, (3) Diabetic-Extract 100 (Dia-Ext 100), (4) Diabetic-Extract 200 (Dia-Ext 200), (5) Diabetic-Extract 400 (Dia-Ext 400), and (6) Diabetic-Metformin (Dia-Met). Groups 3–6 were treated by 100, 200, and 400 mg/kg of the extract or metformin, respectively, for 6 weeks (orally). Results. In passive avoidance test, the latency to enter the dark compartment in Diabetic group was lower than that of Control group (P < 0.01). In Dia-Ext 100, Dia-Ext 200, and Dia-Ext 400 and Metformin groups, the latencies were higher than those of Diabetic group (P < 0.01). Lipid peroxides levels (reported as malondialdehyde, MDA, concentration) in the brain of Diabetic group were higher than Control (P < 0.001). Treatment by all doses of the extract and metformin decreased the MDA concentration (P < 0.01). Conclusions. The results of present study showed that metformin and the hydroalcoholic extract of Teucrium polium prevent diabetes-induced memory deficits in rats. Protection against brain tissues oxidative damage might have a role in the beneficial effects of the extract and metformin.
doi:10.1155/2015/493729
PMCID: PMC4354963  PMID: 25810947
10.  Playing a Musical Instrument as a Protective Factor against Dementia and Cognitive Impairment: A Population-Based Twin Study 
Increasing evidence supports that playing a musical instrument may benefit cognitive development and health at young ages. Whether playing an instrument provides protection against dementia has not been established. In a population-based cotwin control study, we examined the association between playing a musical instrument and whether or not the twins developed dementia or cognitive impairment. Participation in playing an instrument was taken from informant-based reports of twins' leisure activities. Dementia diagnoses were based on a complete clinical workup using standard diagnostic criteria. Among 157 twin pairs discordant for dementia and cognitive impairment, 27 pairs were discordant for playing an instrument. Controlling for sex, education, and physical activity, playing a musical instrument was significantly associated with less likelihood of dementia and cognitive impairment (odds ratio [OR] = 0.36 [95% confidence interval 0.13–0.99]). These findings support further consideration of music as a modifiable protective factor against dementia and cognitive impairment.
doi:10.1155/2014/836748
PMCID: PMC4269311  PMID: 25544932
11.  Anticholinesterase and Antioxidative Properties of Aqueous Extract of Cola acuminata Seed In Vitro 
Background. Cola acuminata seed, a commonly used stimulant in Nigeria, has been reportedly used for the management of neurodegenerative diseases in folklore without scientific basis. This study sought to investigate the anticholinesterase and antioxidant properties of aqueous extracts from C. acuminata seed in vitro. Methodology. The aqueous extract of C. acuminata seed was prepared (w/v) and its effect on acetylcholinesterase (AChE) and butyrylcholinesterase activities, as well as some prooxidant (FeSO4, sodium nitroprusside (SNP), and quinolinic acid (QA)) induced lipid peroxidation in rat brain in vitro, was investigated. Results. The results revealed that C. acuminata seed extract inhibited AChE (IC50 = 14.6 μg/mL) and BChE (IC50 = 96.2 μg/mL) activities in a dose-dependent manner. Furthermore, incubation of rat's brain homogenates with some prooxidants caused a significant increase P < 0.05 in the brain malondialdehyde (MDA) content and inhibited MDA production dose-dependently and also exhibited further antioxidant properties as typified by their high radicals scavenging and Fe2+ chelating abilities. Conclusion. Inhibition of AChE and BChE activities has been the primary treatment method for mild Alzheimer's disease (AD). Therefore, one possible mechanism through which the seed exerts its neuroprotective properties is by inhibiting cholinesterase activities as well as preventing oxidative-stress-induced neurodegeneration. However, this is a preliminary study with possible physiological implications.
doi:10.1155/2014/498629
PMCID: PMC4251883  PMID: 25506036
12.  Enhancing Resourcefulness to Improve Outcomes in Family Caregivers and Persons with Alzheimer's Disease: A Pilot Randomized Trial 
This pilot randomized trial tested an intervention aimed at enhancing resourcefulness in family caregivers of persons with dementia, postulating that caregivers' emotional outcomes (anxiety and depression) and role outcomes (reward, strain, mutuality, and preparedness) would be improved, and problem behaviors in the care recipients (persons with dementia) would be reduced as a result of the intervention. Subjects were stratified by race (white or African American) and by baseline resourcefulness (high or low). Family caregivers were randomly assigned to an intervention group in which subjects attended six resourcefulness training sessions, meeting for 2 hours weekly over 6 weeks, or to a control group that received no treatment. Small to medium effects were shown for the intervention program on resourcefulness, anxiety, and preparedness of the caregivers and on frequency of behavior problems in the care recipients. Caregivers in the intervention group reported significantly more resourcefulness skills, with a medium effect at week 6 and a small effect 12 weeks later, compared with the control group. Persons with dementia had fewer behavior problems in the intervention group compared with control, although the difference was not significant. Caregivers' anxiety was reduced in the intervention group at 12 weeks.
doi:10.1155/2014/323478
PMCID: PMC4195254  PMID: 25328754
13.  The Role of the Blood-Brain Barrier in the Pathogenesis of Senile Plaques in Alzheimer's Disease 
The accumulation of beta-amyloid [Aβ] within senile plaques [SP] is characteristic of these lesions in Alzheimer's disease. The accumulation of Aβ42, in particular, in the superior temporal [ST] cortex may result from an inability of the blood brain barrier (BBB) to regulate the trans-endothelial transport and clearance of the amyloid. Lipoprotein receptor-related protein [LRP] and P-glycoprotein [P-gp] facilitate the efflux of Aβ out of the brain, whereas receptor for advanced glycation end products [RAGE] facilitates Aβ influx. Additionally, vascular endothelial growth factor [VEGF] and endothelial nitric oxide synthase [eNOS] may influence the trans-BBB transport of Aβ. In this study we examined ST samples and compared SP burden of all types with the capillary expression of LRP, p-gp, RAGE, VEGF, and e-NOS in samples from 15 control and 15 Alzheimer brains. LRP, P-gp, RAGE, VEGF, and eNOS positive capillaries and Aβ42 plaques were quantified and statistical analysis of the nonparametric data was performed using the Mann-Whitney and Kruskal-Wallis tests. In the Alzheimer condition P-gp, VEGF, and eNOS positive capillaries were negatively correlated with SP burden, but LRP and RAGE were positively correlated with SP burden. These results indicate altered BBB function in the pathogenesis of SPs in Alzheimer brains.
doi:10.1155/2014/191863
PMCID: PMC4189524  PMID: 25309772
14.  High-Dimensional Medial Lobe Morphometry: An Automated MRI Biomarker for the New AD Diagnostic Criteria 
Introduction. Medial temporal lobe atrophy assessment via magnetic resonance imaging (MRI) has been proposed in recent criteria as an in vivo diagnostic biomarker of Alzheimer's disease (AD). However, practical application of these criteria in a clinical setting will require automated MRI analysis techniques. To this end, we wished to validate our automated, high-dimensional morphometry technique to the hypothetical prediction of future clinical status from baseline data in a cohort of subjects in a large, multicentric setting, compared to currently known clinical status for these subjects. Materials and Methods. The study group consisted of 214 controls, 371 mild cognitive impairment (147 having progressed to probable AD and 224 stable), and 181 probable AD from the Alzheimer's Disease Neuroimaging Initiative, with data acquired on 58 different 1.5 T scanners. We measured the sensitivity and specificity of our technique in a hierarchical fashion, first testing the effect of intensity standardization, then between different volumes of interest, and finally its generalizability for a large, multicentric cohort. Results. We obtained 73.2% prediction accuracy with 79.5% sensitivity for the prediction of MCI progression to clinically probable AD. The positive predictive value was 81.6% for MCI progressing on average within 1.5 (0.3 s.d.) year. Conclusion. With high accuracy, the technique's ability to identify discriminant medial temporal lobe atrophy has been demonstrated in a large, multicentric environment. It is suitable as an aid for clinical diagnostic of AD.
doi:10.1155/2014/278096
PMCID: PMC4164123  PMID: 25254139
15.  Drug Utilization Pattern in Patients with Different Types of Dementia in Western India 
Background. Dementia is one of the most frequent disorders among elderly patients, reaching to epidemic proportions with an estimated 4.6 million new cases globally annually. Partially effective treatments are available for dementia. Aims & Objectives. We aim to study drugs used in dementia and find out frequency of types of Dementia. Method. This was an observational study conducted at rurally based tertiary care hospital. Prospective data was collected from outpatient department, while retrospective data was collected from medical records. Descriptive statistics were used to analyze data. Result. Total 125 prescriptions of patients diagnosed with dementia were analyzed. Alzheimer's dementia was most common (65.6%), followed by vascular dementia (21.6%), and frontotemporal dementia (10.4%), with the rarest being Lewy body dementia in (2.4%) cases. 60.57% of patients were males. Mini Mental Score Examination mean score was 15.93 ± 1.37. Frontal Battery Assessment mean score was 4.75 ± 1.01. Prescribed drugs were Donepezil (68.49%), Rivastigmine (13.63%), Donepezil + Memantine (6.43%) and Galantamine (12.83%), Quetiapine (38.46%), Lorazepam (23.07%), Clozapine (11.53%), Escitalopram (10.25%), Haloperidol (3.84%), Zolpidem, Sertraline, Olanzepine (2.56%), Nitrazepine, Lamotrigine, Fluoxetine, Tianeptine (1.28%), Folic acid, and Vitamin B12, respectively. Conclusion. Alzheimer's is the most common type of dementia while Donepezil was the most frequent drug.
doi:10.1155/2014/435202
PMCID: PMC4163299  PMID: 25243092
16.  Epidemiology of Dementia among the Elderly in Sub-Saharan Africa 
Objectives. To review epidemiologic studies on the prevalence, incidence, and risk factors of dementia in sub-Saharan Africa (SSA). Methods. A MEDLINE search (from January 1992 to December 31, 2013) of epidemiologic studies, with no language restriction, was conducted using the keywords “dementia” or “Alzheimer's” and “Africa.” We selected for review population and hospital-based studies that reported the prevalence, incidence, or risk factors of dementia in SSA in people aged 60 years and above. References of selected articles were reviewed to identify additional relevant articles that met our selection criteria. Results. Of a total of 522 articles, 41 were selected and reviewed. The reported prevalence of dementia in SSA varied widely (range: 2.29%–21.60%); Alzheimer's disease was the most prevalent type of dementia. Only two studies conducted in Nigeria reported incidence data. Major risk factors identified include older age, female gender, cardiovascular disease, and illiteracy. Conclusion. Data on the epidemiology of dementia in SSA is limited. While earlier studies reported a lower prevalence of dementia in older persons, recent studies have put these findings into question suggesting that dementia prevalence rates in SSA in fact parallel data from Western countries.
doi:10.1155/2014/195750
PMCID: PMC4142168  PMID: 25177512
17.  The Association between Apolipoprotein E Gene Polymorphism and Mild Cognitive Impairment among Different Ethnic Minority Groups in China 
The association, in different ethnic groups, of apolipoprotein E (apoE) gene polymorphism with mild cognitive impairment (MCI) has been unclear. Few studies have examined the association in Chinese minorities. The current study explores the association between apoE gene polymorphism and MCI in one of the biggest ethnic groups—the Hui—and compares it with the Han. The Minimental State Exam, Activities of Daily Living Scale, and Geriatric Depression Scale were administered to 306 ethnic Hui and 618 ethnic Han people aged ≥55 years. ApoE genotypes were determined using the high resolution melting curve method. The distribution of the apoE genotype and the frequency of alleles ε2, ε3, and ε4 were similar in the Hui and Han groups. In analyses adjusted for age, gender, and education level, the ε4 allele was a risk factor for MCI in both the Hui group (OR = 2.61, 95% CI: 1.02–6.66) and the Han group (OR = 2.36, 95% CI: 1.19–4.67), but the apoE ε2 allele was protective for MCI only in the Han group (OR = 0.48, 95% CI: 0.38–0.88). The association of some apoE genotypes with MCI may differ in different ethnic groups in China. Further studies are needed to explore this effect among different populations.
doi:10.1155/2014/150628
PMCID: PMC4138891  PMID: 25161798
18.  Comparison of the Inhibition of Monoamine Oxidase and Butyrylcholinesterase Activities by Infusions from Green Tea and Some Citrus Peels 
This study sought to investigate the effect of infusions from green tea (Camellia sinensis) and some citrus peels [shaddock (Citrus maxima), grapefruit (Citrus paradisi), and orange (Citrus sinensis)] on key enzymes relevant to the management of neurodegenerative conditions [monoamine oxidase (MAO) and butyrylcholinesterase (BChE)]. The total phenol contents and antioxidant activities as typified by their 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radicals scavenging abilities, ferric reducing antioxidant properties, and Fe2+ chelating abilities were also investigated. Green tea had the highest total phenol (43.3 mg/g) and total flavonoid (16.4 mg/g) contents, when compared to orange [total phenol (19.6 mg/g), total flavonoid (6.5 mg/g)], shaddock [total phenol (16.3 mg/g), total flavonoid (5.2 mg/g)], and grapefruit [total phenol (17.7 mg/g), total flavonoid (5.9 mg/g)]. Orange (EC50 = 1.78 mg/mL) had the highest MAO inhibitory ability, while green tea had the least MAO inhibitory ability (EC50 = 2.56 mg/mL). Similarly, green tea had the least BChE inhibitory ability (EC50 = 5.43 mg/mL) when compared to the citrus peels' infusions. However, green tea infusions had the strongest highest ABTS radical scavenging ability, reducing power, and Fe2+ chelating ability. The inhibition of MAO and BChE activities by the green tea and citrus peels infusions could make them good dietary means for the prevention/management of neurodegenerative conditions.
doi:10.1155/2014/586407
PMCID: PMC4138732  PMID: 25243093
19.  Differential Network Analyses of Alzheimer's Disease Identify Early Events in Alzheimer's Disease Pathology 
In late-onset Alzheimer's disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with low topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.
doi:10.1155/2014/721453
PMCID: PMC4132486  PMID: 25147748
20.  Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780 
Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-β peptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aβ production. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβ peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aβ1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects.
doi:10.1155/2014/431858
PMCID: PMC4109680  PMID: 25097793
21.  A Research on Functional Status, Environmental Conditions, and Risk of Falls in Dementia 
This study aimed to determine the effects of disability, physical activity, and functional status as well as environmental conditions on the risk of falls among the elderly with dementia after adjusting for sociodemographic factors. Data were derived from a group including 1210 Malaysian elderly who were demented and noninstitutionalized. The study was a national cross-sectional survey that was entitled “Determinants of Health Status among Older Malaysians.” Approximately 17% of subjects experienced falls. The results showed that ethnic non-Malay (OR = 1.73) and functional decline (OR = 1.67) significantly increased the risk of falls in samples (P < 0.05). The findings indicated that increased environmental quality (OR = 0.64) significantly decreased the risk of falls (P < 0.05). Disability, age, marital status, educational level, sex differences, and physical activity were found irrelevant to the likelihood of falls in subjects (P > 0.05). It was concluded that functional decline and ethnic non-Malay increased the risk of falls but the increased environmental quality reduced falls.
doi:10.1155/2014/769062
PMCID: PMC4055300  PMID: 24963440
22.  Altered Proteolysis in Fibroblasts of Alzheimer Patients with Predictive Implications for Subjects at Risk of Disease 
There is great interest in developing reliable biomarkers to support antemortem diagnosis of late-onset Alzheimer's disease (AD). Early prediction and diagnosis of AD might be improved by the detection of a proteolytic dysfunction in extracts from cultured AD fibroblasts, producing altered isoelectrophoretic forms of the enzyme transketolase (TK-alkaline bands). The TK profile and apolipoprotein E (APOE) genotype were examined in fibroblasts from 36 clinically diagnosed probable late-onset sporadic AD patients and 38 of their asymptomatic relatives, 29 elderly healthy individuals, 12 neurological non-AD patients, and 5 early-onset AD patients. TK alterations occurred in (i) several probable AD patients regardless of age-of-onset and severity of disease; (ii) all early-onset AD patients and APOE ε4/4 carriers; and (iii) nearly half of asymptomatic AD relatives. Normal subjects and non-AD patients were all negative. Notably, culture conditions promoting TK alterations were also effective in increasing active BACE1 levels. Overall, the TK assay might represent a low-cost laboratory tool useful for supporting AD differential diagnosis and identifying asymptomatic subjects who are at greater risk of AD and who should enter a follow-up study. Moreover, the cultured fibroblasts were confirmed as a useful in vitro model for further studies on the pathogenetic process of AD.
doi:10.1155/2014/520152
PMCID: PMC4052202  PMID: 24949214
23.  Electroencephalogram and Alzheimer's Disease: Clinical and Research Approaches 
Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by cognitive deficits, problems in activities of daily living, and behavioral disturbances. Electroencephalogram (EEG) has been demonstrated as a reliable tool in dementia research and diagnosis. The application of EEG in AD has a wide range of interest. EEG contributes to the differential diagnosis and the prognosis of the disease progression. Additionally such recordings can add important information related to the drug effectiveness. This review is prepared to form a knowledge platform for the project entitled “Cognitive Signal Processing Lab,” which is in progress in Information Technology Institute in Thessaloniki. The team tried to focus on the main research fields of AD via EEG and recent published studies.
doi:10.1155/2014/349249
PMCID: PMC4020452  PMID: 24868482
24.  Dementia Coding, Workup, and Treatment in the VA New England Healthcare System 
Growing evidence suggests that Alzheimer's disease and other types of dementia are underdiagnosed and poorly documented. In our study, we describe patterns of dementia coding and treatment in the Veteran's Administration New England Healthcare System. We conducted a retrospective cohort study with new outpatient ICD-9 codes for several types of dementia between 2002 and 2009. We examined healthcare utilization, medication use, initial dementia diagnoses, and changes in diagnoses over time by provider type. 8,999 veterans received new dementia diagnoses during the study period. Only 18.3% received a code for cognitive impairment other than dementia, most often “memory loss” (65.2%) prior to dementia diagnosis. Two-thirds of patients received their initial code from a PCP. The etiology of dementia was often never specified by ICD-9 code, even by specialists. Patients followed up exclusively by PCPs had lower rates of neuroimaging and were less likely to receive dementia medication. Emergency room visits and hospitalizations were frequent in all patients but highest in those seen by dementia specialists. Dementia medications are commonly used off-label. Our results suggest that, for the majority the patients, no prodrome of the dementia syndrome is documented with diagnostic code, and patients who do not see dementia specialists have less extensive diagnostic assessment and treatment.
doi:10.1155/2014/821894
PMCID: PMC3950831  PMID: 24701364
25.  Novel Point Mutations and A8027G Polymorphism in Mitochondrial-DNA-Encoded Cytochrome c Oxidase II Gene in Mexican Patients with Probable Alzheimer Disease 
Mitochondrial dysfunction has been thought to contribute to Alzheimer disease (AD) pathogenesis through the accumulation of mitochondrial DNA mutations and net production of reactive oxygen species (ROS). Mitochondrial cytochrome c-oxidase plays a key role in the regulation of aerobic production of energy and is composed of 13 subunits. The 3 largest subunits (I, II, and III) forming the catalytic core are encoded by mitochondrial DNA. The aim of this work was to look for mutations in mitochondrial cytochrome c-oxidase gene II (MTCO II) in blood samples from probable AD Mexican patients. MTCO II gene was sequenced in 33 patients with diagnosis of probable AD. Four patients (12%) harbored the A8027G polymorphism and three of them were early onset (EO) AD cases with familial history of the disease. In addition, other four patients with EOAD had only one of the following point mutations: A8003C, T8082C, C8201T, or G7603A. Neither of the point mutations found in this work has been described previously for AD patients, and the A8027G polymorphism has been described previously; however, it hasn't been related to AD. We will need further investigation to demonstrate the role of the point mutations of mitochondrial DNA in the pathogenesis of AD.
doi:10.1155/2014/794530
PMCID: PMC3950951  PMID: 24701363

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