The presence of amyloid deposits consisting primarily of Amyloid-beta (Abeta) fibril in the brain is a hallmark of Alzheimer's disease (AD). The morphologies of these fibrils are exquisitely sensitive to environmental conditions. Using molecular dynamics simulations combined with data from previously published solid-state NMR experiments, we propose the first atomically detailed structures of two asymmetric polymorphs of the Abeta(9-40) peptide fibril. The first corresponds to synthetic fibrils grown under quiescent conditions and the second to fibrils derived from AD patients' brain-extracts. Our core structure in both fibril structures consists of a layered structure in which three cross-beta subunits are arranged in six tightly stacked beta-sheet layers with an antiparallel hydrophobic-hydrophobic and an antiparallel polar-polar interface. The synthetic and brain-derived structures differ primarily in the side-chain orientation of one beta-strand. The presence of a large and continually exposed hydrophobic surface (buried in the symmetric agitated Abeta fibrils) may account for the higher toxicity of the asymmetric fibrils. Our model explains the effects of external perturbations on the fibril lateral architecture as well as the fibrillogenesis inhibiting action of amphiphilic molecules.

OBJECTIVE:: The overall aim was to evaluate to what extent the diagnosis of dementia subtypes, obtained by three clinical rating scales, concurred with postmortem neuropathologic (NP) diagnosis of Alzheimer disease (AD), frontotemporal dementia (FTD), vascular dementia (VaD) and mixed AD/VaD. DESIGN:: A prospective longitudinal clinical work-up with postmortem NP examination. PARTICIPANTS:: Two hundred nine patients with dementia referred for clinical evaluation and follow-up. METHODS:: The diagnostic scores in a set of three short clinical rating scales for AD, FTD, and VaD were evaluated against NP diagnoses. RESULTS:: The sensitivity and specificity of the AD scale were 0.80 and 0.87, respectively, of the FTD scale 0.93 and 0.92, respectively, and of the Hachinski Ischemic Score (HIS, VaD diagnosis) 0.69 and 0.92, respectively. Cases with mixed AD/VaD generally presented a combination of high AD and ischemic scores. A preferred cutoff score of six was identified for both the AD and FTD scales. CONCLUSIONS:: All three clinical rating scales showed a high sensitivity and specificity, in close agreement with final NP diagnosis-for the HIS a moderate sensitivity. These scales may thus be considered good diagnostic tools and are recommended for clinical and research center settings.

BACKGROUND:: Frontotemporal lobar degeneration (FTLD) encompasses different clinical subtypes but with overlapping features. Establishing whether FTLD represents a continuum or recognizes distinct subgroups may be crucial for diagnostic purposes and therapeutic approaches. OBJECTIVE:: To investigate whether cognitive profiles in a large sample of FTLD patients reflect qualitatively distinct subtypes, variants along a single continuum of severity, or severity differences within subtypes. METHOD:: Latent class analysis (LCA), exploratory factor analysis (FA), and mixture factor analysis (MFA) modeling were applied to a wide neuropsychological assessment data. LCA corresponds to qualitatively distinct subtypes, FA corresponds to quantitatively severity differences, and MFA allows for both subtypes and severity differences within subtypes. RESULTS:: The authors consecutively enrolled 314 FTLD patients. A comparison of the different models shows that MFA models provided a superior fit to the data than any of the LCA or exploratory FA models. The "best" MFA model was defined by two continuous variables evaluating the disease severity within two groups of patients ("good" and "bad" performers). These two populations have been called "benign" and "malignant" FTLD. CONCLUSIONS:: FTLD recognizes distinct subgroups beyond the disease severity, namely a benign form and a more malignant form. This observation needs to be taken into account in future clinical trials and for therapeutic approaches.

BACKGROUND:: Depression and antidepressant use are common in Alzheimer disease (AD), but the effect of antidepressant treatment for depression on longer term outcomes is unknown. The authors report the Week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD. METHODS:: One hundred thirty-one participants (sertraline = 67, placebo = 64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimer's Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, nonmood neuropsychiatric symptoms, global cognition, function, and quality of life. RESULTS:: One hundred seventeen (89.3%) participants completed all study assessments and 74 (56.5%; sertraline = 38, placebo = 36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline = 44.8%, placebo = 35.9%; odds ratio [95% CI] = 1.23 [0.64-2.35]), change in CSDD score (median difference = 0.6 [95% CI: -2.26 to 3.46], chi [df = 2] = 1.03), remission rates (sertraline = 32.8%, placebo = 21.8%; odds ratio [95% CI] = 1.61 [0.70-3.68]), or secondary outcomes. Common selective serotonin reuptake inhibitor-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events were more frequent in sertraline-randomized patients than in placebo subjects. CONCLUSIONS:: Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.

INTRODUCTION:: Alzheimer dementia (ALZ-D) is among the most frequent diseases in the elderly. Several somatic and psychiatric disorders have been suggested to be related to this diagnosis. The aim of this analysis of a large and representative U.S. nationwide inpatient sample (NIS) was to identify diagnostic correlates of ALZ-D in subjects aged 60 years and older. METHODS:: Of the total sample of 800,457 inpatient subjects ( approximately 2% of all inpatients in 2004), 315,244 individuals were 60 years or older. Of these, 9,572 (3.03%) received a diagnosis of ALZ-D, whereas 33,367 (10.59%) were diagnosed with osteoarthritis (OA) and served as a comparison group. Comparisons of potential somatic and psychiatric diagnostic correlates were conducted. RESULTS:: As determined by both univariate comparison and multivariate logistic regression analysis, after controlling for age and gender, subjects with ALZ-D (versus OA) had an overall higher rate of diagnoses of diseases of the vascular system (stroke: odds ratio 1.69; 95% confidence interval: 1.25-2.30) and psychotic and affective disorders (bipolar: 2.78 [1.26-6.12]; schizoaffective: 3.06 [2.10-4.47]). Increasing age and male gender were positively associated with the diagnosis of ALZ-D. DISCUSSION:: Many somatic diagnoses related to ALZ-D were confirmed by these analyses of the NIS. However, psychotic and affective disorders were identified to be equally significant correlates of ALZ-D, even in the presence of all other disorders. Prospective and longitudinal data are needed to investigate potential causal and temporal relationships between ALZ-D with somatic and psychiatric disorders.

OBJECTIVES:: To identify patient groups with Alzheimer disease (AD) according to the presence of psychological and behavioral syndromes and to determine the clinical differences among these groups. METHODS:: Cross-sectional and observational study of 491 patients with probable AD whom were administered the Neuropsychiatric Inventory (NPI) at the baseline visit and reevaluated after 12 months. RESULTS:: Principal component analysis (PCA) of baseline NPI data revealed three factors, including a psychosis factor (delusions, hallucinations, and aberrant motor behavior), a depressive factor (depression, anxiety, irritability, agitation, and apathy) and a hypomanic factor (euphoria and disinhibition). Cluster analysis of factor scores indicated the presence of three patient groups: one group was characterized by low scores in factors, a second group including patients with high scores in the depressive factor, and a third group that included patients with high scores in the three factors. The PCA of the NPI scores carried out after 1 year showed the persistence of the three factors. The cluster analysis of their factor scores also showed the presence of the same three patient groups but with a few differences in certain symptoms. A higher frequency of personal psychiatric history but no family history was observed in the cluster with depressive symptoms. CONCLUSIONS:: Three neuropsychiatric syndromes have been identified, which have made it possible to classify patients with AD in three distinct large groups. A temporal stability is evidenced among the group with low symptoms. Patients with high scores in depressive factor or in three factors showed greater temporal instability. Certain differences among the groups suggest that different physiopathogenic mechanisms may be involved in neuropsychiatric syndromes.

OBJECTIVE:: Visuospatial deficits are among the first symptoms of Alzheimer disease (AD) and linked to lower activation in the superior parietal cortex as assessed with functional imaging. Near-infrared spectroscopy (NIRS) is an optical method to measure changes in the concentration of oxygenated hemoglobin and deoxygenated hemoglobin in the microvascular system of the cortex. Because of its advantages in measurement situation, NIRS has proven to be especially suited for investigating psychiatric patients. The aim of this study was to probe the activation of parietal regions in patients with AD, performing a visuospatial task by means of functional NIRS (fNIRS). METHODS:: Thirteen patients with suspected mild AD and 13 healthy subjects comparable in age and gender were investigated while working on a modified version of the Benton Line Orientation Task. RESULTS:: During the spatial task, healthy subjects showed explicit parietal activation, whereas patients displayed only activation during the control task. Interestingly, there was no difference in visuospatial performance between the two groups. CONCLUSION:: The results indicate that fNIRS is able to measure parietal activation deficits in patients with AD, which could be developed into an early detection method in the future.

OBJECTIVES:: This study aimed to validate the two total scores (TS-I and TS-II) of the Consortium to Establish a Registry for Alzheimer Disease neuropsychological battery (CERAD-NP) for a large elderly population including mild cognitive impairment (MCI) and dementia patients with various etiologic backgrounds. The authors also investigated whether the addition of frontal-executive function score can improve the discrimination accuracy of the total scores for dementia and MCI. DESIGN, SETTING, AND PARTICIPANTS:: One thousand three hundred thirty-six normal comparison (NC), 583 dementia (420 AD, 111 non-AD dementia, and 52 mixed AD with non-AD dementia), and 250 MCI (223 amnestic and 27 nonamnestic MCI) individuals living in the community were included (all aged 60 years and older). RESULTS:: Both TS-I and TS-II were highly correlated with other global cognitive and functional scales. Both total scores showed, though modest, superior NC versus MCI discrimination ability to Mini-Mental State Examination (MMSE). Their discrimination ability for NC versus dementia was excellent and significantly better, especially in discriminating very mild dementia, than MMSE. The addition of frontal-executive test score to TS-I or TS-II did not make a significant improvement in dementia or MCI discrimination ability. Both of them also showed higher test-retest and interrater reliability than MMSE or any individual neuropsychological tests in the CERAD-NP. CONCLUSION:: These results strongly support the validity and usefulness of CERAD total scores for early detection and progression monitoring of MCI and dementia in clinical and research settings.

OBJECTIVE:: Apathy is the most common behavioral problem in persons with dementia of the Alzheimer type (DAT). Treatment of apathy in DAT is not systematically studied. The purpose of this study was to evaluate the response of apathy to methylphenidate treatment and to examine whether functional status improved. METHODS:: The authors conducted a 12-week open-labeled study with immediate release formulation of methylphenidate. Twenty-three patients with DAT scoring >40 on the Apathy Evaluation Scale (AES) were recruited. Repeated measures analysis of variance and correlation analysis were performed. RESULTS:: None of the patients dropped out of the study because of adverse events. Significant improvement in apathy was noted during 12 weeks. Significant improvement was also noted in depression, Mini-Mental State Examination score, and functional status. There was no correlation between changes in the AES and depression scores. CONCLUSIONS:: Methylphenidate was well tolerated in these patients with DAT. Apathy improved with the use of methylphenidate.

BACKGROUND:: Population-based diagnosis- and condition-specific health-related quality of life (HRQoL) scores are required for decision-making and research purposes. These HRQoL scores do not exist for hospital-based long-term care (LTC) residents. OBJECTIVE:: To estimate the impact of 60 diseases and 15 conditions on caregiver-assessed preference-based HRQoL. METHODS:: Residents in hospital-based LTC facilities in Ontario, Canada were identified from administrative databases containing resident minimum data set (MDS) assessments completed between August 1st, 2003 and March 31st, 2008. A preference-based HRQoL measure, the MDS Health-Status Index (MDS-HSI) score, was calculated for 66,193 residents. Average MDS-HSI scores and multivariate linear regression models were used to estimate the impact of the diagnoses and conditions, respectively. RESULTS:: After adjusting for age, sex, and other diagnoses, aphasia exhibited the largest negative relationship to the MDS-HSI (-0.085), followed by cancer (-0.072) and Alzheimer disease (-0.062). Cancer was also the second most prevalent diagnosis (27.6%). Lack of balance was a common condition (87.3%) and it had the greatest negative relationship to MDS-HSI scores among the 15 conditions (-0.099). The diagnoses and conditions regression models had R values of 0.12 and 0.34, respectively, suggesting that clinical conditions provided better explanatory variables for the MDS-HSI than diagnoses. CONCLUSIONS:: The findings suggest that diseases affect preference-based HRQoL differently in a hospital-based LTC population compared with previous studies in the general population. The population-based MDS-HSI scores from this study can be used as reference values in cost-effectiveness analyses for hospital-based LTC populations.

The principal hypothesis for pathogenesis of Alzheimer disease (AD) is the amyloid cascade hypothesis, which emphasizes an imbalance between production and clearance of beta-amyloid (Abeta) in the brain. Insulin has important effects on the regulation of the Abeta level in the brain, modulating both Abeta production and clearance. An optimal brain insulin level promotes Abeta clearance, which may play protective roles against AD. A functional human leptin receptor gene (LEPR) polymorphism, a glutamine to an arginine substitution at codon 223 (Gln223Arg), has been associated with insulin resistance capacity and an altered leptin-binding activity. The LEPR Gln223Arg polymorphism may thus play an important role in the pathogenesis of AD. In this study, we examined the association between the LEPR Gln223Arg polymorphism and late-onset Alzheimer disease (LOAD) in a Japanese population. Our sample includes 49 patients with LOAD and 134 normal controls. Our preliminary data showed no significant association between the LEPR Gln223Arg polymorphism and LOAD (genotype distribution: chi=0.11, df=2, P=0.945; allele frequency: chi=0.058, df=1, P=0.81, odds ratio=1.08, 95% confidence interval=0.59 to 2.03). Our results suggest that the LEPR polymorphism may not play a major role in the development of LOAD.

OBJECTIVE: To describe the characteristics and associated factors of Alzheimer disease (AD) patients with balance and gait impairments. METHODS: Balance and gait impairments were assessed in 380 AD patients using the Tinetti test. RESULTS: A total of 120 (31.5%) patients had an abnormal Tinetti test, 96 (25.2%) had balance impairments, and 72 (18.9%) patients presented gait impairments. Global Tinetti score was associated with age [odds ratio (OR), 1.09; 95% confidence interval (CI), 1.05-1.14], Mini-Mental State Examination (MMSE) score (OR, 0.94; 95% CI, 0.90-0.99), activities of daily living (ADL) score (OR, 0.62; 95% CI, 0.47-0.83), and being man (OR, 0.44; 95% CI, 0.25-0.78). Balance impairment was associated with age (OR, 1.11; 95% CI, 1.05-1.17), ADL score (OR, 0.60; 95% CI, 0.43-0.84), and being female (OR, 0.19; 95% CI, 0.08-0.49). Gait impairment was associated with age (OR, 1.09; 95% CI, 1.03-1.15), MMSE score (OR, 0.92; 95% CI, 0.87-0.98), ADL score (OR, 0.63; 95% CI, 0.46-0.87), body mass index (OR, 1.10; 95% CI, 1.01-1.18), presence of comorbidities (OR, 2.13; 95% CI, 1.14-3.96), and the Cornell score (OR, 2.97; 95% CI, 1.12-7.89). CONCLUSIONS: AD patients are frequently concerned with balance and gait impairments. These impairments were associated to factors related to the severity of the disease (low MMSE and low ADL); nonmodifiable factors such as age or sex; and modifiable factors such as depression, obesity, and presence of comorbidities.

We studied the impact of 2 types of dementia on marital satisfaction and on the emotional language that spouses use during conflictive marital interactions. Fifteen frontotemporal dementia (FTD) and 16 Alzheimer disease (AD) patient-caregiver couples, and 21 control couples, discussed a relationship problem in a laboratory setting. Marital satisfaction was assessed through questionnaire, and emotion language was quantified using text analysis. FTD couples reported lower marital satisfaction than AD and control couples. During the interactions, FTD and AD caregivers used significantly more negative emotion words than their patient spouses (no spousal differences were found in control couples). FTD caregivers also used more negative words than AD caregivers and controls. We interpret these findings as reflecting challenges that the behavioral changes in FTD create for maintaining a healthy marital bond.

We compared the predictive value of cerebral perfusion as measured by arterial-spin labeling magnetic resonance imaging (ASL-MRI) with MRI-derived hippocampal volume for determining future cognitive and functional decline and subsequent conversion from mild cognitive impairment to dementia. Forty-eight mild cognitive impairment subjects received structural and ASL-MRI scans at baseline and clinical and neuropsychologic assessments annually. Thirteen subjects became demented during the period of longitudinal observation (2.7+/-1.0 y). Cox regression analyses suggest that baseline hippocampal volume [relative risk (RR)=0.99, P=0.004], baseline right inferior parietal (RR=0.64, P=0.01) and right middle frontal (RR=0.73, P=0.01) perfusion were associated with conversion to dementia. Results from linear mixed effects modeling suggest that baseline perfusion from the right precuneus predicted subsequent declines in Clinical Dementia Rating Sum of Boxes (P=0.002), Functional Activates Questionnaire (P=0.01), and selective attention (ie, Stroop switching, P=0.009) whereas baseline perfusion from the right middle frontal cortex predicted subsequent episodic memory decline (ie, total recognition discriminability score from the California Verbal Learning Test, P=0.03). These results suggest that hypoperfusion as detected by ASL-MRI can predict subsequent clinical, functional, and cognitive decline and may be useful for identifying candidates for future Alzheimer disease treatment trials.

We report on a 58-year-old woman with Prader-Willi syndrome (PWS) and dementia. This case report illustrates a new research area in older adults with PWS. Dementia might be associated with PWS. In the case of dementia, more clinical studies are warranted to observe whether premature Alzheimer changes or indications of other dementia forms indeed occur more prevalent in people with PWS.

The effects on comprehension of presenting medical prescription information in a pictorial format were compared to a verbal format in healthy old adults and in patients suffering from Alzheimer disease (AD). Participants received medical prescription instructions in one of two formats: with verbal instructions only, or with verbal instructions associated with pictorial representations. The results indicated that comprehension for prescription information of healthy old subjects and AD patients was facilitated by the combined presentation. Furthermore, the pictorial instructions appeared acting on the capacity to work out a specific medication schemata, that is to say on their real, operational, understanding. These results suggest that analogical pictorial format leads more directly to the medical prescriptions' situation model and alleviates the particularization deficiency of the therapeutic schemata, independently of global cognitive functioning, visual perception, space perception and visual semantic analysis in AD. The presentation of illustrations representing medical prescriptions would allow to decrease doubts and errors, which are frequent in normal aging and even more in Alzheimer's disease, and contribute to a better medical compliency.

Aphasia is common in elderly patients in the context of vascular or neurodegenerative disorders. In some cases, aphasia is an isolated symptom, occurring suddenly after a stroke, or developing progressively as a primary progressive aphasia. The diagnosis and treatment are then very similar in older and younger patients. Therapy may be more complicated because of the high prevalence, in older patients, of associated non linguistic symptoms (attentional and dysexecutive symptoms, behavioral and psychological symptoms or sensorial deficits), fatigability, and comprehension deficits. It may then become very difficult to recognize aphasia among all these disorders and to appreciate the physiopathology. A complete evaluation of language, cognitive functions, psychopathology, and behavior is very helpful, as are neuroimaging techniques (MRI is the most relevant). A good knowledge of classical aphasic pictures associated with stroke, Alzheimer disease or related disorders, is highly recommended. Rehabilitation must be proposed even for older patients, so far as aphasia alters the communication abilities. It must be kept in mind that associated symptoms may limit considerably the therapy.

Sleep in dementias has been mainly studied in Alzheimer disease (AD). Sleep disturbances are found in 25 to 35% of subjects with AD. Subjective and objective disturbances are described. Long nocturnal awakenings disrupt sleep; total sleep time and sleep efficiency are reduced. Slow wave sleep is decreased and sometimes disappears. REM sleep percentage is also reduced and at a later stage of the disease, REM latency is increased. Sleep fragmentation can be associated with excessive daytime napping and sleepiness, and with other behavioral symptoms such as the sundowning syndrome and nocturnal agitation. Sleep abnormalities closely parallel the level of severity of dementia. The rest/activity ratio and the sleep-wake rhythms are more and more disturbed; the phase delay of the temperature rhythm is associated with the severity of the sundowning syndrome. Sleep disturbances and behavioral symptoms are the main reasons to institutionalize the patient. Sleep disturbances are related to multiple factors. Pathophysiological changes resulting of the disease itself, such as damage to the cholinergic pathways and to the circadian pacemaker in the suprachiasmatic nucleus, contribute to sleep changes in AD. Associated medical and psychiatric illness and their different treatments as well as environmental factors also induced sleep disturbances. Sleep-disordered breathing is a highly prevalent condition in AD patients and restless leg syndrome may account for nocturnal agitation. In Parkinson and in Lewy body dementias, sleep disturbances are more severe than in DA and REM sleep behavior disorder can precede by several years these diseases. Sleep attacks and sleepiness are very frequent in Parkinson disease. Specific etiologies should drive specific treatment. Several non pharmacologic treatments are usually associated to treat sleep disturbances in AD: information, increased daytime physical, social activities to minimize daytime naps and exposure to bright light. Some studies found advantages to associate melatonin in the evening.

Alzheimer's disease (AD) is the most common cause of dementia affecting the elderly. Treatment for effective cure of this complex neurodegenerative disease does not yet exist. In AD, otherwise soluble, monomeric form of amyloid ss (Ass) peptide converts into toxic, fibrillar form rich in ss-sheet content. Several immunological approaches that prevent this conversion of Ass into pathological form or that accelerate its clearance are being actively pursued worldwide. As part of these attempts, we report here, the design and characterization of a non-amyloidogenic homologue of Ass (Ass-KEK). We demonstrate that this peptide is helical in nature and retains the immunoneutralizing epitopes of native Ass. More importantly, Fab fragments of the polyclonal anti-Ass-KEK antibodies interfere with formation of Ass fibrils as well as dissociate the preformed Ass aggregates in vitro. These results suggest that non-amyloidogenic Ass-KEK may serve as a safer alternative vaccine for Alzheimer's disease.