Mild-moderate Alzheimer's Disease Patients Research Articles

Predicting Alzheimer's disease CSF core biomarkers: a multimodal Machine Learning approach.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current core cerebrospinal fluid (CSF) AD biomarkers, widely employed for diagnosis, require a lumbar puncture to be performed, making them impractical as screening tools. Considering the role of sleep disturbances in AD, recent research suggests quantitative sleep electroencephalography features as potential non-invasive biomarkers of AD pathology. However, quantitative analysis of comprehensive polysomnography (PSG) signals remains relatively understudied. PSG is a non-invasive test enabling qualitative and quantitative analysis of a wide range of parameters, offering additional insights alongside other biomarkers. Machine Learning (ML) gained interest for its ability to discern intricate patterns within complex datasets, offering promise in AD neuropathology detection. Therefore, this study aims to evaluate the effectiveness of a multimodal ML approach in predicting core AD CSF biomarkers. Mild-moderate AD patients were prospectively recruited for PSG, followed by testing of CSF and blood samples for biomarkers. PSG signals underwent preprocessing to extract non-linear, time domain and frequency domain statistics quantitative features. Multiple ML algorithms were trained using four subsets of input features: clinical variables (CLINVAR), conventional PSG parameters (SLEEPVAR), quantitative PSG signal features (PSGVAR) and a combination of all subsets (ALL). Cross-validation techniques were employed to evaluate model performance and ensure generalizability. Regression models were developed to determine the most effective variable combinations for explaining variance in the biomarkers. On 49 subjects, Gradient Boosting Regressors achieved the best results in estimating biomarkers levels, using different loss functions for each biomarker: least absolute deviation (LAD) for the Aβ42, least squares (LS) for p-tau and Huber for t-tau. The ALL subset demonstrated the lowest training errors for all three biomarkers, albeit with varying test performance. Specifically, the SLEEPVAR subset yielded the best test performance in predicting Aβ42, while the ALL subset most accurately predicted p-tau and t-tau due to the lowest test errors. Multimodal ML can help predict the outcome of CSF biomarkers in early AD by utilizing non-invasive and economically feasible variables. The integration of computational models into medical practice offers a promising tool for the screening of patients at risk of AD, potentially guiding clinical decisions.

RTMS concurrent with cognitive training rewires AD brain by enhancing GM-WM functional connectivity: a preliminary study.

Repetitive transcranial magnetic stimulation (rTMS) and cognitive training for patients with Alzheimer's disease (AD) can change functional connectivity (FC) within gray matter (GM). However, the role of white matter (WM) and changes of GM-WM FC under these therapies are still unclear. To clarify this problem, we applied 40Hz rTMS over angular gyrus (AG) concurrent with cognitive training to 15 mild-moderate AD patients and analyzed the resting-state functional magnetic resonance imaging before and after treatment. Through AG-based FC analysis, corona radiata and superior longitudinal fasciculus (SLF) were identified as activated WM tracts. Compared with the GM results with AG as seed, more GM regions were found with activated WM tracts as seeds. The averaged FC, fractional amplitude of low-frequency fluctuation (fALFF), and regional homogeneity (ReHo) of the above GM regions had stronger clinical correlations (r/P = 0.363/0.048 vs 0.299/0.108, 0.351/0.057 vs 0.267/0.153, 0.420/0.021 vs 0.408/0.025, for FC/fALFF/ReHo, respectively) and better classification performance to distinguish pre-/post-treatment groups (AUC = 0.91 vs 0.88, 0.65 vs 0.63, 0.87 vs 0.82, for FC/fALFF/ReHo, respectively). Our results indicated that rTMS concurrent with cognitive training could rewire brain network by enhancing GM-WM FC in AD, and corona radiata and SLF played an important role in this process.

Polysaccharides: potential bioactive macromolecules for Alzheimer's disease.

Alzheimer's disease (AD) is one of the leading causes of death and disability. AD is a devastating disease that has caused an overwhelming burden. However, no disease-modified treatment was discovered. The approval of sodium oligomannate (GV-971) in mild-moderate AD patients has attracted great attention to investigate the role of saccharides in AD. Therefore, summarizing and explaining the role of saccharides in AD is urgent and promising. Recent studies showed that polysaccharides (PSs) potentially benefit AD in vitro and in vivo. PSs could alleviate the pathological damage and improve cognitive symptoms via (1) antagonizing the toxicity of abnormal amyloid-beta and tau proteins; (2) attenuating oxidative stress and proinflammation; (3) rebuilding neuroplasticity. PSs exhibit one-multiple pathological hits of AD. However, a thorough chemical investigation is needed for further study.

Balance performance measured by posturography in mild-moderate Alzheimer's Disease: An undervalued assessment

PurposeThe aim of the study was to compare balance performance in mild-moderate stage Alzheimer's disease (AD) patients and healthy peers using clinical balance tests and computerized posturography. MethodsWe recruited 95 patients and divided them into two groups; 51 patients (62 % (n=32) female) in AD group and 44 patients in healthy controls group (50 % (n=22) female). Berg Balance Scale (BBS) and Timed Up & Go (TUG) test were performed. Computerized posturography was performed. ResultsThe mean age was 77.2±5.5 years in the AD group and 73.8±4.4 years in the control group (p<0.001). Sensory organization test composite equilibrium score (60[30-81], p<0.001), step quick turn-sway velocity (69.2 [38.2-95.8], p<0.001) and step quick turn-time (3.8 [1.6-8.4], p<0.001) were significantly impaired in mild-moderate stage AD patients. Berg Balance Scale (50 [32-56], p<0.001) and TUG test (13.0 [7.0-25.7], p<0.001) results were worse in AD. ConclusionsComputerized posturography measures were impaired in mild-moderate AD patients. The results highlight importance of early screening for balance and fall risk in AD patients. The study provides multi-dimensional and holistic assessment of balance performance in early-stage AD patients. Alzheimer's disease patients at earlier stages are prone to fall risk and should be evaluated accordingly.

Home EEG sleep assessment shows reduced slow-wave sleep in mild-moderate Alzheimer's disease.

IntroductionSleep disturbances are common in Alzheimer's disease (AD), with estimates of prevalence as high as 65%. Recent work suggests that specific sleep stages, such as slow‐wave sleep (SWS) and rapid eye movement (REM), may directly impact AD pathophysiology. A major limitation to sleep staging is the requirement for clinical polysomnography (PSG), which is often not well tolerated in patients with dementia. We have recently developed a deep learning model to reliably analyze lower quality electroencephalogram (EEG) data obtained from a simple, two‐lead EEG headband. Here we assessed whether this methodology would allow for home EEG sleep staging in patients with mild–moderate AD.MethodsA total of 26 mild–moderate AD patients and 24 age‐matched, healthy control participants underwent home EEG sleep recordings as well as actigraphy and subjective sleep measures through the Pittsburgh Sleep Quality Index (PSQI). Each participant wore the EEG headband for up to three nights. Sleep was staged using a deep learning model previously developed by our group, and sleep stages were correlated with actigraphy measures as well as PSQI scores.ResultsWe show that home EEG with a headband is feasible and well tolerated in patients with AD. Patients with mild–moderate AD were found to spend less time in SWS compared to healthy control participants. Other sleep stages were not different between the two groups. Actigraphy or the PSQI were not found to predict home EEG sleep stages.DiscussionOur data show that home EEG is well tolerated, and can ascertain reduced SWS in patients with mild–moderate AD. Similar findings have previously been reported, but using clinical PSG not suitable for the home environment. Home EEG will be particularly useful in future clinical trials assessing potential interventions that may target specific sleep stages to alter the pathogenesis of AD.Highlights Home electroencephalogram (EEG) sleep assessments are important for measuring sleep in patients with dementia because polysomnography is a limited resource not well tolerated in this patient population.Simplified at‐home EEG for sleep assessment is feasible in patients with mild–moderate Alzheimer's disease (AD).Patients with mild–moderate AD exhibit less time spent in slow‐wave sleep in the home environment, compared to healthy control participants.Compared to healthy control participants, patients with mild–moderate AD spend more time in bed, with decreased sleep efficiency, and more awakenings as measured by actigraphy, but these measures do not correlate with EEG sleep stages.

Alzheimer's Disease Progressively Alters the Face-Evoked Visual-Processing Network.

Postmortem studies of Alzheimer's disease (AD) brains not only find amyloid-β (Aβ) and neurofibrillary tangles (NFT) in the primary and associative visual cortical areas, but also reveal a temporally successive sequence of AD pathology beginning in higher-order visual association areas, followed by involvement of lower-order visual processing regions with disease progression, and extending to primary visual cortex in late-stage disease. These findings suggest that neuronal loss associated with Aβ and NFT aggregation in these areas may alter not only the local neuronal activation but also visual neural network activity. Applying a novel method to identify the visual functional network and investigate the association of the network changes with disease progression. To investigate the effect of AD on the face-evoked visual-processing network, 8 severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a task-fMRI study of viewing face photos. For the HS, the identified group-mean visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, this network was disrupted and reduced in the AD patients in a disease-severity dependent manner: for the MAD patients, the network was disrupted and reduced mainly in the higher-order visual association areas; for the SAD patients, the network was nearly absent in the higher-order association areas, and disrupted and reduced in the lower-order areas. This finding is consistent with the current canonical view of the temporally successive sequence of AD pathology through visual cortical areas.

Chinese Medicine for Alzheimer's Disease: A Meta-Analysis of Randomized Controlled Trials.

To evaluate the effificacy of oral Chinese medicine (CM) in comparison with donepezil, a cholinesterase inhibitor (ChEI), for the treatment of Alzheimer's disease (AD). Randomized controlled trials (RCTs) have been searched, and the effect of CM compared with donepezil in AD has been investigated. An electronic search of MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biological Medicine Database (CBMdisc), and China National Knowledge Infrastructure (CNKI) to identify articles in English and Chinese from the inception of the database until October 18, 2015. A modifified Jadad score (7-points) to judge the methodological quality of studies, comprehensive meta-analysis was performed with Cochrane Collaboration Revman 5.3. Dichotomous data were analyzed by relative risk (RR) with a 95% confifidence interval (CI), while continuous variables were analyzed by using mean differences (MD) with 95% CI for effect size. Six studies involving 596 AD patients through Jadad assessment with low bias were included in the meta-analysis. No signifificant difference was observed in cognitive improvement and daily abilities of patients using the Mini Mental State Examination (MMSE) (MD: 0.69, 95% CI:-0.17 to 1.56) and Activities of Daily Living (ADL) scale (MD: 0.94, 95% CI:-1.54 to 3.43). There were no signifificant differences in status of illness or MD for mild-moderate AD patients at 24 weeks (MD: 0.62, 95% CI:-2.99 to 4.23) and 48 weeks (MD:-0.73, 95% CI:-5.02 to 3.56). Severe AD patients were also assessed at 24 weeks (MD: 3.13, 95% CI:-6.92 to 13.18) and 48 weeks (MD: 4.23, 95% CI:-6.38 to 14.84). Furthermore, compared with donepezil, Xin (Heart)-regulating CM and Shen (Kidney)-tonifying groups were observed (MD:-1.50, 95% CI:-3.08 to 0.08; MD:-1.92, 95% CI:-3.50 to-0.33; respectively). CM had fewer side effects in AD patients. Compared with donepezil, oral CM showed no signifificant difference in effectiveness in AD patients, and more evidence is needed to verify the fifindings.

Evaluation of inner retinal layers as biomarkers in mild cognitive impairment to moderate Alzheimer’s disease

Inner retina in Alzheimer's Disease (AD) may experience neuroinflammation resulting in atrophy. The objective of our study was to determine whether retinal GCIPL (ganglion cell-inner plexiform layer) or nerve fiber layer (NFL) thickness may serve as noninvasive biomarkers to diagnose AD. This cross-sectional case-control study enrolled 15 mild cognitive impairment (MCI) patients, 15 mild-moderate AD patients, and 18 cognitively normal adults. NFL and GCIPL thicknesses on optical coherence tomography (OCT) were measured using Duke Optical Coherence Tomography Retinal Analysis Program (DOCTRAP) and Spectralis software. We demonstrated that regional thicknesses of NFL or GCIPL on macular or nerve OCTs did not differ between groups. However, a multi-variate regression analysis identified macular areas with a significant thickening or thinning in NFL and GCIPL in MCI and AD patients. Our primary findings controvert previous reports of thinner NFL in moderate-to-severe AD. The areas of thickening of GCIPL and NFL in the macula adjacent to areas of thinning, as revealed by a more complex statistical model, suggest that NFL and GCIPL may undergo dynamic changes during AD progression.

Clinical meaningfulness of Alzheimer's Disease Assessment Scale–Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors

IntroductionThe clinical meaningfulness of Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. MethodsThis exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement. ResultsPatients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog “no change” (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5–19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14–0.64). DiscussionADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. Clinical trial registration numberISRCTN26167328.

Analysis of the MIRIAD Data Shows Sex Differences in Hippocampal Atrophy Progression

Hippocampus (HC) atrophy is a hallmark of early Alzheimer's disease (AD). Atrophy rates can be measured by high-resolution structural MRI. Longitudinal studies have previously shown sex differences in the progression of functional and cognitive deficits and rates of brain atrophy in early AD dementia. It is important to corroborate these findings on independent datasets. To study temporal rates of HC atrophy over a one-year period in probable AD patients and cognitively normal (CN) subjects by longitudinal MRI scans obtained from the Minimal Interval Resonance Imaging in AD (MIRIAD) database. We used a novel algorithm to compute an index of hippocampal (volumetric) integrity (HI) at baseline and one-year follow-up in 43 mild-moderate probable AD patients and 22 CN subjects in MIRIAD. The diagnostic power of longitudinal HI measurement was assessed using a support vector machines (SVM) classifier. The HI was significantly reduced in the AD group (p < 10(-20)). In addition, the annualized percentage rate of reduction in HI was significantly greater in the AD group (p < 10(-13)). Within the AD group, the annual reduction of HI in women was significantly greater than in men (p = 0.008). The accuracy of SVM classification between AD and CN subjects was estimated to be 97% by 10-fold cross-validation. In the MIRIAD patients with probable AD, the HC atrophies at a significantly faster rate in women as compared to men. Female sex is a risk factor for faster descent into AD. The HI measure has potential for AD diagnosis, as a biomarker of AD progression and a therapeutic target in clinical trials.

Low-Dose Atypical Antipsychotic Risperidone Improves the 5-Year Outcome in Alzheimer's Disease Patients with Sleep Disturbances

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.

Short-term white matter alterations in Alzheimer's disease characterized by diffusion tensor imaging.

To investigate whether there are any white matter changes in a 6-month follow-up of mild-moderate Alzheimer's patients using diffusion tensor imaging (DTI). We recruited 18 mild-moderate Alzheimer's disease patients and they underwent magnetic resonance imaging (MRI) at recruitment and at 6-month follow-up. Diffusion MRI images were processed using DTI-ToolKit to create a population-based tensor template. This template was integrated with a voxel-wise and atlas-based analysis in FSL to determine the magnitude and location of change in diffusion metrics over the 6-month follow-up period. There were significant widespread changes in diffusion metrics across the entire white matter skeleton (P < 0.001), 95% confidence interval (CI) difference in fractional anisotropy: -0.007 (-0.011, -0.002), mean diffusivity: 0.040 (0.023, 0.058), axial diffusivity: 0.015 (0.008, 0.022), radial diffusivity: 0.012 (0.006, 0.019), as well as regions of interest in the splenium and superior longitudinal fasciculus. Our findings show that diffusion metrics are altered in a 6-month follow-up period of mild-moderate Alzheimer's patients, supporting the potential of DTI metrics to act as sensitive biomarkers for disease progression even over a relatively short time interval, and the potential utility to be applied to clinical trials of putative disease-modifying therapies.

Change patterns, influencing factors and predictors of quality of life in patients with Alzheimer's disease

To explore the change patterns, influencing factors and predictors of quality of life for 4 years in patients with Alzheimer's disease (AD). A total of 96 mild-moderate AD patients on combined therapies of medicine and recuperation were enrolled. Their clinical symptoms were graded by mini-mental state examination (MMSE), activity of daily living (ADL), global deterioration scale (GDS), neuropsychiatric inventory (NPI), Hamilton depression scale (HRSD), Hamilton anxiety scale (HAMA) and Pittsburgh sleep quality index (PQSI). And their qualities of life were evaluated by Quality of Life-Alzheimer's Disease (QOL-AD) at baseline and at the end of 1, 2, 3, 4 year. (1) During a 4-year follow-up, the scores of QOL-AD, MMSE, ADL, GDS, NPI, HRSD, HAMA and PQSI decreased markedly compared with baseline [(17.5±1.9), (12±3), (45±9), (5.2±0.8), (31±11), (20±6), (14±6), (14±4) vs (30.5±4.6), (21±4), (34±10), (3.3±0.9), (22±9), (18±6), (11±4), (12±4) respectively, t=25.31, 15.42, -7.16, -14.83, -5.56, -2.94, -4.45, -5.60, all P<0.01]. With the deterioration of AD, their qualities of life decreased significantly. (2) Spearman's correlation analysis showed that the scores of 4-year QOL-AD were correlated with the 4-year score changes of MMSE, ADL, GDS (r=0.344, 0.368, 0.213; P=0.002, 0.001, 0.047). (3) Multiple Logistic regression model showed that the baseline scores of NPI and HRSD were strong predictors of loss of quality of life (OR=1.697, 1.269; P=0.000, 0.006). And the area under the curve of receiver operating characteristic (ROC) of NPI and HRSD were 0.918 (95% CI: 0.844-0.991) and 0.878 (95% CI: 0.804-0.953) respectively. With the deterioration of AD, the quality of life decreases significantly and has correlations with the score changes of MMSE, ADL and GDS. High scores of NPI and HRSD are the important predictors for a loss of quality of life in AD patients. Early detection and timely interventions are necessary.

Recognition of personally familiar faces and functional connectivity in Alzheimer's disease

Studies have reported that patients in the severe stages of Alzheimer's disease (AD) experience difficulties recognizing their own faces in recent photographs. Two case reports of late-stage AD showed that this loss of self-face recognition was temporally graded: photographs from the remote past were recognized more easily than more recent photographs. Little is known about the neural correlates of own face recognition abilities in AD patients, while neuroimaging studies in healthy adults have related these abilities to a bilateral fronto-parieto-occipital network. In this study, two behavioral experiments (experiments 1 and 2) and one functional magnetic resonance imaging (fMRI) experiment (second part of experiment 2) were conducted to compare mild AD patients (experiment 1) and moderate AD patients (experiment 2) with healthy older participants in a recognition task involving self and familiar faces from different decades of the participants' life. In moderate AD patients, variable performance allowed us to examine correlations between scores and resting-state fMRI in order to link behavioral data to cerebral activity. At the behavioral level, the results revealed that, in mild AD, self and familiar face recognition was preserved. Moreover, mild AD patients and healthy older participants showed an inverse temporal gradient, with faster recognition of self and familiar recent photographs than self and familiar remote photographs. However, in moderate AD, both self and familiar face recognition were affected. fMRI results showed that the higher the connectivity between the dorsomedial prefrontal cortex (dMPFC) and the right superior frontal gyrus (rSFG), the lower the self and familiar face recognition scores in moderate AD patients. Given that previous studies have related the superior frontal region to control processes rather than face recognition processes, these results might reflect less segregation and more interference between brain networks in AD. In other words, impaired face recognition in AD may be related to functional dedifferentiation of specific brain regions.

Diagnostic Validity of the Alzheimer's Disease Functional Assessment and Change Scale in Mild Cognitive Impairment and Mild to Moderate Alzheimer's Disease

Background: The Alzheimer's Disease Functional Assessment and Change Scale (ADFACS) is a functional assessment instrument widely used in clinical research. Aims: To test the diagnostic and concurrent validity of the Spanish version of this scale and to describe the functional deficit pattern for mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. Methods: The ADFACS, the Interview for Deterioration in Daily Living Activities in Dementia (IDDD), and the Mini Mental State Examination (MMSE) were administered to 146 control subjects (CS) and 165 patients (67 MCI and 98 AD). Nonparametric tests were used to compare the diagnostic groups. Cronbach's α and correlations with the MMSE and the IDDD were calculated. Sensitivity, specificity and predictive values were studied. Results: The ADFACS had a high internal consistency (α = 0.95). Three cutoff points of 1, 4, and 17 were provided to separate CS and MCI patients, MCI and mild AD patients, and mild AD and moderate AD patients, respectively. The ADFACS strongly correlated with functional (IDDD, 0.927) and cognitive (MMSE, 0.747) measures. A similar pattern of dysfunction, but in different grades, was found for the MCI and AD groups. Conclusion: The ADFACS is a reliable, valid, and sensitive instrument to assess functional abilities; it is useful in dementia assessment for elderly populations.

Cognitive evidence in people with Alzheimer's disease that compromised hippocampal neurogenesis is related both to APOE-ɛ4 status and CSF beta-amyloid 42

Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis was reduced by knock-in alleles for human ApoE4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in 3xTg-AD mice; this reduction being directly associated with the presence of Aß plaques and an increase in the number of Aß-containing neurons in the hippocampus. Cognitive tasks involving difficult object pattern separations (OPS) have been shown to reflect DG activity and thus neurogenesis in both animals and man. Data presented at this meeting (Wesnes K. Alzheimer's & Dementia 2010, 6: Supplement e45) showed selective difficult OPS age-related declines in healthy individuals aged 18 to 87 (n=3065); and selective declines in amnestic Mild Cognitive Impairment (n=73). This study used the same OPS paradigm in ADto seek relationships with APOE4 status and CSF Aß42. The CDR System OPS task involves the presentation of pictures which must later be discriminated from closely similar pictures (difficult OPS); a paradigm shown by fMRI to reflect DG activity. This paper presents previously unanalysed and unpresented OPS data from 74 genotyped mild-moderate AD patients in whom CSF Aß42 was measured (Wesnes K et al, Acta Neurologica Scandinavica 2010, 122: 270–277). APOE4 homozygotes were not compromised on the easy OPS compared with the other patients (E2/E3;E2/E4;E3/E3;E3/E4). In contrast the E4/E4 patients were poorer at the difficult OPS (F=2.9, df 4,45 p=0.031). In all patients CSF Aß42 correlated with the ability to make the difficult OPS discriminations (r=0.3.p=0.014), but not easier discriminations (r=0.14). OPS decision speed correlated negatively, and thus the association was not due to increased impulsivity. No significant association was seen on a non-DG sensitive word recognition paradigm (r=0.15).

Profiling spontaneous speech decline in Alzheimer's disease: a longitudinal study.

This study aims to document the nature and progression of spontaneous speech impairment suffered by patients with Alzheimer's disease (AD) over a 12-month period, using both cross-sectional and prospective longitudinal design. Thirty one mild-moderate AD patients and 30 controls matched for age and socio-cultural background completed a simple and complex oral description task at baseline. The AD patients then underwent follow-up assessments at 6 and 12 months. Cross-sectional comparisons indicated that mild-moderate AD patients produced more word-finding delays (WFDs) and empty and indefinite phrases, while producing fewer pictorial themes, repairing fewer errors, responding to fewer WFDs, produce shorter and less complex phrases and produce speech with less intonational contour than controls. However, the two groups could not be distinguished on the basis of phonological paraphasias. Longitudinal follow-up, however, suggested that phonological processing deteriorates over time, where the prevalence of phonological errors increased over 12 months. Discussion Consistent with findings from neuropsychological, neuropathological and neuroimaging studies, the language deterioration shown by the AD patients shows a pattern of impairment dominated by semantic errors, which is later joined by a disruption in the phonological aspects of speech.

Treatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study

This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.

The ADAS‐cog and clinically meaningful change in the VISTA clinical trial of galantamine for Alzheimer's disease

A minimum 4-point change at 6 months on the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) is deemed clinically important, but this cut-point has been little studied in relation to clinical meaningfulness. In an investigator-initiated, clinical trial of galantamine, we investigated the extent to which a 4-point change classifies goal attainment by individual patients. Secondary analysis of the video imaging synthesis of treating Alzheimer's disease (VISTA) study: a 4-month, multi-centre, parallel-group, double-blind, placebo-controlled, trial of galantamine in 130 mild-moderate Alzheimer's disease patients (4-month open-label follow-up). ADAS-cog responses at 6 months were compared with outcomes on three clinical measures: clinician's interview based impression of change-plus caregiver input (CIBIC+), patient/carer-goal attainment scaling (PGAS) and clinician-GAS (CGAS). Thirty-seven of 99 patients improved by > or = 4 points on the ADAS-cog at 6 months, and 16/99 showed > or = 4-point worsening. ADAS-cog change scores correlated notionally to modestly with changes on the CGAS (r = -0.31), the PGAS (r = -0.29) and the CIBIC+ (r = 0.31). As a group, patients with ADAS-cog improvement were significantly more likely to improve on the clinical measures; those who worsened showed non-significant clinical decline. Individually, about half were misclassified in relation to each clinical measure; often when the ADAS-Cog detected 'no change', clinically meaningful effects could be detected. Even so, no ADAS-Cog cut-point optimally classified patients' clinical responses. A 4-point ADAS-cog change at 6 months is clinically meaningful for groups. Substantial individual misclassification between the ADAS-cog and clinical measures suggests no inherent meaning to a 4-point ADAS-cog change for a given patient.

Iron, copper, and iron regulatory protein 2 in Alzheimer's disease and related dementias

Accumulating evidence implicates a role for altered iron and copper metabolism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, imbalances in the levels of the various forms of iron at different stages of AD have not been examined. In this pilot study we extracted and measured the levels of loosely bound, non-heme and total iron and copper in the frontal cortex and hippocampus of patients with mild–moderate AD ( n = 3), severe AD ( n = 8) and dementia with Lewy bodies (DLB, n = 6), using graphite furnace atomic absorption spectrometry (GFAAS). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD and DLB, amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies, by immunohistochemistry. We found significantly decreased loosely bound iron in the hippocampal white matter of mild–moderate and severe AD patients and a trend towards increased non-heme iron in the hippocampal gray matter of severe AD patients. Furthermore, decreased levels of total copper were seen in severe AD and DLB frontal cortex compared to controls, suggesting an imbalance in brain metal levels in both AD and DLB. The decrease in loosely bound iron in mild–moderate AD patients may be associated with myelin breakdown seen in the beginning stages of AD and implicates that iron dysregulation is an early event in AD pathogenesis.