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Background: Alzheimer's disease (AD) is affected by apolipoprotein E (ApoE); however, its effects assessed by means of cognitive tests and by neuroimaging have not been sufficiently studied. Methods: We administered the Alzheimer's Disease Assessment Scale (ADAS) and single-photon emission computed tomography imaging in patients with AD medicated with donepezil at baseline and after 1 year. Patients were classified as with or without ApoE4 and we evaluated the progress of AD. Results: Analysis of covariance showed that cerebral blood flow after 1 year in subjects with ApoE4 is significantly reduced in some areas including the left lenticular nucleus, left thalamus, and right hippocampus compared with subjects without ApoE4. Paired t tests showed significantly reduced blood flow in several regions including the right hippocampus in subjects with ApoE4 and significant deterioration of ideational praxis in subjects without ApoE4. Conclusion: This study provides evidence that supports the notion of ApoE4 playing an important role in the progress of AD.

Background: There is a close genetic relationship between Alzheimer's disease (AD) and Down syndrome (DS), AD being the most severe mental disorder affecting ageing individuals with DS. The objective of the present study was to evaluate the efficacy of cognitive rehabilitation interventions in DS patients with AD by means of a critical literature review. Summary: Because AD is progressive and irreversible, treatment is aimed at delaying and reducing the cognitive and functional decline in order to preserve or improve quality of life. The effects that pharmacological treatments and cognitive interventions have on elderly individuals with AD are well documented. Recent clinical trials have investigated the use of pharmacological treatment in DS patients with AD, generating preliminary results that have been unfavourable. Key Messages: There is a clear lack of studies addressing the efficacy of cognitive rehabilitation interventions in DS patients with AD, and there is an urgent need for studies providing evidence to inform decisions regarding the appropriate choice of treatment strategies.

Background: After hypertensive disorders of pregnancy, more subjective cognitive complaints and white matter lesions are reported compared to women after normal pregnancies. Both have a causal relationship with Alzheimer's disease (AD). Aim: To investigate if women whose pregnancy was complicated by hypertensive disorders have an increased risk of AD. Methods: A case-control study in women with AD from the Alzheimer Center of the VU University Medical Center Amsterdam and women without AD. Paper and telephone surveys were performed. Results: The response rate was 85.2%. No relation between women with (n = 104) and without AD (n = 129) reporting pregnancies complicated by hypertensive disorders (p = 0.11) was found. Women with early-onset AD reported hypertensive disorders of pregnancy more often (p = 0.02) compared to women with late-onset AD. Conclusion: A reported history of hypertensive disorders of pregnancy appears not to be associated with AD later in life.

Aim: To investigate whether 1-step titration of the rivastigmine patch (initiated at 5 cm2 and titrated to 10 cm2 after 4 weeks) is well tolerated in Japanese patients with Alzheimer's disease (AD) as compared to 3-step titration (initiated at 2.5 cm2 and titrated by 2.5 cm2 every 4 weeks to 10 cm2). Methods: A 24-week, multicenter, randomized, double-blind study was conducted in Japan between July 2012 and May 2014. Patients with mild to moderate AD aged 50-85 years were randomized 1:1 to 1-step or 3-step titration of the rivastigmine once-daily patch. The primary endpoint was the proportion of patients with adverse events leading to discontinuation. Results: Of 216 patients randomized, 215 (1-step, n = 107; 3-step, n = 108) were included in the safety analysis. The primary endpoint outcome was 15.0% in the 1-step group and 18.5% in the 3-step group. The observed treatment difference was −3.6% (95% confidence interval: −17.0, 9.6), falling within the prespecified acceptance range. Conclusion: The tolerability of two different titration schemes was similar in Japanese patients with AD.

Background/Aims: Behavioral and psychological symptoms of dementia (BPSD) are common in the clinical manifestation of dementia. Although most patients with dementia exhibit some BPSD during the course of the illness, the association of BPSD with the stage of dementia remains unclear. It was the aim of this study to evaluate the impact of severity of dementia on the expression of BPSD in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Methods: Ninety-seven patients with DLB and 393 patients with AD were recruited from 8 dementia clinics across Japan. BPSD were assessed by the Neuropsychiatric Inventory (NPI). A relationship between BPSD and dementia stage classified by the Clinical Dementia Rating (CDR) in each type of dementia was assessed. Results: No significant difference was seen in NPI total score across CDR staging in the DLB group. On the other hand, the NPI total score significantly increased with dementia stage in the AD group. Conclusion: The relationship of dementia stage with the expression of BPSD was different according to the type of dementia. BPSD and dementia stage were correlated in AD subjects, in whom psychiatric symptoms increase as the disease progresses, but not in DLB subjects.

Background/Aims: Although delirium is generally regarded as a transient syndrome, persistence of delirium in patients with cognitive impairment - even with fatal outcome - has been reported as well. This study aims to describe the clinical features and neuropathological correlates of this type of delirium. Methods: Inclusion criteria for this case series were: (1) severe persistent delirium until death, (2) history of cognitive decline and (3) consent for brain autopsy. Medical records were examined in combination with collected clinical data and neuropathological findings. Result: In 15 patients, all living at home before admission, episodes with delirium lasted for 4.2 months on average. No distinct medical causes of persistent delirium could be identified. Pathological diagnoses included Alzheimer's disease and dementia with Lewy bodies as well as single cases of Creutzfeldt-Jakob disease and progressive supranuclear palsy. Conclusion: Severe, persistent and fatal delirium in patients with cognitive impairment can occur relatively early in the disease trajectory and is associated with diverse neuropathologies.

Background/Aims: The present study evaluated the differences in treatment outcomes and brain perfusion changes among 3 types of acetylcholinesterase inhibitors (AchEIs, i.e. donepezil, rivastigmine, and galantamine). Methods: This was a prospective, longitudinal, randomized, open-label, 3-arm (donepezil, rivastigmine, or galantamine), parallel-group, 12-month clinical trial carried out in 55 patients with AD. Results: At 6 months, the results of the Mini-Mental State Examination (MMSE) and the Trail Making Test (TMT)-Part A showed an improvement versus baseline in the donepezil treatment group. All groups showed a significant increase in regional cerebral blood flow (rCBF), mainly in the frontal lobe. Significant rCBF reduction was observed in the temporal lobe and cingulate gyrus in all 3 groups. Conclusion: AchEI treatment prevents the progression of cognitive impairment and increases the relative rCBF in the frontal lobe.

Background/Aims: Performance on the Montreal Cognitive Assessment (MoCA) has been demonstrated to be dependent on the educational level. The purpose of this study was to identify how to best adjust MoCA scores and to identify MoCA items most sensitive to cognitive decline in incipient Alzheimer's disease (AD) in a Spanish-speaking population with varied levels of education. Methods: We analyzed data from 50 Spanish-speaking participants. We examined the pattern of diagnosis-adjusted MoCA residuals in relation to education and compared four alternative score adjustments using bootstrap sampling. Sensitivity and specificity analyses were performed for the raw and each adjusted score. The interval reliability of the MoCA as well as item discrimination and item validity were examined. Results: We found that with progressive compensation added for those with lower education, unexplained residuals decreased and education-residual association moved to zero, suggesting that more compensation was necessary to better adjust MoCA scores in those with a lower educational level. Cube copying, sentence repetition, delayed recall, and orientation were most sensitive to cognitive impairment due to AD. Conclusion: A compensation of 3-4 points was needed for

Background: MLC601 is a possible modulator of amyloid precursor protein processing, and in a clinical trial study MLC601 showed some effectiveness in cognitive function in Alzheimer's disease (AD) patients. We aimed to evaluate the effectiveness and safety of MLC601 in the treatment of mild to moderate AD as compared to 3 approved cholinesterase inhibitors (ChEIs) including donepezil, rivastigmine and galantamine. Methods: In a multicenter, nonblinded, randomized controlled trial, 264 volunteers with AD were randomly divided into 4 groups of 66; groups 1, 2, 3 and 4 received donepezil, rivastigmine, MLC601 and galantamine, respectively. Subjects underwent a clinical diagnostic interview and a cognitive/functional battery including the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog). Patients were visited every 4 months, and the score of cognition was recorded by the neurologists. Results: There were no significant differences in age, sex, marital status and baseline score of cognition among the 4 groups. In total, 39 patients (14.7%) left the study. Trend of cognition changes based on the modifications over the time for MMSE and ADAS-cog scores did not differ significantly among groups (p = 0.92 for MMSE and p = 0.87 for ADAS-Cog). Conclusion: MLC601 showed a promising safety profile and also efficacy compared to 3 FDA-approved ChEIs.

Background/Aims: In the present study, we examined whether DNA methylation of the brain-derived neurotrophic factor (BDNF) promoter is associated with the manifestation and clinical presentation of Alzheimer's disease (AD). Methods: Of 20 patients with AD and 20 age-matched normal controls (NCs), the DNA methylation of the BDNF promoter (measured using peripheral blood samples) was completely analyzed in 12 patients with AD and 6 NCs. The resulting methylation levels were compared statistically. Next, we investigated the correlation between the DNA methylation levels and the clinical presentation of AD. Results: The total methylation ratio (in %) of the 20 CpG sites was significantly higher in the AD patients (5.08 ± 5.52%) than in the NCs (2.09 ± 0.81%; p Conclusion: These results suggest that the DNA methylation of the BDNF promoter may significantly influence the manifestation of AD and might be associated with its neurocognitive presentation.

Aims: We investigated the performance in scene categorization of patients with Alzheimer's disease (AD) using a saccadic choice task. Method: 24 patients with mild AD, 28 age-matched controls and 26 young people participated in the study. The participants were presented pairs of coloured photographs and were asked to make a saccadic eye movement to the picture corresponding to the target scene (natural vs. urban, indoor vs. outdoor). Results: The patients' performance did not differ from chance for natural scenes. Differences between young and older controls and patients with AD were found in accuracy but not saccadic latency. Conclusions: The results are interpreted in terms of cerebral reorganization in the prefrontal and temporo-occipital cortex of patients with AD, but also in terms of impaired processing of visual global properties of scenes.

Background/Methods: The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal study that recruited 644 cognitively healthy older subjects (aged between 75 and 93 years, 58% women) at baseline and evaluated their cognitive change over 4 years. The study was structured like a clinical trial to anticipate a prevention trial and to determine the performance of novel trial instruments in a longitudinal non-interventional trial framework. Behavioral symptoms were assessed at baseline. Results: The existence of participant-reported behavioral symptoms at baseline predicted conversion to Clinical Dementia Rating scale score ≥0.5 over the 4-year period. Conclusions: The results imply that early anxiety and depression may be harbingers of future cognitive decline, and that patients exhibiting such symptoms, even in the absence of co-occurring cognitive symptoms, should be closely followed over time.

Background: TheRI-48 cued recall test was devised to discriminate between healthy elderly and patients with mild cognitive impairment who are at risk of developing Alzheimer’s disease (AD). However, no long-term follow-up studies have been conducted using this test. Methods: We analyzed the predictive power of the RI-48 test for determining the patients who will convert to AD dementia within the decade after testing. During 10 years, we followed up 40 non-demented patients who attended our Memory Clinic and underwent complete neuropsychological evaluation including the RI-48. Results: Of the 40 patients, 21 developed dementia (converters, CO) and 19 remained stable patients (SP). Of the tests performed at inclusion, only the RI-48 (p Conclusion: The RI-48 had the best overall diagnostic accuracy at 5- and at 10-year follow-ups.

Background/Aims: The Stroop test is commonly applied in elderly subjects for the evaluation of cognitive impairment related to Alzheimer’s disease (AD) and related disorders. This study aimed to investigate the functional neural correlates of the Stroop performance in AD. Methods: In 136 probable AD patients and 54 cognitively normal elderly, a [18F]-fluorodeoxyglucose positron emission tomography scan and Stroop Color Word Test (SCWT) were performed. The correlations between the Stroop effect, which was measured by 6 different scoring methods, and regional cerebral glucose metabolism (rCMglc) were explored using a region-of-interest (ROI) approach and voxel-based analysis. Results: Among 6 Stroop interference measures, only 2 scores, including the SCWT color-word (CW) score, were significantly correlated with rCMglc of the dorsolateral prefrontal and anterior cingulate ROIs. Voxel-based analysis revealed significant positive correlations between SCWT CW scores and rCMglc in the inferior parietal lobule, middle temporal gyrus and middle frontal gyrus. Such correlations remained significant only in the less severe AD group. Conclusion: In AD patients, the Stroop effect depends on the functional integrity of the prefrontal cortices. Some parietotemporal regions also appear to be responsible for the Stroop effect in AD individuals.

Background: Vascular risk factors (VRF) may influence response to rivastigmine in Alzheimer’s disease (AD). Methods: AD patients who participated in a randomized, double-blind, placebo-controlled trial of rivastigmine patch and capsule treatment were stratified by baseline VRF status. Treatment response was evaluated using the AD Assessment Scale-cognitive subscale (ADAS-cog), AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Results: ADAS-cog scores significantly improved in all rivastigmine-treated patients (p Conclusion: VRF may influence AD progression and response to rivastigmine.

Background: As of 2010, the rivastigmine patch was licensed for the treatment of Alzheimer’s disease (AD) in 64 countries. Methods: This 24-week, multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy, safety and tolerability of the 5-cm2 (9-mg loading dose; 4.6 mg/24 h delivery rate) and 10-cm2 (18-mg loading dose; 9.5 mg/24 h delivery rate) rivastigmine patch in Japanese patients with AD. Results: In the primary analysis population (intent-to-treat last observation carried forward) at week 24, delayed deterioration was seen with the 10-cm2 patch versus placebo on the Japanese version of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-J cog; p = 0.005) and the Japanese version of the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC plus-J; p = 0.067). Participants receiving the rivastigmine patch showed numerically less decline versus placebo at week 24 on the CIBIC plus-J, although this did not reach statistical significance. Statistical significance for the CIBIC plus-J was met following adjustment for body weight and baseline Mini-Mental State Examination score as dynamic allocation factors (p = 0.042) and on the Disability Assessment for Dementia (DAD; p = 0.024) and Mental Function Impairment (MENFIS; p = 0.016) subscales. Serious adverse events were rare and were consistent with the known safety profile of the rivastigmine patch. Conclusion: The rivastigmine patch has a favorable efficacy and tolerability profile in Japanese patients with AD.

Aim: To study long-term effects of dietary patterns on dementia and Alzheimer’s disease (AD). Methods: Of 525 subjects randomly selected from population-based cohorts surveyed at midlife, a total of 385 (73%) subjects were re-examined 14 years later in the CAIDE study. A healthy-diet index (range 0–17) was constructed including both healthy and unhealthy dietary components. Results: Persons with a healthy diet (healthy-diet index >8 points) had a decreased risk of dementia (OR 0.12, 95% CI 0.02–0.85) and AD (OR 0.08, 95% CI 0.01–0.89) compared with persons with an unhealthy diet (0–8 points), adjusting for several possible confounders. Conclusions: Healthy diet at midlife is associated with a decreased risk of dementia/AD in late life. These findings highlight the importance of dietary patterns and may make more effective measures for dementia/AD prevention or postponement possible.

Objectives: To determine if mild cognitive impairment (MCI) represents a continuum of cognitive and functional deficits. Methods: Clinical data of 164 subjects with no dementia (ND, n = 52), uncertain dementia (n = 69), and mild probable Alzheimer’s disease (AD, n = 43) were reviewed. Uncertain dementia patients were classified as pre-MCI (n = 11), early amnestic MCI (e-aMCI, n = 15) and late amnestic MCI (l-aMCI, n = 15). Cognitive assessments [Chinese Mini-Mental State Examination (CMMSE) and a validated neuropsychological battery], functional assessments (Lawton’s scale for instrumental activities of daily living) and neuroimaging (ischemic lesions and medial temporal lobe atrophy) were reviewed. Results: ND, aMCI and mild AD subjects demonstrated a significant trend for worsening performance for all cognitive and functional measures (ANOVA, p Conclusions: Clinical delineation of aMCI allows the differentiation of those likely to progress for better correlation to biomarker development.

We compared indices of the revised version of the Wechsler Memory Scale (WMS-R) and scaled scores of the five subtests of the revised version of the Wechsler Adult Intelligence Scale (WAIS-R) in 30 elderly schizophrenia (ES) patients and 25 Alzheimer’s disease (AD) patients in the amnestic mild cognitive impairment (aMCI) stage (AD-aMCI). In the WMS-R, attention/concentration was rated lower and delayed recall was rated higher in ES than in AD-aMCI, although general memory was comparable in the two groups. In WAIS-R, digit symbol substitution, similarity, picture completion, and block design scores were significantly lower in ES than in AD-aMCI, but the information scores were comparable between the two groups. Delayed recall and forgetfulness were less impaired, and attention, working memory and executive function were more impaired in ES than in AD-aMCI. These results should help clinicians to distinguish ES combined with AD-aMCI from ES alone.

Background: Novel biomarkers are important for identifying as well as differentiating subcortical vascular dementia (SVD) and Alzheimer’s disease (AD) at an early stage in the disease process. Methods: In two independent cohorts, a multiplex immunoassay was utilized to analyze 90 proteins in cerebrospinal fluid (CSF) samples from dementia patients and patients at risk of developing dementia (mild cognitive impairment). Results: The levels of several CSF proteins were increased in SVD and its incipient state, and in moderate-to-severe AD compared with the control group. In contrast, some CSF proteins were altered in AD, but not in SVD. The levels of heart-type fatty acid binding protein (H-FABP) were consistently increased in all groups with dementia but only in some of their incipient states. Conclusions: In summary, these results support the notion that SVD and AD are driven by different pathophysiological mechanisms reflected in the CSF protein profile and that H-FABP in CSF is a general marker of neurodegeneration.

Aims: To determine the effect of diabetes mellitus (DM) on regional cerebral blood flow (rCBF) patterns in patients with Alzheimer’s disease (AD). Methods: We investigated the initial rCBF of 71 AD patients (36 without DM and 35 with DM) and the final rCBF of 23 AD patients (12 without DM and 11 with DM) after an average of 32 months. Single-photon emission computed tomography (SPECT) data were analyzed by statistical brain imaging. Results: The initial SPECT showed that AD patients without DM had lower rCBF in the left and right inferior temporal gyri than AD patients with DM. A follow-up SPECT demonstrated that rCBF decreased in more widespread regions, including the parietal, temporal, frontal, and limbic lobes, in AD patients without than with DM. Conclusion: This study suggests that functional brain abnormalities in AD differ depending on the DM status at baseline and during follow-up, reflecting neuropathologic differences.

Background: Alzheimer's disease (AD), the most common form of dementia in the elderly, is a neurodegenerative disorder associated with a complex pathophysiology. It is accepted that inflammation contributes to the pathogenesis of AD. All-trans-retinoic acid (ATRA) is a bioactive derivative of vitamin A that has shown immunomodulatory effects in many immune disorders. Objectives: In our study, we aimed to investigate in vitro immunomodulatory effects of ATRA on inducible nitric oxide synthase (iNOS) expression and interleukin-17A production during AD. Methods: Peripheral blood mononuclear cells (PBMCs) isolated from 30 Algerian AD patients and 14 age-matched nondemented controls were treated (or not) with ATRA. Production of NO and IL-17A in culture media was measured by the modified Griess method and enzyme-linked immunosorbent assay, respectively. Expression of iNOS in PBMCs was examined by fluorescence immunostaining. Results: Our results showed higher spontaneous in vitro production of NO related to overexpression of iNOS in AD patients compared to controls. Remarkably, ATRA treatment showed an important downregulatory effect on NO production and iNOS expression in patients. This effect was associated with a reduction in IL-17A production and increased IL-10 release. Conclusions: Taken together, our results indicate that ATRA exerts anti-inflammatory effects in AD. Furthermore, ATRA represents a promising tool for monitoring inflammatory responses associated with disease progression. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease, and its mechanisms have not been clearly elucidated. A large percentage (more than 95%) of cases are late-onset AD without familial traits. Although some genes have been implicated in the pathogenesis and the risk of developing sporadic AD, they only account for the minority of late-onset AD. Recently, accumulating data have suggested a potential role for epigenetic mechanisms in neurodegenerative processes leading to dementia. Alterations in the epigenetic machinery cause aberrant DNA methylation and histone acetylation. Therefore, these changes trigger alterations on the transcriptional level of genes involved in the pathogenesis of AD. In this review, we summarize recent advances in research on AD caused by common epigenetic modification and the potential treatment strategies targeting the epigenetic machinery. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aim: The mechanisms and processes of amyloid beta (Aβ)1-42/Aβ1-40 degeneration and deposition of neuron damage are still not clear. The long noncoding RNA (lncRNA) is one of the members of the noncoding RNA family. In this study, we aimed to investigate whether Aβ1-42 inhibited SH-SY5Y cells in vitro through modulating Meg3 lncRNA. Methods: The Alzheimer's disease (AD) senile plaque cell model was generated using synthetic Aβ1-42-treated SH-SY5Y cells. MTT assays were used to determine the proliferation of SH-SY5Y cells. Quantitative (q)RT-PCR and Western blot analyses were used to test the expression levels of mRNA and protein. Northern blot analysis was used to confirm Meg3 lncRNA expression. Results: The MTT assays showed that exogenous Aβ1-42 suppressed SH-SY5Y cells. The qRT-PCR and Western blot analyses revealed that the expression of p53 mRNA and protein was significantly increased in the AD model group, with a marked decrease in MDM2 and Ki-67 expression on day 7. Moreover, the qRT-PCR and Northern blot analyses confirmed that exogenous Aβ1-42 promoted the expression of Meg3 lncRNA. There was a downregulation of Meg3 lncRNA expression in SH-SY5Y cells by siRNA, which could promote of the ability of MDM2 to degrade p53 protein on the ubiquitin pathway and delay SH-SY5Y apoptosis. Conclusion: Meg3 lncRNA is implicated as an important factor in the formation of mature Aβ peptides. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Treatment of Alzheimer's disease (AD) with cholinesterase inhibitors (ChEI) enhances cholinergic activity and alleviates clinical symptoms. However, there is variation in the clinical response as well as system level changes revealed by functional MRI (fMRI) studies. Methods: We investigated 18 newly diagnosed mild AD patients with fMRI using a face recognition task after a single oral dose of rivastigmine, a single dose of placebo and 1-month treatment with rivastigmine. The clinical follow-up took place at 6 and 12 months. Results: MMSE score difference between baseline and the follow-ups showed a positive correlation with fMRI activation difference between treatment and placebo in the right prefrontal cortex. A negative correlation was found for the left prefrontal cortex and the left fusiform gyrus. In addition, greater signal intensity in the right versus the left fusiform gyrus predicted a response to ChEI with increasing MMSE scores during the follow-up with 77.8% sensitivity and 77.8% specificity. Conclusions: The increased fMRI activation by cholinergic stimulation in brain areas associated with the processing of the visual task reveals still functioning brain networks and a subsequent positive effect of ChEI on cognition. Thus, fMRI may be useful for identifying AD patients most likely to respond to treatment with ChEI. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: We aimed to compare caregiver burden and distress in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) and to investigate which factors contribute to caregivers' burden and distress. Methods: Fifty patients and their caregivers were invited to participate. Among the patients, 20 had a diagnosis of bvFTD and 30 had AD. Caregivers and patients were statistically equivalent for age, sex, education and dementia severity according to Clinical Dementia Rating. The protocol included the Short Zarit Burden Inventory, the Neuropsychiatric Inventory (NPI), Disability Assessment for Dementia (DAD), the Cornell Scale for Depression in Dementia (CSDD), Addenbrooke's Cognitive Examination-Revised, the Executive Interview with 25 Items, Direct Assessment of Functional Status and the Geriatric Anxiety Inventory (GAI). Results: In the NPI, caregivers of bvFTD patients reported a higher presence and severity of neuropsychiatric symptoms and caregiver distress compared to caregivers of AD patients. There was no significant difference in the perceived burden. In bvFTD, DAD and GAI scores were significantly correlated with burden, whereas in AD, burden was correlated with CSDD and NPI scores. Psychiatric symptoms were associated with distress in both groups. Conclusions: Caregivers of bvFTD patients experienced higher levels of distress than caregivers of AD patients. Patients' functional limitations were associated with burden of caregivers of bvFTD patients, whereas neuropsychiatric symptoms were associated with caregiver strain in both groups. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-β levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next-generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles. [ABSTRACT FROM AUTHOR]

Background/Aims: To this date, the only available drugs for treating Alzheimer's disease are cognitive enhancers, which may improve the cognitive function of patients for a few years while the disease continues to progress. As such, there are intense investigations to develop disease-modifying drugs to suppress progressive neurodegeneration. Methods: In this study, a range of procognitive compounds are tested in a primary neuronal culture to determine their relative potential for promoting neuritogenesis. Results: We report that donepezil, memantine, dimebon, Pre-084 and 4-IBP are neuritogenic while tacrine, rosemarinic acid, memoquin and a BACE1 inhibitor suppress neurite outgrowth of neurons. Conclusions: The results of this study indicate that some procognitive compounds may possess a disease-modifying potential. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sleep disturbances (SD) accelerate the progression of Alzheimer's disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: The aims of this study were to determine baseline factors related to the progression of subjective memory impairment (SMI) in elderly subjects and to develop a new modeling scale to predict progression. Methods: Elderly subjects with SMI were recruited from the nationwide Clinical Research Centers for Dementia of South Korea (CREDOS) multicenter cohort and divided into two groups: (1) progressed to mild cognitive impairment or Alzheimer's disease or (2) stable without progression. Baseline clinical characteristics were compared between the groups, and the most relevant predictors of progression were assessed. A new modeling scale combining the predictors was developed. Results: In total, 129 subjects with SMI were analyzed. The follow-up duration was 0.5-4.7 years, and the median time to event was 3.64 years. The progressing group (n = 29) differed from the stable group (n = 100) in terms of baseline age, apolipoprotein E4 (APOE4) status, and some cognitive domains. Older age, a lower Mini-Mental State Examination recall score, APOE4 carrier, and a lower verbal delayed recall score were the most relevant predictors of progression, and a new modeling scale with these 4 predictors provided a better explanation of progression. Conclusion: SMI subjects with a higher risk of progression can be identified using a new modeling scale and might need further evaluations and more frequent follow-up. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: To examine the validity of Addenbrooke's Cognitive Examination III (ACE-III) in detecting early dementia in UK memory clinic patients aged 75-85 years. Methods: The ACE-III was administered to 59 patients prior to diagnosis. The extent to which scores predicted the membership of the dementia or no-dementia group was explored using receiver operating characteristic curve analysis and other parameters of diagnostic performance. Thirty-three participants (55.9%) were diagnosed with dementia (Alzheimer's disease = 56.3%, Alzheimer's disease with cerebrovascular disease = 31.3%, and vascular dementia = 12.5%). Results: The optimal cut-off for detecting dementia was 81/100 (scores <81 indicating dementia with a sensitivity of 0.79, a specificity of 0.96, and a positive predictive value of 0.96), with superiority over published cut-offs (88/100 and 82/100) at medium and lower prevalence rates. The number of years of full-time education had a significant positive relationship to total ACE-III scores (r = 0.697, p < 0.001) for the no-dementia group. Exploratory analysis indicated that optimal cut-offs were different for higher versus lower education groups. Conclusions: The ACE-III has excellent accuracy for the detection of dementia in day-to-day clinical practice. Lower cut-offs than those specified in the index paper, and the consideration of the patients' years of full-time education may be necessary for optimal diagnostic performance. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common disease causing neurodegeneration. The lower concentration of β-amyloid 1-42 (Aβ1-42) together with increased levels of total tau protein (T-tau) and phosphorylated tau protein (P-tau) in the cerebrospinal fluid (CSF) make a panel of well-established biomarkers in AD diagnosis. Addition of novel biomarkers to the gold standard biomarker panel might improve the diagnostic accuracy of neurodegeneration. This goal might be reached by the use of multiplexing, which is a simultaneous measurement of multiple analytes in a single sample volume and within a single cycle or run. Objective/Methods: Therefore the aim of the current review was to present, according to our best knowledge, available data concerning the evaluation of concentrations and diagnostic accuracy of well-established biomarkers in AD as well as novel biomarkers analyzed with the use of the bead-based technique. Additionally we discuss the utilization of the bead-based technique as compared to the conventional ELISA method. Results: Literature data indicate that the bead-based technique revealed diagnostic sensitivity, specificity and coefficients of variation at the levels similar to ELISA. Moreover, an addition of novel biomarkers (tested by means of the bead-based technique) to the gold standard biomarker panel improved the diagnostic accuracy of neurodegeneration. Conclusion: Review of literature data shows that the combined analysis of classical CSF biomarkers with novel biomarkers might increase the specificity and sensitivity of performed tests. However, we concluded that the replacement of conventional ELISA with the bead-based technique requires new reference intervals for Aβ1-42, T-tau and P-tau concentrations. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: β-Synuclein (β-Syn) is a member of the highly homologous synuclein protein family. The most prominent family member, α-synuclein (α-Syn), abnormally accumulates in so-called Lewy bodies, one of the major pathological hallmarks of α-synucleinopathies. Notably, parts of the peptide backbone, called the nonamyloid component, are also found in amyloid plaques. However, β-Syn seems to have beneficial effects by reducing α-Syn aggregation, and amyloid antiaggregatory activity has been described. Objective: The aim of the study was to analyze if wild-type β-Syn can counteract functional and pathological changes in a murine Alzheimer model over different time periods. Methods: At the onset of pathology, lentiviral particles expressing human β-Syn were injected into the hippocampus of transgenic mice overexpressing human amyloid precursor protein with Swedish and London mutations (APPSL). An empty vector served as the control. Behavioral analyses were performed 1, 3 and 6 months after injection followed by biochemical and histological examinations of brain samples. Results: β-Syn expression was locally concentrated and rather modest, but nevertheless changed its effect on APP expression and plaque load in a time- and concentration-dependent manner. Interestingly, the phosphorylation of glycogen synthase kinase 3 beta was enhanced in APPSL mice expressing human β-Syn, but an inverse trend was observed in wild-type animals. Conclusion: The initially reported beneficial effects of β-Syn could be partially reproduced, but locally elevated levels of β-Syn might also cause neurodegeneration. To enlighten the controversial pathological mechanism of β-Syn, further examinations considering the relationship between concentration and exposure time of β-Syn are needed. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To analyze the association between TREM2 exon 2 variants and late-onset (sporadic) Alzheimer's disease (AD) in an elderly Iranian population. Materials and Methods: Exon 2 of TREM2 in a total of 131 AD patients and 157 controls was genotyped using polymerase chain reaction and Sanger sequencing. Fisher's exact test was used to compare the allele and genotype frequency between the 2 study groups. Results: One homozygous and 2 heterozygous carriers of rs75932628-T in the AD patients and 1 heterozygous carrier in the control group were identified. One novel damaging variant, G55R, was also detected in the AD patient group. The frequency of rs75932628-T as well as the amount of rare variants were higher in the AD patients than in the controls, but this did not reach a statistically significant association with AD (odds ratio: 4.8; 95% confidence interval: 0.54 to 43.6; p = 0.270). Conclusion: The rs75932628-T allele frequency in the elderly Iranian population (0.86%) was high. [ABSTRACT FROM AUTHOR]

Background: Animal studies suggest that statins may have a protective effect on Alzheimer's disease (AD), but some clinical trials have reported negative results. Objective: To evaluate the efficacy and safety of statins in the treatment of AD. Methods: We searched the PubMed, Cochrane Library, EMBASE, OVID SP, and ProQuest databases to select double-blind, randomized controlled trials pertaining to statins given to patients diagnosed with AD. The meta-analysis used main outcomes such as scores on the Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale (ADAS-Cog) and secondary outcomes such as scores on the Dependence Scale, Activities of Daily Living Scale (ADCS-ADL), Neuropsychiatric Inventory (NPI), Clinical Global Impression of Change (CGIC), and Alzheimer's Disease Functional Assessment and Change Scale (ADFACS). Safety measures included the standard reporting of any adverse events or laboratory abnormalities. Results: Four studies (1,127 participants) involving patients with a diagnosis of probable or possible AD were included. There were no significant differences between the statins and placebo groups regarding the main outcomes, secondary outcomes, or adverse events. Most of the studies ignored or downplayed risk factors for cerebral vascular disease. Conclusion: Statins are well tolerated without unexpected adverse events. However, more research is needed to determine whether statins are effective for AD with vascular risk factors. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We reported a procedure of serum anticholinergic activity (SAA) measurement and the reliability and reproducibility of the receptor binding assay, and we also described the usefulness of SAA measurement reflecting the anticholinergic activity (AA) in the central nervous system (CNS). According to the results of a 10 times repeated measurement of standard atropine binding, the relative error was between -5.5 and +3.7%, and we considered that measurement of SAA in our studies is accurate and validated. Downregulation of acetylcholine activates inflammation in both CNS and peripheral tissue, which causes AA in both sites. Therefore, changes of AA in the CNS link with SAA in the peripheral system even if a substance having AA does not penetrate through the blood-brain barrier. Then we redescribe issues that require attention in the measurement of SAA. It is generally defined that any SAA greater than the detection limit of a quantitative atropine equivalent level (≥ 1.95 n M in our study) is positive. According to previous studies, SAA is considered to be positive when its atropine equivalent is ≥ 1.95 n M and undetectable when this is <1.95 n M . Nevertheless, as a low SAA can act as AA in the CNS, we should assume that SAA might also be positive if its marker concentration is between 0 and 1.95 n M . In addition, SAA should be measured around 11 a.m. or somewhat later because of the diurnal rhythm of cortisol in humans. [ABSTRACT FROM AUTHOR]

We have previously proposed a hypothesis in which we argue that anticholinergic activity (AA) appears endogenously in Alzheimer's disease (AD). Acetylcholine (ACh) controls both cognitive function and inflammation. Consequently, when the downregulation of ACh reaches critical levels, the inflammatory system is upregulated and proinflammatory cytokines with AA appear. However, factors other than downregulation of ACh can produce AA; even if ACh downregulation does not reach critical levels, AA can still appear if one of these other AA-producing factors is added. These factors can include neurocognitive disorders other than AD, such as delirium and Lewy body disease (LBD). In delirium, ACh downregulation fails to reach critical levels, but AA appears due to the use of medicines, physical illnesses or mental stress (termed 'AA inserts'). In LBD, we speculate that AA appears endogenously, even in the absence of severe cognitive dysfunction, for 2 reasons. One reason is that patterns of ACh deterioration are different in LBD from those in AD, with synergistic actions between amyloid and α-synuclein thought to cause additional or severe symptoms that accelerate the disease course. The second reason is that AA occurs through disinhibition by reduced cortisol levels that result from severe autonomic parasympathetic dysfunction in LBD. [ABSTRACT FROM AUTHOR]

In this article, we review and repropose our hypothesis of the endogenous appearance of anticholinergic activity (AA) in Alzheimer's disease (AD). First, we introduce our previous articles and speculate that, because acetylcholine (ACh) regulates both cognitive function and inflammation, downregulation of this neurotransmitter causes upregulation of the inflammatory system. AA then appears endogenously with the production of cytokines and the downregulation of ACh in AD. To support our hypothesis, we present a female AD patient whose AA was considered to occur endogenously through her AD pathology. Her serum anticholinergic activity (SAA) was positive at her first visit to our memory clinic, was negative at the 1-year and 2-year follow-up visits, and had become positive again by 3 years. We speculate that the initial positive SAA was related to her AD pathology plus mental stress, and that her SAA at 3 years was related to her AD pathology only. Consequently, we believe that 2 patterns of SAA positivity (and therefore AA) exist. One occurs when the downregulation of ACh reaches a critical level, and the other occurs with the addition of some other factor such as medication, induced illness or mental stress that causes AA to affect AD pathology. Finally, we consider the pharmacotherapy of AD based on the proposed hypothesis and conclude that cholinesterase inhibitors can be used to prevent rapid disease progression, whereas N-methyl- D -aspartate receptor antagonists should be reserved for the treatment of AD that is already in a stage of rapid progression. We also propose a staging schema for patients with AD. [ABSTRACT FROM AUTHOR]

The brain of Alzheimer's disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of β-amyloid protein, which leads to oxygen stress and inflammation. The active oxygen directly damages the neuron by increasing intracellular Ca 2+. The inflammation is due to activation of the microglia, thereby producing cytokines which inhibit the production of brain-derived neurotrophic factor (BDNF). As the BDNF acts by neuronal protection, synaptogenesis and neurogenesis, the reduction of BDNF in the brain of AD patients worsens the symptoms of AD. On the other hand, treatment of AD patients with a cholinesterase inhibitor enhances ACh activity and inhibits inflammation. Then the expression of BDNF is restored and neuroprotection reestablished. However, there are several reports which showed controversial results concerning the relationship between BDNF and AD. We speculate that BDNF is related to some neurocognitive process and reflects neuronal activity in other neurodegenerative and neuropsychiatric disorders and that in the mild cognitive impairment stage, BDNF and choline acetyltransferase (ChAT) activities are hyperactivated because of a compensatory mechanism of AD pathology. In contrast, in the mild stage of AD, BDNF and ChAT activity are downregulated. [ABSTRACT FROM AUTHOR]

We report a case of a 54-year-old woman presenting with amnesia, apathy, work-related difficulties and mental stress. At presentation, her Mini-Mental State Examination score was 27 and her serum anticholinergic activity (SAA) was positive without medication or recent physical illnesses. In addition, magnetic resonance imaging revealed mild atrophy of the frontal and temporal lobes, with a relatively intact hippocampus. Consequently, we diagnosed mild cognitive impairment due to Alzheimer's disease and prescribed a cholinesterase inhibitor (donepezil, 10 mg/day); her SAA fully disappeared and clinical symptoms partially resolved. Addition of duloxetine coupled with environmental adjustments caused her cognitive function to return to a normal level, so we diagnosed pseudodementia due to depression. In this case, we believe that the simultaneous cholinergic burden and mental stress led to positive SAA, which made it reasonable to prescribe a cholinesterase inhibitor to ameliorate the associated acetylcholine hypoactivity. We believe that it is essential to recognize the importance of prescribing a cholinesterase inhibitor for specific patients, even those with pseudodementia, to control their clinical symptoms. Moreover, SAA might be a useful biomarker for identifying this subgroup of patients. We propose that anticholinergic activity appears endogenously in mood disorders (depression and bipolar disorder) and set out our rationalization for this hypothesis. [ABSTRACT FROM AUTHOR]

One characteristic neuropathological feature of Alzheimer's disease (AD) is profound neuronal loss in the nucleus basalis of Meynert, the major source of cholinergic innervation of the cerebral cortex. Clinically, anticholinergic activity causes a decline in cognitive function and increases the risk of dementia, thus possibly enhancing AD pathologies and neurodegeneration. Until now there has been insufficient human neuropathological data to support this conclusion. Experimental studies using a tauopathy mouse model demonstrated anticholinergics enhanced tau pathology and neurodegeneration corresponding to central anticholinergic activity. Additionally, donepezil, a cholinesterase inhibitor, ameliorated tau pathology and neurodegeneration in the same mouse model. These results indicate the balance between cholinergic and anticholinergic activities might affect neurodegeneration. Importantly, neurodegeneration observed in the mouse model seemed to correspond to the distribution of microglial activation, and it was reported that neuroinflammation plays an important role in the pathomechanism of AD, while anticholinergic activity augments inflammatory responses. Moreover, some studies indicated β-amyloid itself depletes cholinergic function similarly to anticholinergic activity. Thus, anticholinergic activity might initiate and/or accelerate AD pathology. Limited human data support the conclusion that anticholinergic activity enhances AD-related neuropathology and neurodegeneration. However, experimental data from a tauopathy mouse model indicated anticholinergic activity might enhance neurodegeneration with enhanced neuroinflammation including microglial activation. [ABSTRACT FROM AUTHOR]

Background: Many clinical studies have shown that oxidative stress pathways and the efficiency of the oxidative DNA damage base excision repair (BER) system are associated with the pathogenesis of Alzheimer's disease (AD). Reduced BER efficiency may result from polymorphisms of BER-related genes. In the present study, we examine whether single nucleotide polymorphisms (SNPs) of BER genes are associated with increased risk of AD. Methods: SNP genotyping was carried out on DNA isolated from peripheral blood mononuclear cells obtained from 120 patients with AD and 110 healthy volunteers. Samples were genotyped for the presence of BER-related SNPs, i.e. XRCC1-rs1799782, rs25487; MUTYH-rs3219489, and PARP1-rs1136410. Results: We found a positive association between AD risk and the presence of G/A genotype variant of the XRCC1 rs25487 polymorphism [odds ratio (OR) = 3.762, 95% CI: 1.793-7.891]. The presence of the A/A genotype of this polymorphism reduced the risk of AD (OR = 0.485, 95% CI: 0.271-0.870). In cases of the PARP1 gene rs1136410 polymorphism, we observed that the T/C variant increases (OR = 4.159, 95% CI: 1.978-8.745) while the T/T variant reduces risk (OR = 0.240, 95% CI: 0.114-0.556) of AD. Conclusions: We conclude that BER gene polymorphisms may play an important role in the etiology of AD. Diagnosing the presence or absence of particular genetic variants may be an important marker of AD. Further research on a larger population is needed. There is also a need to examine polymorphisms of other BER in the context of AD risk. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Social interaction is a lifestyle factor associated with a decreased risk of dementia in several studies. However, specific aspects of these social factors influencing dementia are unknown. This study aimed at evaluating the role of the distinct aspects of social support on the incidence of dementia in acommunity-based cohort of older people in Brazil. Methods: A total of 345 healthy and independent elderly subjects living in the community were followed by 12 years. Incident cases of dementia and probable Alzheimer's disease were defined by DSM-IV criteria and NINCDS-ADRDA criteria, respectively. Social variables evaluated were marital status, living arrangement, living children, living sibling, confidant and attending recreational groups. Sex, age, education, Mini-Mental State Examination (MMSE) score, depressive symptoms and family income were entered as co-variates in a Cox proportional hazard model. Results: The absence of confidant was the only social variable associated to higher risk of developing dementia (HR = 5.31; p < 0.001), even after adjustment for age (HR = 1.08; p = 0.048) and baseline MMSE score (HR = 0.79; p = 0.002). Conclusions: Our data suggest that to have a confidant could be an important lifestyle factor associated with dementia. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Observational epidemiological studies such as cross-sectional, case-control, and cohort studies have reported inconsistent findings regarding the association between caffeine intake from coffee or tea and the risk of cognitive disorders such as dementia, Alzheimer's disease, cognitive impairment, and cognitive decline. Methods: We searched PubMed and EMBASE in September 2014. Three evaluators independently extracted and reviewed articles, based on predetermined selection criteria. Results: Out of 293 articles identified through the search and bibliographies of relevant articles, 20 epidemiological studies from 19 articles, which involved 31,479 participants (8,398 in six cross-sectional studies, 4,601 in five case-control studies, and 19,918 in nine cohort studies), were included in the final analysis. The pooled odds ratio (OR) or relative risk (RR) of caffeine intake from coffee or tea for cognitive disorders (dementia, Alzheimer's disease, cognitive impairment, and cognitive decline) was 0.82 (95% confidence interval [CI], 0.67-1.01, I2 = 63.2%) in a random-effects meta-analysis. In the subgroup meta-analysis by caffeine sources, the summary OR or RR of coffee intake was 0.83 (95% CI, 0.70-0.98; I2 = 44.8%). However, in the subgroup meta-analysis by study design, the summary estimates (RR or OR) of coffee intake for cognitive disorders were 0.70 (95% CI, 0.50-0.98; I2 = 42.0%) for cross-sectional studies, 0.82 (95% CI, 0.55-1.24; I2 = 33.4%) for case-control studies, and 0.90 (95% CI, 0.59-1.36; I2 = 60.0%) for cohort studies. Conclusions: This meta-analysis found that caffeine intake from coffee or tea was not associated with the risk of cognitive disorders. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by the dynamic accumulation of extracellular amyloid deposits from the interplay between amyloid-β (Aβ) plaques, reactive astrocytes and activated microglia. Several immunotherapies against Aβ have been shown to reduce amyloid neuropathology. However, the role of the associated glia in the recovery process requires clarification. Previously, we described the safety and effectiveness in aged domestic canine with cognitive dysfunction syndrome of a new active vaccine candidate for the treatment of AD in humans. Objective: The aim of this article is to gain a better understanding of how immunotherapy modifies the amyloid burden and its effects on astroglial and microglial reactivity in immunized dogs. Methods: In order to achieve this, we compared and quantified amyloid plaques and astroglial and microglial reactions in the frontal cortex of unimmunized and immunized aged domestic dogs. Results: We found amyloid plaques from immunized dogs to be smaller and more compact than those from unimmunized dogs. In these new plaques, the associated astrocytes were closer and less immunoreactive to the β subunit of S100 protein (S100B). We also found no modification in the microglial reaction associated with immunization. Conclusion: The anti-Aβ immunotherapy developed in our laboratory modifies the equilibrium between soluble and insoluble Aβ in aged dogs in close correlation with S100B-negative astrocytosis and microglial reaction. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Senile plaques in Alzheimer's disease (AD) are composed of amyloid-β (Aβ), especially N-truncated forms including Aβ4-42. These are thought to be neurotoxic. However, individuals may live for decades with biomarker evidence of cerebral β-amyloidosis (positive amyloid PET imaging and/or low cerebrospinal fluid levels of the 42 amino acid form of Aβ) without cognitive impairment. This condition may be termed pathological ageing (PA). Objective: To investigate whether there is a difference in the cerebral Aβ fragment pattern in brain specimens from non-demented (PA) and demented (AD) individuals expressing the full neuropathological triad of AD (senile plaques, neurofibrillary tangles and neurodegeneration). Methods: We extracted Aβ using formic acid and hybrid (6E10 and 4G8) immunoprecipitation from fresh-frozen temporal cortex tissue of 6 elderly individuals (mean age ± SD: 89 ± 3.5 years) with PA and 10 patients with AD (mean age ± SD: 72 ± 8.5 years). The full spectrum of Aβ peptides was determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Results: AD patients had generally more N-terminally truncated and pyroglutamate-modified Aβ than PA patients, whereas PA patients had on average more Aβ1-40 than AD patients. Conclusion: Senile plaques in AD may have an Aβ fragment composition distinct from PA with more N-terminally and pyroglutamate-modified Aβ peptides that may be linked to neurotoxicity. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Poly-T repeat lengths of rs10524523 in TOMM40 together with APOE polymorphism have been reported to affect the risk of late-onset Alzheimer's disease (LOAD) and the age of onset (AOO). Objective: To explore whether the AOO and cerebrospinal fluid biomarkers Aβ42, total tau and phosphorylated tau are associated with different repeat lengths. Methods: We conducted both the fragment and sequencing analysis of rs10524523 in 336 LOAD patients with a known APOE genotype. Results: AOO and Aβ42 levels associated significantly with certain poly-T repeat lengths of rs10524523 in LOAD patients encompassing APOE 34/44 genotype. Conclusion: We conclude that the poly-T repeat associations of rs10524523 in TOMM40 reflect the APOE ε4-dependent association in LOAD. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Cholinesterase inhibitors (ChEIs) are not allowed to be prescribed in combination, which means that we need to select 1 of 3 ChEIs for use in a patient with Alzheimer's disease (AD). However, there is no quantitative analysis on the differences between these agents. In this article, we propose that plasma cholinesterase activity (pChE) could be used as the standard for differentiating between rivastigmine (Riv) and donepezil (Don) in the management of AD. To date, we have treated 6 patients with Riv 18 mg and 5 patients with Don 5 mg. The pChE is related to low-grade inflammation associated with AD, diabetes mellitus and lipid metabolic dysfunction. Moreover, low pChE is related to liver dysfunction. The pChE must be kept under control. We speculated that Riv is the most appropriate therapy for patients with relatively high pChE, whereas Don is best reserved for those AD patients with relatively low pChE. [ABSTRACT FROM AUTHOR]

Ninety-two patients with dementia were thoroughly assessed by domiciliary interview and a period of day hospital attendance which included the completion of Camdex and Camcog schedules. Domiciliary visit letters described getting lost outside the home as a problem in 20.6% of patients, and inside the home in 3.3% of patients. The corresponding figures obtained from interviews were 36.9% and 28.3%. According to interview data, patients with senile dementia of Alzheimer's type were more likely to get lost outside the home than those with vascular dementia and there was no correction between the severity of cognitive impairment and the prevalence of getting lost outside the home. [ABSTRACT FROM AUTHOR]

Memory performance of elderly patients in the early stages of Alzheimer's disease (DAT) was compared with that of elderly control subjects. In explicit tests of recognition memory, which involve conscious recollection, the DAT patients were grossly impaired. In implicit tests of anagram resolution and wordstem completion, which do not require conscious recollection, the DAT patients were not impaired. These findings further support the idea that a separate memory system, episodic memory, underlines conscious recollection, that it is this system which is most commonly damaged in amnesia, and that memory systems not involving conscious recollection may be spared in the early stages of Alzheimer's disease. [ABSTRACT FROM AUTHOR]