Among Alzheimer's Disease Research Articles

Central cholinergic dysfunction measured “in vivo” correlates with different behavioral disorders in Alzheimer’s disease and dementia with Lewy body

Cholinergic deficits have been largely correlated to behavioral disorders in dementia. However, cholinergic deficits are not homogeneous and they are distributed differently in the basal forebrain and brainstem among Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The different cholinergic networks involved suggest different patterns of behavior symptomatology in the two groups. To correlate the deficit of cholinergic activity, measured invivo by the short latency afferent inhibition (SAI) technique, with the behavioral symptoms in patients affected by DLB and AD. Behavioral and neuropsychologic tests including Neuropsychiatric Inventory (NPI), mini-mental status examination (MMSE), and an extensive neuropsychologic investigation were administered to 18 DLB patients and 18 one-to-one matched AD patients. SAI data were compared with those from a control group of age-matched healthy individuals and the level of SAI in patients was correlated with behavioral measures. AD tended to be more impaired than DLB on long-term memory, whereas DLB were more impaired than AD on constructional praxis tasks. NPI total score was similar but with a different behavioural pattern in DLB and AD. In particular, delusions and hallucinations prevailed in DLB patients, whereas affective disturbances prevailed in AD patients. SAI was significantly reduced both in AD and DLB patients when compared with controls; SAI correlated with hallucinations in DLB patients and with euphoric manic state and disinhibition in AD patients. Reduction of cholinergic activity as evaluated by SAI measurement correlates with different behavior disorders in AD and DLB patients.

Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative‐induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy

There is a widely shared view among Alzheimer's disease (AD) investigators that the amyloid hypothesis best describes the pathogenic cascade that leads, ultimately, to neuronal degeneration and irreversible dementia. The most persuasive evidence comes from studies of damaged brains of patients in the late stages of AD and from animal studies that attempt to mimic the hereditary forms of early-onset dementia. Despite this impressive body of knowledge, we still lack the means to either arrest or prevent this horrible contagion. This essay attempts to describe what we know, and do not know, about the earliest stages of the disease, focusing on the possibility that the initial pathological changes involve oxidative-induced inflammatory damage to small blood vessels. The resulting ischemia activates amyloid-processing enzymes and other proinflammatory factors that eventually compromise neuronal functions, leading, over time, to the complex lesions that characterize advanced disease. The idea that blood vessel damage is primary has a long history and many prior advocates. The novel addition offered here is the speculation that low-abundance, gain-of-function somatic mutations of the amyloid precursor protein may be part of the triggering mechanism.

Quality of life and Alzheimer's disease: Influence of participation in a rehabilitation center.

Quality of life is seldom explored in evaluations of therapeutic interventions in Alzheimer’s disease.ObjectiveTo verify whether participation in a cognitive and functional rehabilitation program improves quality of life (QOL) among Alzheimer’s disease (AD) patients.Methods19 AD patients participated in this study, 12 of whom attended 24 multi-professional intervention sessions – the experimental group – whereas the remaining 7 comprised the control group. The following tools were used to assess changes: a) Mini-Mental State Examination (MMSE); b) Geriatric Depression Scale (GDS); c) Quality of Life in AD evaluation scale (QOL-AD); d) Open question on QOL.ResultsParticipation had no positive impact on quantitative clinical variables (MMSE, GDS, QOL-AD). The answers to the open question, examined using the Collective Subject Discourse (CSD) method, suggested that QOL improved after the intervention.ConclusionCombining pharmacological treatment with psychosocial intervention may prove to be an effective strategy to enhance the QOL of AD patients.

Computer-assisted diagnostic system for neurodegenerative dementia using brain SPECT and 3D-SSP

To develop a computer-assisted automated diagnostic system to distinguish among Alzheimer disease (AD), dementia with Lewy bodies (DLB), and other degenerative disorders in patients with mild dementia. Single photon emission computed tomography (SPECT) images with injection of N-Isopropyl-p-[(123)I]iodoamphetamine (IMP) were obtained from patients with mild degenerative dementia. First, datasets from 20 patients mild AD, 15 patients with dementia with DLB, and 17 healthy controls were used to develop an automated diagnosing system based on three-dimensional stereotactic surface projections (3D-SSP). AD- and DLB-specific regional templates were created using 3D-SSP, and critical Z scores in the templates were established. Datasets from 50 AD patients, 8 DLB patients, and 10 patients with non-AD/DLB type degenerative dementia (5 with frontotemporal dementia and 5 with progressive supranuclear palsy) were then used to test the diagnostic accuracy of the optimized automated system in comparison to the diagnostic interpretation of conventional IMP-SPECT images. These comparisons were performed to differentiate AD and DLB from non-AD/DLB and to distinguish AD from DLB. A receiver operating characteristic (ROC) analysis was performed. The area under the ROC curve (Az) and the accuracy of the automated diagnosis system were 0.89 and 82%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the visual inspection were 0.84 and 77%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the combination of visual inspection and this system were 0.96 and 91%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 66%, respectively, for AD vs. DLB patients. The system developed in the present study achieved as good discrimination of AD, DLB, and other degenerative disorders in patients with mild dementia as the commonly performed visual inspection of conventional SPECT images. A combination of visual inspection and this system is helpful in the differential diagnosis of patients with mild dementia.

Interpreting the Clinical Significance of Capacity Scores for Informed Consent in Alzheimer Disease Clinical Trials

Among Alzheimer disease (AD) patients enrolled in a clinical trial, the authors assessed the ability of a standardized capacity assessment procedure to identify persons who are capable of giving their own informed consent. Cross-sectional interview. Thirteen sites participating in a randomized and placebo controlled study of simvastatin for the treatment of mild to moderate AD. Persons with mild to moderate AD and their study partners enrolled in the simvastatin clinical trial. Interviews to assess decision-making capacity using the MacArthur Competency Assessment Tool for Clinical Research (MacCAT-CR). Judges blinded to the subject's clinical status had a high rate of agreement on patients capable of giving their own informed consent (kappa = 0.73). The understanding subscale had the best receiver operator characteristic and an analysis of positive and negative predictive values over a range of hypothetical prevalences of incapacity to consent demonstrated the value of a range of understanding cut-points. Among mild to moderate AD patients, enrolled in an actual clinical trial, these results suggest evidence based guidelines for using the MacCAT-CR understanding subscale to help guide judgments about whether a patient has the capacity to consent.

Perceived stress and resilience in Alzheimer's disease caregivers: Testing moderation and mediation models of social support

Objective: The study examined whether social support functioned as a protective, resilience factor among Alzheimer's disease (AD) caregivers. Moderation and mediation models were used to test social support amid stress and resilience. Method: A cross-sectional analysis of self-reported data was conducted. Measures of demographics, perceived stress, family support, friend support, overall social support, and resilience were administered to caregiver attendees (N = 229) of two AD caregiver conferences. Hierarchical regression analysis showed the compounded impact of predictors on resilience. Odds ratios generated probability of high resilience given high stress and social supports. Social support moderation and mediation were tested via distinct series of regression equations. Path analyses illustrated effects on the models for significant moderation and/or mediation. Results: Stress negatively influenced and accounted for most variation in resilience. Social support positively influenced resilience, and caregivers with high family support had the highest probability of elevated resilience. Moderation was observed among all support factors. No social support fulfilled the complete mediation criteria. Conclusion: Evidence of social support as a protective, moderating factor yields implications for health care practitioners who deliver services to assist AD caregivers, particularly the promotion of identification and utilization of supportive familial and peer relations.

Role of Apolipoprotein E in Anxiety

Anxiety is most common among Alzheimer's disease (AD) patients with an age at onset under age 65. Apolipoprotein E4 (apoE4) is a risk factor for developing AD at an earlier age and might contribute to this effect. In mice, apoE plays a role in the regulation of anxiety, which might involve histamine receptor-mediated signaling and steroidogenesis in the adrenal gland. In addition, human apoE isoforms have differential effects on anxiety in adult mice lacking apoE and probable AD patients. Compared to wild-type mice, mice lacking apoE and apoE4 mice showed pathological alterations in the central nucleus of the amygdala, which is involved in regulation of anxiety. ApoE4, but not mice lacking apoE, or apoE3 mice showed impaired dexamethasone suppression of plasma corticosterone. Understanding how apoE modulates measures of anxiety might help the developments of therapeutic targets to reduce or even prevent measures of anxiety in health and in dementing illnesses.

Object Perception Impairments Predict Instrumental Activities of Daily Living Dependence in Alzheimer's Disease

This study examined the contribution of object perception and spatial localization to functional dependence among Alzheimer's disease (AD) patients. Forty patients with probable AD completed measures assessing verbal recognition memory, working memory, object perception, spatial localization, semantic knowledge, and global cognition. Primary caregivers completed a measure of activities of daily living (ADLs) that included instrumental and basic self-care subscales (i.e., IADLs and BADLs, respectively). Stepwise multiple regressions revealed that global cognition accounted for significant portions of variance among the ADL total, IADL, and BADL scores. However, when global cognition was removed from the model, object perception was the only significant cognitive predictor of the ADL total and IADL subscale scores, accounting for 18.5% and 19.3% of the variance, respectively. When considering multiple cognitive components simultaneously, object perception and the integrity of the inferotemporal cortex is important in the completion of functional abilities in general and IADLs in particular among AD patients. This research was supported by F32-AG022773 (ALJ), K23-MH065857 (RPH), K24-NS002140 (GG), and P30-AG013846 (BU ADC). A portion of these data served in partial fulfillment of the PhD requirements from Drexel University for Angela L. Jefferson under the research mentorship of Dr. Guila Glosser. Portions of these data were presented in October 2003 at the 23rd annual meeting of the National Academy of Neuropsychology, Dallas, TX, and in February 2004 at the 32nd annual meeting of the International Neuropsychological Society in Baltimore, MD. The authors wish to thank the physicians who supported recruitment efforts at Brown Medical School (i.e., Dr. Norman Gordon) and the University of Pennsylvania Medical Center (i.e., Drs. Chris Clark, Jason Karlawish, and Branch Coslett). The authors also wish to thank Ms. Jennifer Gallo (Drexel) and Mr. Jay Lawrence (Brown) for their data collection efforts. Lastly, the authors wish to thank Dr. Adam Brickman for his insightful comments on earlier versions of this manuscript.

A QUALITATIVE ANALYSIS OF THE MINI MENTAL STATE EXAMINATION ON ALZHEIMER’S DISEASE PATIENTS TREATED WITH CHOLINESTERASE INHIBITORS

The improvement in cognitive performances due to cholinesterase inhibitors (ChEls) is not homogeneous among Alzheimer's disease (AD) subjects. Aim of this study is to evaluate whether a specific pattern of change in mini mental state examination (MMSE) could be observed in AD subjects after 9-month treatment with ChEls. From September 2000 to September 2002, 99 subjects enrolled in the CRONOS project. They have never been previously treated with ChEls. All of them completed both the 3- and the 9-month follow-up. The multidimensional assessment included MMSE, activity of daily living (ADL), instrumental activity of daily living (IADL), somatic health status, according to design of the CRONOSproject. The MMSE was analyzed both as a total score and disaggregated in 11 items. All subjects were divided in 2 groups according to the degree of change in MMSE total score from baseline to the 9th month. Subjects with a change </= -1 were defined as non-responders(NR), whereas those with a change >0 as responders (R). At start, no statistically significant differences were found between the 2 groups. MMSE score was significantly higher in the R group both at 3 (p < 0.0001) and 9 months (p < 0.0001), while functional status (ADL and IADL) was significantly lower in NR group at 9 months (p = 0.025; p =0.018, respectively). In MMSE qualitative analysis of 3-month, NR significantly worsened in temporal (p </= 0.05) and spatial orientation (p </= 0.001), and in delayed recall items (p </= 0.0005) in comparison to their counterpart. At 9-month the differences between the 2 groups were observed also for registration (p < 0.001), attention (p </= 0.0005), obeying oral commands (p < 0.0005), reading and obeying commands (p </= 0.0005), writing a sentence (p </= 0.0005) and copying a design (p </= 0.05). In a multivariate regression model, after adjustment for demographic (age, education, gender) and clinical factors (duration of disease), only the change at 3 months in 5 MMSE items (temporal and spatial orientation,delayed recall, obeying an oral command and reading and obeying command) is associated with global cognitive change observed at 9 months. Data suggest that the change in cognitive performances of AD subjects treated with ChEls involves few and specific MMSE items at 3-month, while it tend to generalize to almost all the others at 9-month treatment.

Biochemistry. Intramembrane proteases--mixing oil and water.

The report that the newly characterized signal peptide peptidase is an aspartic protease that resembles presenilin ([ Weihofen et al .][1]) has generated excitement among Alzheimer's disease (AD) researchers. As [Wolfe and Selkoe][2] explain in their Perspective, the new work supplements existing evidence that presenilin (which is mutated in a rare familial form of AD) is an aspartic protease responsible for the intramembranous cleavage of many substrates, including the amyloid precursor protein. [1]: http://www.sciencemag.org/cgi/content/short/296/5576/2215 [2]: http://www.sciencemag.org/cgi/content/full/296/5576/2156

Analysis of association between Alzheimer disease and the K variant of butyrylcholinesterase (BCHE-K)

Butyrylcholinesterase (BCHE) is an enzyme expressed in most human tissues. Recently, an increased odds of carrying the K variant of BCHE (BCHE-K) was reported among Alzheimer disease (AD) cases as compared with controls. We tested our data set of 245 sporadic AD cases and 241 controls for an association between BCHE-K, APOE4, and AD using logistic regression and chi-square analyses. The sib transmission disequilibrium test (S-TDT) was also used to test for differences in BCHE-K allele frequencies between 163 discordant sib-pairs selected from multiplex AD families. No statistically significant differences were noted between BCHE-K case and control allele frequencies even after stratifying by APOE4 status. S-TDT analysis between the BCHE-K variant and AD was also not significant (P=0.52). We conclude that BCHE-K is not a major genetic risk factor for AD in our study population.

A quantitative study of neurofibrillary tangles, senile plaques and astrocytes in the hippocampal subdivisions and entorhinal cortex in Alzheimer's disease, normal controls and non-Alzheimer neuropsychiatric diseases.

The present quantitative study was performed in order to discriminate pathological substrates for dementia from Alzheimer changes in normal controls (NC) and non-Alzheimer neuropsychiatric diseases (NAND). Regional densities of senile plaques (SP), neurofibrillary tangles (NFT) and astrocytes in the cornu ammonis (CA), subiculum and entorhinal cortex were measured and differences in these densities among Alzheimer's disease (AD), NAND and NC were statistically compared. Densities of NFT in the CA and subiculum were significantly higher in AD than in NAND, and densities of SP in all regions were significantly higher in AD than in NAND. Similarly, NFT density in the subiculum and SP density in all regions were higher in AD than in NC. Regional densities of astrocytes in most regions were closely correlated with those of Alzheimer changes. In conclusion, the attribution of the Alzheimer changes, particularly of NFT, to dementia is neglected when they are confined to the entorhinal cortex. However, the attribution of the Alzheimer changes to dementia should be appreciated when they spread from the entorhinal cortex to the subiculum and/or CA.

Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease.

We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.

Apolipoprotein E and Alzheimer's disease: strength of association is related to age at onset.

Apolipoprotein E (apoE) epsilon 4 allele frequency among Alzheimer's disease (AD) patients is increased compared to control subjects and is influenced by the presence of other genetic factors and age at symptom onset. We examined the relationship between age at AD symptom onset and apoE by comparing the apoE epsilon 4 allele frequency of normal, elderly control subjects (n = 107) to that in AD patients (n = 123), divided into four age-at-onset periods. Additionally, the distribution of symptom onset ages of AD patients with and without apoE epsilon 4 alleles was determined. We observed increased apoE epsilon 4 allele frequencies between the AD onset ages of 55 and 75 years, but not at the extremes of onset ages (i.e. onset between 45 and 54 years of age and after age 75). Our data suggests that having an apoE epsilon 4 allele increases the likelihood that AD patients will develop symptoms in the middle range of onset ages. At the extremes of AD onset ages, non-apoE factors, including other genetic factors and age, are more important determinants of risk of developing AD.