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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/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: 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

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: 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.

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/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: 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.

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 < 0.05 vs. placebo), except 9.5 mg/24 h patch-treated patients with VRF, and were significantly affected by VRF status in the study population as a whole. Significant benefits were seen on the ADCS-ADL in 9.5 mg/24 h patch- and capsule-treated patients with, but not without, VRF. The ADCS-CGIC significantly improved in capsule-treated patients with, and patch-treated patients without VRF. Although non-significant, patients without VRF showed an apparent faster rate of placebo decline. Conclusion: VRF may influence AD progression and response to rivastigmine.

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 < 0.05). Pre-MCI subjects performed significantly better than aMCI subjects in all verbal memory domains (p < 0.001), while l-aMCI had worse functional performance (p = 0.007), a trend towards greater depressive symptoms (p = 0.05) and higher medial temporal lobe atrophy scores (p = 0.06). l-aMCI subjects were more likely than either pre-MCI or e-aMCI to progress to dementia over a mean follow-up period of 2.5 years (46.7 vs. 9.1 and 20.0%, respectively). 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: 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: 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.