Mild-moderate Alzheimer's Disease Research Articles

The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil-treated AD patients.

Review of the Evidence that Transcranial Electromagnetic Treatment will be a Safe and Effective Therapeutic Against Alzheimer's Disease.

We have demonstrated in multiple studies that daily, long-term electromagnetic field (EMF) treatment in the ultra-high frequency range not only protects Alzheimer’s disease (AD) transgenic mice from cognitive impairment, but also reverses such impairment in aged AD mice. Moreover, these beneficial cognitive effects appear to be through direct actions on the AD process. Based on a large array of pre-clinical data, we have initiated a pilot clinical trial to determine the safety and efficacy of EMF treatment to mild-moderate AD subjects. Since it is important to establish the safety of this new neuromodulatory approach, the main purpose of this review is to provide a comprehensive assessment of evidence supporting the safety of EMFs, particularly through transcranial electromagnetic treatment (TEMT). In addition to our own pre-clinical studies, a rich variety of both animal and cell culture studies performed by others have underscored the anticipated safety of TEMT in clinical AD trials. Moreover, numerous clinical studies have determined that short- or long-term human exposure to EMFs similar to those to be provided clinically by TEMT do not have deleterious effects on general health, cognitive function, or a variety of physiologic measures—to the contrary, beneficial effects on brain function/activity have been reported. Importantly, such EMF exposure has not been shown to increase the risk of any type of cancer in human epidemiologic studies, as well as animal and cell culture studies. In view of all the above, clinical trials of safety/efficacy with TEMT to AD subjects are clearly warranted and now in progress.

Idalopirdine, a 5-HT6 receptor antagonist in development for the treatment of mild-moderate Alzheimer’s disease: the scientific rationale

Idalopirdine, a 5-HT6 receptor antagonist in development for the treatment of mild-moderate Alzheimer’s disease: the scientific rationale

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.

Detection of Alzheimer's disease at mild cognitive impairment and disease progression using autoantibodies as blood-based biomarkers

IntroductionThere is an urgent need to identify biomarkers that can accurately detect and diagnose Alzheimer's disease (AD). Autoantibodies are abundant and ubiquitous in human sera and have been previously demonstrated as disease-specific biomarkers capable of accurately diagnosing mild-moderate stages of AD and Parkinson's disease. MethodsSera from 236 subjects, including 50 mild cognitive impairment (MCI) subjects with confirmed low CSF Aβ42 levels, were screened with human protein microarrays to identify potential biomarkers for MCI. Autoantibody biomarker performance was evaluated using Random Forest and Receiver Operating Characteristic curves. ResultsAutoantibody biomarkers can differentiate MCI patients from age-matched and gender-matched controls with an overall accuracy, sensitivity, and specificity of 100.0%. They were also capable of differentiating MCI patients from those with mild-moderate AD and other neurologic and non-neurologic controls with high accuracy. DiscussionAutoantibodies can be used as noninvasive and effective blood-based biomarkers for early diagnosis and staging of AD.

Contact Heat Evoked Potentials (CHEPs) in Patients with Mild-Moderate Alzheimer's Disease and Matched Control--A Pilot Study.

Clinical studies have found that patients with Alzheimer's disease report pain of less intensity and with a lower affective response, which has been thought to be due to altered pain processing. The authors wished to examine the cerebral processing of non-painful and painful stimuli using somatosensory evoked potentials and contact heat evoked potentials in patients with Alzheimer's disease and in healthy elderly controls. Case-control study Twenty outpatients with mild-moderate Alzheimer's disease and in 17 age- and gender-matched healthy controls were included Contact heat evoked potentials and somatosensory evoked potentials were recorded in all subjects. Furthermore, warmth detection threshold and heat pain threshold were assessed. Patients and controls also rated quality and intensity of the stimuli. The authors found no difference on contact heat evoked potential amplitude (P = 0.59) or latency of N2 or P2 wave (P = 0.62 and P = 0.75, respectively) between patients and controls. In addition, there was no difference in regard to pain intensity scores or pain quality. The patients and controls had similar warmth detection threshold and heat pain threshold. Somatosensory evoked potentials, amplitude, and latency were within normal range and similar for the two groups. The findings suggest that the processing of non-painful and painful stimuli is preserved in patients with mild to moderate Alzheimer's disease.

Prospective longitudinal study of frailty transitions in a community-dwelling cohort of older adults with cognitive impairment.

BackgroundFrailty and cognitive impairment are seemingly distinct syndromes, but have a shared vulnerability to stress in older adults, resulting in poorer outcomes. Although there has been recent interest in cognitive frailty, frailty transitions in relation to cognitive deterioration in older adults with cognitive impairment have not yet been well studied. We thus aim to study frailty transitions and change in cognitive status over 1-year follow-up among subjects with cognitive impairment attending a tertiary Memory Clinic.MethodsThis is a prospective cohort study of mild cognitive impairment (MCI) and mild-moderate Alzheimer’s disease (AD) community-dwelling subjects. We obtained data on clinical measures, muscle mass and physical performance measures. Cognitive status was measured using Chinese Mini-Mental State Examination (CMMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. We measured gait speed, hand grip strength, exhaustion and weight loss at baseline, 6 and 12 months to classify subjects according to the modified Fried criteria (involving strength, gait speed, body composition and fatigue) into non-frail (<2 frail categories) and frail categories (≥2 frail categories). Frailty transitions between baseline and 12-months were assessed. We performed random effects statistical modelling to ascertain baseline predictors of longitudinal frailty scores for all subjects and within MCI subgroup.ResultsAmong 122 subjects comprising 41 MCI, 67 mild and 14 moderate AD, 43.9, 35.8 and 57.1 % were frail at baseline respectively. Frailty status regressed in 32.0 %, remained unchanged in 36.0 %, and progressed in 32.0 % at 12 months. Random effects modelling on whole group showed longitudinal CDR-SB scores (coeff 0.09, 95 % confidence interval (CI) 0.03–0.15) and age (coeff 0.04, 95 % CI 0.02–0.07) to be significantly associated with longitudinal frailty score. Among MCI subjects, only female gender (coeff 1.28, 95 % CI 0.21–2.36) was associated with longitudinal frailty score, while mild-moderate AD subjects showed similar results as those of the whole group.ConclusionsThis is the first study to show longitudinal frailty state transitions in cognitively-impaired older adults. Frailty transitions appear to be independent of progression in cognitive status in earliest stages of cognitive impairment, while mild-moderate AD subjects showed associations with age and cognitive deterioration. The potential for cognitive frailty as a separate therapeutic entity for future physical frailty prevention requires further research with a suitably powered study over a longer follow-up period.

The Independent Role of Inflammation in Physical Frailty among Older Adults with Mild Cognitive Impairment and Mild-to-Moderate Alzheimer's Disease.

To examine the independent and combined effects of inflammation and endocrine dysregulation on (i) baseline frailty status and (ii) frailty progression at one year, among cognitively impaired community dwelling older adults. Prospective cohort study. Tertiary Memory Clinic. We recruited patients with mild cognitive impairment and mild-moderate Alzheimer's disease. Physical frailty status was assessed at baseline and 1-year. Blood biomarkers of systemic inflammation [interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α)] and anabolic hormones [insulin-like growth factor-1 (IGF-1), dehydroepiandrosterone sulphate (DHEAS)] were measured at baseline and examined in relation to physical frailty status at baseline and progression at 1-year. Each subject was categorized as (i) neither pro-inflammatory nor endocrine deficient, (ii) pro-inflammatory (IL-6 or TNF-α, or both, being in highest quartile) but not endocrine deficient, (iii) endocrine deficient (IGF-1 or DHEAS, or both, being in lowest quartile) but not pro-inflammatory and (iv) both pro-inflammatory and endocrine deficient. Twenty (20.2%) of 99 subjects were physically frail at baseline. There was no association between severity of cognitive impairment and baseline frailty status, but the frail group had significantly greater hippocampal atrophy (median MTA: 2 (2-3) vs 1 (1-2), p=0.010). TNF-α was significantly higher in subjects who were physically frail at baseline (median TNF-α: 1.30 (0.60-1.40) vs 0.60 (0.50-1.30) pg/mL, p=0.035). In multiple logistic regression adjusted for age and gender, a pro-inflammatory state in the absence of concomitant endocrine deficiency was significantly associated with physical frailty at baseline (OR=4.99, 95% C.I 1.25-19.88, p=0.023); this was no longer significant when MTA score was included in the model. Isolated pro-inflammatory state (without endocrine deficiency) significantly increased the odds of frailty progression (OR=4.06, 95% CI 1.09-15.10, p=0.037) at 1-year. The combination pro-inflammatory and endocrine deficient state was not significantly associated with either baseline or progressive physical frailty. A pro-inflammatory state exerts differential effects on physical frailty, contributing to the increased risk of baseline and progressive frailty only in the absence of a concomitant endocrine deficient state, with potential mediation via neurodegeneration.

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.

Differential diagnosis of depression and Alzheimer's disease with the Addenbrooke's Cognitive Examination-Revised (ACE-R).

BackgroundOne of the usual problems psychologists and clinicians face in clinical practice is differential diagnostics of Alzheimer’s disease and depression. It has been reported that the ACE and ACE-R could discriminate the cognitive dysfunctions due to depression from that due to dementia, although this is not uniform in all studies. The current study aimed to evaluate the utility of the ACE-R to differentiate late-life onset depression (with severe episode) from mild-moderate Alzheimer’s Disease (AD).MethodsThis study received approval from the Lithuanian Bioethics Committee. All participants were older than 50 years (mean age = 66.52 (±8.76) years). The study sample consisted of 295 individuals: 117 with severe depression, 85 with mild-moderate Alzheimer’s disease (AD), and 94 age, gender and education matched participants of control group.ResultsThe ACE-R had high sensitivity (100%) and specificity (81%) at detecting cognitive impairments related to AD. Patients with late-life onset depression (ACE-R mean 76.82, SD = 7.36) performed worse than controls (ACE-R mean 85.08, SD = 7.2), but better than the AD group (ACE-R mean 54.74, SD = 12.19). Participants with late-life onset depression were differentiated by mild impairment in the ACE-R total score with mild memory (13.79, SD = 6.29) and greater deficits in letter fluency (3.65, SD = 1.21) than in semantic fluency (4.68, SD = 1.23). Participants with AD were differentiated by severely impaired performance on attention and orientation (11.80, SD = 2.93), memory (8.25, SD = 3.47) and language subtests (17.21, SD = 4.04), and moderately impaired performance on verbal fluency (6.07, SD = 2.74).ConclusionsACE-R has diagnostic accuracy in detecting people with AD and can be used in differential diagnostics of late-life onset depression (severe episode) and AD. Diagnostic accuracy may be improved by analyzing the neuropsychological profiles and using lower cutoffs for different age groups.

A Phase II Study to Evaluate the Efficacy and Safety of Plasma Replacement with 5[percnt] Albumin in Beta-amyloid Peptide Clearance in Cerebrospinal Fluid and Plasma, and its Clinical Effects in Patients with Mild-Moderate Alzheimer's Disease (P7.107)

A Phase II Study to Evaluate the Efficacy and Safety of Plasma Replacement with 5[percnt] Albumin in Beta-amyloid Peptide Clearance in Cerebrospinal Fluid and Plasma, and its Clinical Effects in Patients with Mild-Moderate Alzheimer's Disease (P7.107)

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.

Associations between CAMCOG-R subscale performance and formal education attainment in South African older adults.

ABSTRACT Background: The Cambridge Cognitive Examination-Revised (CAMCOG-R) is a sensitive screening tool for the early diagnosis of dementia in older adults. Overall performance on the CAMCOG-R is influenced by educational attainment. Few studies have, however, examined the association between educational attainment and performance on the individual CAMCOG subscales. We aimed to address this question in a sample from a low-and middle-income country (LAMIC), where resource constraints may have compromised access to, and quality of, education for many older adults. Methods: Participants, all over 60 years of age, were 51 cognitively healthy community-dwelling volunteers and 47 individuals diagnosed with mild-moderate stage Alzheimer's disease (AD). Most participants had some high school education. They were administered the CAMCOG-R under standardized conditions. Results: Within both the control and AD patient groups, there were significant associations between years of completed education and CAMCOG-R total score, MMSE score, and CAMCOG-R Language subscale score. In both groups, level of education was not associated with scores on these subscales: in controls, recent memory, R 2 = .21, p = .055, learning memory, R 2 = .16, p = .398, attention/calculation, R 2 = .19, p = .467, and perception, R 2 = .18, p = .984; in AD patients, recent memory, R 2 = .14, p = .340, learning memory, R 2 = .03, p = .680, perception, R 2 = .09, p = .723, and attention/calculation, R 2 = .19, p = .097. Conclusions: Some CAMCOG-R subscale scores were more strongly associated with educational attainment than others. Importantly, however, performance on the recent memory and learning memory subscales was not affected by education. These subscales are sensitive indicators of amnestic mild cognitive impairment (MCI) and early AD. These subscales may therefore remain valid for use as an AD screening tool in resource-poor healthcare settings.

A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease.

Intranasal (IN) insulin acutely improves verbal memory in mild cognitive impairment (MCI)/Alzheimer's disease (AD), but its therapeutic effects may be attenuated in apolipoprotein E4 (ApoE4) carriers. Furthermore, rapid-acting (RA) insulins may have superior therapeutic effects compared with regular insulin types. To measure the safety and efficacy of intranasally delivered RA glulisine in ApoE4 carriers with mild-moderate AD. We performed a double-blinded, randomized, cross-over study of RA insulin glulisine in nine mild-moderate AD subjects to better understand the relationship between RA insulin, ApoE4 carrier status and memory performance. IN glulisine was well tolerated but failed to have an acute impact on cognition in ApoE4 carriers with AD. Serum insulin levels acutely dropped following treatment, but peripheral glucose levels remained unchanged. Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.

Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease

Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated, pyroglutamate-modified Aβ (NpE3) forms, and their correlations to cognitive dysfunction in AD, are unknown. We quantified AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 concentrations in soluble (nonfibrillar) and insoluble (fibrillar) pools in PCC from subjects with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild-moderate AD. In clinical AD, increased PCC concentrations of Aβ were observed for all Aβ forms in the insoluble pool but only for Aβ1-42 in the soluble pool. Lower Mini-Mental State Exam and episodic memory scores correlated most strongly with higher concentrations of soluble and insoluble Aβ1-42. Greater neuropathology severity by Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging-Reagan pathologic criteria was associated with higher concentrations of all measured Aβ forms, except soluble AβNpE3-40. Low concentrations of soluble pyroglutamate Aβ across clinical groups likely reflect its rapid sequestration into plaques, thus, the conversion to fibrillar Aβ may be a therapeutic target.

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.

Can theory of mind deficits be measured reliably in people with mild and moderate Alzheimer's dementia?

BackgroundPatients suffering from Alzheimer’s dementia develop difficulties in social functioning. This has led to an interest in the study of “theory of mind” in this population. However, difficulty has arisen because the associated cognitive demands of traditional short story theory of mind assessments result in failure per se in this population, making it challenging to test pure theory of mind ability.MethodsSimplified, traditional 1st and 2nd order theory of mind short story tasks and a battery of alternative theory of mind cartoon jokes and control slapstick cartoon jokes, without memory components, were administered to 16 participants with mild-moderate Alzheimer’s dementia, and 11 age-matched healthy controls.ResultsNo significant differences were detected between participants with Alzheimer’s dementia and controls on the 1st or 2nd order traditional short story theory of mind tasks (p = 0.155 and p = 0.154 respectively). However, in the cartoon joke tasks there were significant differences in performance between the Alzheimer participants and the control group, this was evident for both theory of mind cartoons and the control ‘slapstick’ jokes.ConclusionIt remains very difficult to assess theory of mind as an isolated phenomenon in populations with global cognitive impairment, such as Alzheimer’s dementia, as the tasks used to assess this cognition invariably depend on other cognitive functions. Although a limitation of this study is the small sample size, the results suggest that there is no measurable specific theory of mind deficit in people with Alzheimer's dementia, and that the use of theory of mind representational models to measure social cognitive ability may not be appropriate in this population.Electronic supplementary materialThe online version of this article (doi:10.1186/2050-7283-1-28) contains supplementary material, which is available to authorized users.

PharmGKB summary

The many uses of methylene blue Methylene blue (methylthioninium chloride) is a ‘jack of all trades’ with a litany of clinical uses. In vivo, it is indicated for use as a therapy for drug-induced methemoglobinemia [1-3], can be used for the treatment of infections, pathologies, or poisoning, and as a dye for diagnostics. It is also commonly used as a dye in vitro – for example, as a component in staining of cells, tissues, DNA, parasites, and bacteria [4-6]. In the 1890s, Ehrlich demonstrated its use to target the malarial parasite, and more recently it has been reinvestigated for inclusion in antimalarial regimens in the wake of parasite drug resistance [7-9]. Further examples of its clinical use include treatment of ifosfamide-induced neurotoxicity (although treatment has been reported ineffective), an antidote for cyanide poisoning, visualization of fallopian tubes or ruptured membranes, a marker of tumors, and even as a potential therapy for septic shock and ischemic brain injury [5,8,10-18]. In phase II clinical trials, a modified version of methylene blue is reported to slow cognitive decline in mild–moderate Alzheimer’s disease patients compared to placebo, and phase III trials are planned, although these results remain unpublished [19]. The mechanism of action is unclear – possibly by preventing tau protein aggregation or increasing amyloid-β clearance by enhancing proteasome activities [19,20]. As a photodynamic therapy, methylene blue could be used to treat psoriasis, West Nile virus infection, AIDS-related Kaposi’s sarcoma, antibiotic-resistant bacterial strains and decontaminate blood before transfusion [5,21-25]. Methylene blue has also contributed to drug development, forming the structural chemical basis of other therapeutic drugs, including the antimalarial drug, chloroquine; the antihistamine, promethazine; and the antipsychotic, chlorpromazine [5]. Acknowledging the many uses of methylene blue, this article focuses on the pharmacodynamics of methylene blue in the context of methemoglobinemia treatment and the pathways surrounding this, due to known pharmacogenetic associations that relate to these pathways.