piperidines and Atrophy

Topics: Aged; Atrophy; Brain; Cholinesterase Inhibitors; Diagnosis, Differential; Diagnostic Imaging; Donepezil; Female; Humans; Indans; Lewy Body Disease; Piperidines; Reference Standards

Although growth hormone (GH) is primarily associated with linear growth in childhood, it continues to have important metabolic functions in adult life. Adult GH deficiency (AGHD) is a distinct clinical entity, and GH replacement in AGHD can improve body composition, strength, aerobic capacity, and mood, and may reduce vascular disease risk. While there are some hormone-related side effects, the balance of benefits and risks is generally favorable, and several countries have approved GH for clinical use in AGHD. GH secretion declines progressively and markedly with aging, and many age-related changes resemble those of partial AGHD. This suggests that replacing GH, or stimulating GH with GH-releasing hormone or a GH secretagogue could confer benefits in normal aging similar to those observed in AGHD--in particular, could reduce the loss of muscle mass, strength, and exercise capacity leading to frailty, thereby prolonging the ability to live independently. However, while most GH studies have shown body composition effects similar to those in AGHD, functional changes have been much less inconsistent, and older adults are more sensitive to GH side effects. Preliminary reports of improved cognition are encouraging, but the overall balance of benefits and risks of GH supplementation in normal aging remains uncertain.

Topics: Aged; Aging; Atrophy; Cognition; Frail Elderly; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Injections; Muscle, Skeletal; Neurotransmitter Agents; Piperidines; Pyrazoles

The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD).. A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method.. Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups.. A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.

Topics: Aged; Alzheimer Disease; Atrophy; Disease Progression; Donepezil; Double-Blind Method; Female; France; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Organ Size; Piperidines; Prodromal Symptoms; Treatment Outcome

Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration and synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.

Topics: Analysis of Variance; Animals; Atrophy; Brain; Caloric Restriction; Case-Control Studies; Cognition Disorders; Cyclin-Dependent Kinase 5; Disease Models, Animal; Double-Blind Method; Excitatory Postsynaptic Potentials; Female; Green Fluorescent Proteins; Immunoprecipitation; In Vitro Techniques; Long-Term Potentiation; Male; Memory Disorders; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Nerve Tissue Proteins; Neurodegenerative Diseases; Phosphopyruvate Hydratase; Phosphotransferases; Piperidines; Silver Staining; Sirtuin 1; Synapses; Thiazoles; Tumor Suppressor Protein p53; Vitamin E

White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer's disease (AD) is less clear.. Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression.. 55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24 - 2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance.. PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Antioxidants; Atrophy; Brain; Cerebral Ventricles; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Piperidines; Prospective Studies; Temporal Lobe; Time Factors; Treatment Outcome; Vitamin E

The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans. Although a non-significant trend toward slowing of hippocampal atrophy rates was seen in APOE is an element of 4 carriers treated with donepezil; no treatment effect was confirmed for any MRI measure in either treatment group. For each of the four brain atrophy rate measures, APCs were greater in subjects who converted to AD than non-converters, and were greater in APOE is an element of 4 carriers than non-carriers. MRI APCs and changes in cognitive test performance were uniformly correlated in the expected direction (all p<0.000). Results of this study support the feasibility of using MRI as an outcome measure of disease progression in multi center therapeutic trials for MCI.

Topics: Aged; Aged, 80 and over; Antioxidants; Atrophy; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Hippocampus; Humans; Incidence; Indans; Longitudinal Studies; Male; Middle Aged; Piperidines; Treatment Outcome; United States; Vitamin E

Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician.. To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia.. A 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study initially designed to evaluate the efficacy of donepezil hydrochloride or vitamin E vs placebo to delay progression of MCI to dementia.. Memory assessment centers.. A total of 190 individuals with MCI.. Ratings of MTA performed using magnetic resonance images obtained at baseline. Log-rank tests and Cox proportional hazards ratios examining the significance of MTA estimates in predicting progression of MCI to dementia.. A mean MTA score greater than 2.0 was associated with a greater than 2-fold increased likelihood of progression to dementia during the observation period (hazards ratio, 2.30; 95% confidence interval, 1.09-4.92; P = .03) after controlling for age, education, sex, and baseline Mini-Mental State Examination score.. Adjusted estimates of MTA were associated with significantly increased risk of developing dementia within 3 years, suggesting that obtaining a magnetic resonance image during the evaluation of MCI may offer additional independent information about the risk of progression to dementia. Given the relatively high prevalence of MCI in the general population, use of this method as part of routine clinical evaluation may help identify individuals who might benefit from increased surveillance and future treatment.. clinicaltrials.gov Identifier: NCT00000173.

Topics: Aged; Aged, 80 and over; Atrophy; Cognition Disorders; Dementia; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Predictive Value of Tests; Reproducibility of Results; Temporal Lobe; Vitamin E

The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression.. In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups.. The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant.. Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Apolipoproteins E; Atrophy; Cholinesterase Inhibitors; Cohort Studies; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genotype; Geriatric Assessment; Hippocampus; Humans; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Time Factors; Treatment Outcome

To assess neurochemical deficits in patients with Parkinson disease (PD) associated dementia (PDD) in vivo.. The authors performed combined PET with N-[11C]-methyl-4-piperidyl acetate (MP4A) and 18F-fluorodopa (FDOPA) for evaluation of cholinergic and dopaminergic transmitter changes in 17 non-demented patients with PD and 10 patients with PDD. Data were compared to 31 age-matched controls by a combined region-of-interest and voxel-based Statistical Parametric Mapping analysis.. The striatal FDOPA uptake was significantly decreased in PD and PDD without differences between the groups. The global cortical MP4A binding was severely reduced in PDD (29.7%, p < 0.001 vs controls) and moderately decreased in PD (10.7%, p < 0.01 vs controls). The PDD group had lower parietal MP4A uptake rates than did patients with PD. Frontal and temporo-parietal cortices showed a significant covariance of striatal FDOPA reduction and decreased MP4A binding in patients with PDD.. While non-demented patients with Parkinson disease had a moderate cholinergic dysfunction, subjects with Parkinson disease associated dementia (PDD) presented with a severe cholinergic deficit in various cortical regions. The finding of a closely associated striatal FDOPA and cortical MP4A binding reduction suggests a common disease process leading to a complex transmitter deficiency syndrome in PDD.

Topics: Acetates; Acetylcholine; Acetylcholinesterase; Aged; Atrophy; Binding, Competitive; Brain; Brain Mapping; Dihydroxyphenylalanine; Dopamine; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways; Neuropsychological Tests; Parkinson Disease; Piperidines; Positron-Emission Tomography; Synaptic Transmission

Atrophy of the substantia innominata on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, may be an in vivo marker of cholinergic damage. We attempted to investigate whether the MRI features of the substantia innominata predict response to donepezil treatment in Alzheimer's patients. The thickness of the substantia innominata was measured on the coronal T2-weighted MRI through the anterior commissure. Seventy-two patients treated with donepezil were divided into the two groups (responders and non-responders) based on changes in Mini-Mental State Examination (MMSE) scores from baseline to study endpoint. Atrophy of the substantia innominata was more pronounced in responders than non-responders. There was a significant inverse correlation between thickness of the substantia innominata and MMSE changes. MRI analysis of the substantia innominata may be a simple and practical method for the selection of possible treatment responders.

Topics: Acetylcholine; Aged; Alzheimer Disease; Atrophy; Cholinergic Fibers; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Neurons; Patient Selection; Piperidines; Predictive Value of Tests; Substantia Innominata; Treatment Outcome

Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

Topics: Animals; Antigens, Differentiation; Arginase; Atrophy; Benzoxazines; Chemokine CCL2; Cytoprotection; Disease Models, Animal; Hypertension, Renovascular; Kidney; Lectins, C-Type; Macrophages; Male; Mannose Receptor; Mannose-Binding Lectins; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Nephritis, Interstitial; Nitric Oxide Synthase Type II; Piperidines; Protective Agents; Receptors, CCR2; Receptors, Cell Surface; Renal Artery Obstruction; Signal Transduction; Time Factors

Topics: Alzheimer Disease; Atrophy; Cholinesterase Inhibitors; Donepezil; Female; Hemianopsia; Humans; Indans; Magnetic Resonance Imaging; Middle Aged; Neuropsychological Tests; Occipital Lobe; Parietal Lobe; Piperidines; Visual Field Tests; Visual Fields

The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans.. Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment.. A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not.. These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency.

Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Atrophy; Cognition Disorders; Donepezil; Entorhinal Cortex; Female; Hippocampus; Humans; Indans; Language; Lewy Body Disease; Magnetic Resonance Imaging; Male; Mental Recall; Neuropsychological Tests; Nootropic Agents; Piperidines; Software; Temporal Lobe; Verbal Behavior

Small intestine luminal nutrient sensing may be crucial for modulating physiological functions. However, its mechanism of action is incompletely understood. We used a model of enteral nutrient deprivation, or total parenteral nutrition (TPN), resulting in intestinal mucosal atrophy and decreased epithelial barrier function (EBF). We examined how a single amino acid, glutamate (GLM), modulates intestinal epithelial cell (IEC) growth and EBF. Controls were chow-fed mice, T1 receptor-3 (T1R3)-knockout (KO) mice, and treatment with the metabotropic glutamate receptor (mGluR)-5 antagonist MTEP. TPN significantly changed the amount of T1Rs, GLM receptors, and transporters, and GLM prevented these changes. GLM significantly prevented TPN-associated intestinal atrophy (2.5-fold increase in IEC proliferation) and was dependent on up-regulation of the protein kinase pAkt, but independent of T1R3 and mGluR5 signaling. GLM led to a loss of EBF with TPN (60% increase in FITC-dextran permeability, 40% decline in transepithelial resistance); via T1R3, it protected EBF, whereas mGluR5 was associated with EBF loss. GLM led to a decline in circulating glucagon-like peptide 2 (GLP-2) during TPN. The decline was regulated by T1R3 and mGluR5, suggesting a novel negative regulator pathway for IEC proliferation not previously described. Loss of luminal nutrients with TPN administration may widely affect intestinal taste sensing. GLM has previously unrecognized actions on IEC growth and EBF. Restoring luminal sensing via GLM could be a strategy for patients on TPN.

Topics: Animal Nutrition Sciences; Animals; Atrophy; Cell Proliferation; Disease Models, Animal; Down-Regulation; Epithelial Cells; Epithelium; Food; Glucagon-Like Peptide 2; Glutamic Acid; Intestinal Mucosa; Jejunum; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Parenteral Nutrition, Total; Permeability; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, G-Protein-Coupled; Signal Transduction; Thiazoles

Donepezil is an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD). In this study, we used a voxel-based specific regional analysis system for AD (VSRAD) to analyze the hippocampal volume and to assess the pharmacologic effects of donepezil as a disease modifier.. A total of 185 AD patients underwent MRI, 120 (43 men and 77 women, 77.8 ± 7.1 years) without and 65 (29 men and 36 women, 78.4 ± 6.0 years) with donepezil treatment. VSRAD was compared in both groups and against a database of 80 normal subjects. The Z-score was used to assess the degree of hippocampal atrophy.. No significant difference between the groups was found for age, sex, or Z-scores, but a significant difference was found for mean Mini-Mental State Examination (MMSE) scores (p = 0.02, Student's t test). Single regression analysis showed no significant association between Z-scores and MMSE scores in the treated group (p = 0.494), but a significant association in the untreated group (p = 0.001) was observed. This implies that the MMSE score becomes lower when the Z-score is higher in the untreated group, whereas there is no significant trend in the treated group.. Donepezil affects the relationship between hippocampal volume and cognitive function and may therefore have a pharmacologic effect as a disease modifier.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Case-Control Studies; Donepezil; Female; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Organ Size; Piperidines; Regression Analysis; Treatment Outcome

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-) mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

Topics: Animals; Atrophy; Chemistry Techniques, Synthetic; Drug Design; Ligands; Macular Degeneration; Male; Mice; Molecular Docking Simulation; Piperidines; Prealbumin; Protein Conformation; Rats; Retinol-Binding Proteins, Plasma; Stargardt Disease; Structure-Activity Relationship

We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, the BAD-responders showed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that the BAD-responders had larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Biomarkers; Brain; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Piperidines; Treatment Outcome

Previous studies using magnetic resonance imaging (MRI) showed that dementia with Lewy bodies (DLB) had less atrophy in some medial temporal structures than Alzheimer's disease (AD). However, very few studies have focused on the entorhinal cortex, which is closely related to episodic memory. We compared the degree of entorhinal cortex atrophy between the two types of dementia using the voxel-based specific regional analysis system for AD (VSRAD) targeting this region.. The subjects consisted of 60 patients with DLB and 210 patients with AD. The degree of entorhinal cortex atrophy was quantified by application of the VSRAD to MRI data, and a Z score >2 was defined as significant atrophy.. The DLB group had significantly lower Z scores than the AD group (mean ± SD: 2.25 ± 1.10 vs. 2.85 ± 1.33, p < 0.01). The analysis of covariance with possible confounding factors as covariates also showed that Z scores were significantly lower in the DLB group than in the AD group (p < 0.01). The proportion of patients with atrophy was significantly lower in the DLB group than in the AD group (53 vs. 72%, p < 0.01).. The present study using the VSRAD suggests that DLB shows less atrophy in the entorhinal cortex than AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Data Interpretation, Statistical; Donepezil; Entorhinal Cortex; Female; Humans; Image Processing, Computer-Assisted; Indans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Nootropic Agents; Piperidines; Sex Characteristics

Topics: Aged; Alzheimer Disease; Atrophy; Cohort Studies; Combined Modality Therapy; Donepezil; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Indans; Life Style; Magnetic Resonance Imaging; Male; Mental Status Schedule; Motor Activity; Neuropsychological Tests; Nootropic Agents; Piperidines; Positron-Emission Tomography; Psychometrics; Remission, Spontaneous; Temporal Lobe

To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia.. MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields.. A dementia clinic at Washington University School of Medicine.. Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention Patients were prescribed donepezil by their physician.. Hippocampal volume loss and surface deformation.. There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations.. Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome.

Topics: Aged; Alzheimer Disease; Atrophy; Brain Mapping; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nerve Degeneration; Piperidines; Time Factors; Treatment Outcome

Topics: Adult; Alzheimer Disease; Atrophy; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder, Major; Diagnosis, Differential; Donepezil; Drug Therapy, Combination; Female; Follow-Up Studies; Functional Laterality; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Piperidines; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome

We report the case of a patient who presented visual hallucinations and identification disorders associated with a Capgras syndrome. During the Capgras periods, there was not only a misidentification of his wife's face, but also a more global perceptive and emotional sexual identification disorder. Thus, he had sexual intercourse with his wife's "double" without having the slightest recollection feeling of familiarity towards his "wife" and even changed his sexual habits. To the best of our knowledge, he is the only neurological patient who made his wife a mistress. Starting from this global familiarity loss, we discuss the mechanism of Capgras delusion with reference to the role of the implicit system of face recognition. Such behavior of familiarity loss not only with face but also with all intimacy aspects argues for a specific disconnection between the ventral visual pathway of face identification and the limbic system involved in emotional and episodic memory contents.

Topics: Aged; Amnesia; Antipsychotic Agents; Atrophy; Brain; Capgras Syndrome; Donepezil; Hallucinations; Humans; Indans; Male; Memory; Movement Disorders; Neuropsychological Tests; Nootropic Agents; Parkinsonian Disorders; Piperidines; Recognition, Psychology; Risperidone; Sexual Behavior; Spouses; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Little is known about cholinergic activity in the early stage of Alzheimer's disease. We investigated differences in the distribution of vesicular acetylcholine transporter, using [(123)I]-iodobenzovesamicol ([(123)I]-IBVM) and Single Photon Computed Tomography (SPECT), in early AD and age-matched controls.. Sixteen subjects (8 controls, 8 AD) underwent [(123)I]-IBVM SPECT scanning, T1-weighted anatomic scan by Magnetic Resonance (MR) imaging and Mini-Mental State Evaluation (MMSE). Image analysis, using Statistical Parametric Mapping (SPM 02), involved coregistration of each SPECT image to the MR scan, followed by a spatial normalisation to the Montreal Neurological Institute standard brain and a smoothing of each SPECT image. Group effects and correlation were assessed using two sample t-tests and linear regression respectively. Atrophy difference between the two groups was assessed by voxel-based morphometry of each MR scan using two sample t-tests.. MMSE values were significantly different between AD and controls. Relative to controls, a significant decrease in [(123)I]-IBVM binding (47-62%) was apparent in AD subjects in cingulate cortex and parahippocampal-amygdaloïd complex. These patterns appeared to be independent of atrophied areas.. These results strongly suggest that a cholinergic degeneration occurs in the early stage of AD and could be involved in the impairment of the cognitive functions. Imaging of cholinergic neurons used here could be effective in identifying potential cholinergic treatment responders.

Topics: Aged; Alzheimer Disease; Atrophy; Brain; Female; Humans; Image Processing, Computer-Assisted; Isotope Labeling; Male; Neuropsychological Tests; Piperidines; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Vesicular Acetylcholine Transport Proteins

The authors present a case of a patient with dementia with mood symptoms and multiple neurological manifestations of fragile X-associated tremor/ataxia syndrome (FXTAS). Despite a gradually deteriorating neurological course, he was managed for 2 years with combination therapy of donepezil and venlafaxine, which resulted in improvement and relative stabilization of his psychiatric status. Psychiatrists are hereby alerted to the description of a novel dementia syndrome that may respond to pharmacological intervention commonly used for other dementias.

Topics: Aged; Antidepressive Agents, Second-Generation; Ataxia; Atrophy; Brain; Cyclohexanols; Dementia; Dominance, Cerebral; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Carrier Screening; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Mood Disorders; Neurologic Examination; Neuropsychological Tests; Nootropic Agents; Piperidines; Tremor; Trinucleotide Repeats; Venlafaxine Hydrochloride

Topics: Aged; Alzheimer Disease; Atrophy; Brain; Cognition Disorders; Disease Progression; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Herein we provide evidence that substance P (SP) and its neurokinin-1 receptor (NK-1R) expressed on thymocytes counteract thymus depletion induced by neonatal capsaicin (CPS) treatment by affecting thymocyte proliferation and apoptotic death. SP administration reversed the CPS-mediated inhibitory effects on the total thymocyte number and subset distribution, namely CD4+ and CD4- CD8- cells, through its interaction with NK-1R as shown by concomitant NK-1R (SR140333) antagonist administration. SP-induced enhancement of thymus cellularity parallels its ability of inhibiting the thymocyte apoptotic program. Indeed, exogenously administered SP completely nullified CPS-induced apoptosis, and SR140333 abrogated the SP-mediated protective effect. SP administration also stimulated concanavalin A (Con A)-induced thymocyte proliferation of CPS-treated rats, completely reversing the CPS-induced inhibition. The SP-mediated stimulation of Con A-induced thymocyte proliferation was NK-1R dependent as shown by concomitant administration of SP and SR140333 to CPS-treated rats. Our results also demonstrate that CPS treatment induces a marked decrease of thymocyte PPT-A mRNA level and endogenous SP content as evaluated by quantitative RT-PCR, in situ hybridization and cytofluorimetric analysis. By contrast, NK-1R mRNA levels were increased in thymocytes from CPS-treated rats. Exogenous SP administration augmented PPT-A, SP and NK-1R thymocyte expression in CPS-treated rats, and this enhancement was antagonized by SR140333 administration. Overall, our results strongly suggest that the immunomodulatory effects of neonatal CPS treatment on rat thymocyte functions are dependent on vanilloid-mediated regulation of SP and NK-1R functional expression by neuronal and immune cells.

Topics: Adjuvants, Immunologic; Animals; Animals, Newborn; Atrophy; Autocrine Communication; Binding Sites; Capsaicin; Cell Death; Cell Division; Concanavalin A; Growth Substances; Male; Neuroimmunomodulation; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; RNA, Messenger; Substance P; T-Lymphocytes; Thymus Gland; Up-Regulation

To investigate whether atrophy of the substantia innominata as shown on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, predicts response to donepezil treatment in patients with Alzheimer's disease (AD), we studied correlations between the thickness of the substantia innominata and clinical efficacy. Eighty-two patients were divided into responders, including transiently and continuously responding groups, and nonresponders, based on the changes in the Mini-Mental State Examination (MMSE) score from baseline at 3 months and at 12 months. Atrophy of the substantia innominata was more pronounced in transiently and continuously responding groups than nonresponders, but no significant change in the thickness between transiently and continuously responding groups was found. The MMSE score changes from baseline at 3 months and at 12 months significantly inversely correlated with the thickness of the substantia innominata. Logistic regression analysis revealed that the overall discrimination rate with the thickness of the substantia innominata was 70% between responders and nonresponders. We conclude that atrophy of the substantia innominata on MRI helps to predict response to donepezil treatment in patients with AD.

Topics: Aged; Alzheimer Disease; Atrophy; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Logistic Models; Magnetic Resonance Imaging; Male; Piperidines; Prognosis; Substantia Innominata; Treatment Outcome

Topics: Aged; Alzheimer Disease; Atrophy; Cerebral Cortex; Delirium; Donepezil; Humans; Indans; Male; Nootropic Agents; Piperidines

Primary progressive aphasia (PPA) is an uncommon neurodegenerative syndrome characterized by a relatively isolated dissolution of language function at the beginning, followed by deterioration of general cognitive function and of activities of daily living after 2 or more years. On account of neuropathological and clinical findings, PPA is supposed to form part of the spectrum of frontotemporal lobar degeneration. We present a case study of a 66-year-old woman with a probable fluent progressive aphasia. She initially experienced word amnesia and developed after 2 - 3 years gradual regression of word comprehension, over-fluent speech with semantic paraphasias, and at last generalized dementia. In addition to minor bilateral cortical volume reduction on CCT, MRI showed left temporal lobe atrophy involving hippocampus, SPECT revealed reduced uptake left frontal and temporal.

Topics: Aged; Aphasia, Primary Progressive; Atrophy; Brain; Dementia; Diagnosis, Differential; Donepezil; Female; Humans; Indans; Nootropic Agents; Piperidines; Radionuclide Imaging; Temporal Lobe; Treatment Outcome

Twenty-two beagles were divided into two equal groups, and the right hindlimb of each animal was immobilized at 105 degrees of knee flexion by external fixation. After 10 weeks of fixation, the device was removed, allowing free mobility for the following 5 weeks. Each day throughout the 15 weeks, one group received a growth hormone secretagogue (treatment) at a dose of 5 mg/kg, and the other received a lactose placebo (control). At weeks 0, 10, and 15, strength as indicated by maximum isometric extension torque was measured in the right hindlimb, biopsies of the vastus lateralis muscle were taken, and the dogs were weighed. Weekly blood samples were analyzed for insulin-like growth factor-1, blood urea nitrogen, and creatine phosphokinase. Between weeks 0 and 10, tetanic torque declined by about 60% (p < 0.001) in both groups, with no significant difference between the groups (p > 0.7). Between weeks 10 and 15, tetanic torque in the treated group increased by 0.81 Nm; this was significantly greater than the increase of 0.25 Nm in the placebo group (p < 0.05). The diameters of slow (type-1) and fast (type-2) fibers measured from the vastus lateralis muscle followed the same trend. At all time points, fiber diameter correlated strongly with torque; this argues against nonmuscular causes such as nerve injury for strength loss. The mean levels of insulin-like growth factor-1 increased 100% by week 4 in the treated group and remained elevated by about 60% throughout the experiment. Levels of insulin-like growth factor-1 in the placebo group decreased 30% within week 1 and remained depressed throughout the experiment. Our interpretation of these data suggests that the growth hormone secretagogue elevated levels of serum insulin-like growth factor-1, which in turn increased the size and strength of the quadriceps muscle during remobilization. These data may ultimately have therapeutic application to humans during rehabilitation after prolonged inactivity.

Topics: Animals; Atrophy; Dogs; External Fixators; Female; Growth Hormone; Hindlimb; Immobilization; Insulin-Like Growth Factor I; Muscle Contraction; Muscle Fibers, Skeletal; Muscle, Skeletal; Piperidines; Placebos; Spiro Compounds; Torque

Topics: 3,4-Dihydroxyphenylacetic Acid; 3,4-Methylenedioxyamphetamine; 5,7-Dihydroxytryptamine; Animals; Atrophy; Brain; Cerebral Ventricles; Designer Drugs; Dopamine; Fenfluramine; Homovanillic Acid; Hydroxyindoleacetic Acid; Injections, Intraventricular; Male; N-Methyl-3,4-methylenedioxyamphetamine; Norepinephrine; Organ Specificity; Paroxetine; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Stereoisomerism

Topics: Acute Disease; Administration, Oral; Animals; Atrophy; Body Weight; Chronic Disease; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Organ Size; Piperidines; Rats; Rifampin; Sex Factors; Testis