Mild-moderate Alzheimer's Disease Research Articles

Role of repetitive transcranial magnetic stimulation in management of alzheimer's disease

Management strategies in Alzheimer's disease (AD) are challenging and limited in several aspects. Repetitive transcranial magnetic stimulation (rTMS), being a noninvasive brain stimulation method, has recently been studied in the management of AD. The literature available is different on several aspects such as patient enrollment, site of stimulation, outcome measures, and follow-up. We present a narrative review highlighting important aspects of rTMS in AD. We searched the databases of Google Scholar and PubMed using the search terms: rTMS and Alzheimer's disease; rTMS and cognition; rTMS and dementia; and brain stimulation and Alzheimer's disease. Original research, case reports and series, other narrative reviews, systematic reviews, and meta-analyses were included, and studies where only abstracts were available were excluded. Majority of the studies present a modest benefit of rTMS in mild–moderate AD and some in normal aging and mild cognitive impairment. Improvement is marked in high-frequency rTMS as compared to low frequency. The favorite site of stimulation appears to be the dorsolateral prefrontal cortex (DLPFC). Studies chiefly assessed cognitive function, while sparingly involving other areas of impairment such as psychopathology and global functioning. Improvement in cognition is mainly in the weeks ensuring rTMS, and studies assessing improvement in a long-term follow-up are needed. There appears to be minimal to no side effects reported in most studies. Future implications of rTMS in AD are suggested.

Implications of Obstructive Sleep Apnea on the Cognitive Evolution of Alzheimer's Disease Patients

Background: Sleep-disordered breathing encompasses a group of diseases, of which obstructive sleep apnea (OSA) is most frequent. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease; it is manifested as an initial deficit of episodic memory that evolves into global cognitive and psychosocial dysfunction, and its prevalence is increasing around the world. OSA has been described as a risk factor for AD, and its prevalence is higher in AD patients. However, little is known about the influence of OSA on cognition in the AD population.The aim of this study was to evaluate the impact of nontreated OSA on the cognitive evolution of patients with mild-moderate AD, to investigate whether the magnitude of the cognitive decline is associated with the severity of OSA and to evaluate the influence of OSA on several cognitive subdomains in AD patients. Methods: In this single-center study, patients with mild-moderate AD were recruited prospectively from a cognitive impairment unit and underwent overnight polysomnography. OSA was defined as an apnea-hypopnea index (AHI) >15/h. AD severity was assessed using the Mini-Mental State Examination (MMSE). The primary outcome was to measure the change in cognitive score on the Alzheimer’s Disease Assessment Scale-cognitive scale (ADAS-cog) from baseline to 12 months in patients with mild AD with and without OSA. An extensive battery of neuropsychological tests, including the Epworth Sleepiness Scale (ESS), were performed and APOE status was measured. Findings: The cohort included 144 patients with a mean (SD) age of 75.19 (5.30) years; 72 (57.6%) were women, and the mean MMSE score was 23.5 (2.24) points at baseline. The mean (SD) change in the ADAS-cog score at 12 months was 3.19 (5.61) in the non-OSA group and 0.08 (5.62) in the OSA group, with a difference between the groups of -3.36 (95%CI 0.19 to 0.16; p=0.002). Regarding the changes in the ADAS-cog subitems at 12 months, ideational praxis, remembering test instructions and commands showed a significant difference between the groups (p<0.05). We did not observe significant differences in cognitive subdomains, such as memory or executive functioning, or for caregiver overload, on the extensive battery of neuropsychological assessments at 12 months. No significant differences were found according to OSA severity group by ADAS-cog or MMSE at 12 months neither at 36 months by MMSE.According to the MMSE score at 36 months, the mean change was similar between the groups, with a difference of 1.69 (95%CI -1.26 to 4.64; p = 0.445). Interpretation: In this large cohort of patients with AD, we demonstrated that that OSA did not worsen cognitive evolution after 1 year of follow-up, either in global cognition or in the different cognitive subdomains, or global cognition after 3 years of follow-up. Based on these findings, OSA does not modify the cognitive evolution of patients in mild or moderate stages of Alzheimer’s disease. Trial Registration: This study was registered with ClinicalTrials.gov (number NCT02814045). Funding Statement: This work was supported by “Fundacio La Marato TV3” (Gerard Pinol), the Spanish Respiratory Society (SEPAR), PERIS SLT008/18/00050, the Health Department of Generalitat de Catalunya and ALLER. This work was supported by the IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS PT17/0015/0027/. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This study was conducted in accordance with the Declaration of Helsinki, and it was approved by the care ethics committee of Hospital Arnau de Vilanova de Lleida (CE-1218). All patients signed informed consent.

Prevalence of obstructive sleep apnea in Alzheimer's disease patients.

To assess the prevalence of obstructive sleep apnea (OSA) in patients with mild-moderate Alzheimer's Disease (AD) and to evaluate cognitive characteristics according to the severity of OSA. Patients with mild-moderate AD, recruited prospectively from a cognitive impairment unit, underwent overnight polysomnography. OSA was defined as an apnea-hypopnea index > 5/h. AD severity was assessed using the Mini-Mental State Examination and extensive neuropsychological battery. Epworth Sleepiness Scale and APOE status were analyzed. The cohort included 128 patients with a median [IQR] age of 75.0 [72.0;79.2] years and 57.8% were women. OSA was diagnosed in 116 subjects (90.6%). The distribution of mild, moderate and severe severity ofOSA was 29 (22.7%), 37 (28.9%) and 50 (39.1%), respectively. Regarding sleep symptoms, the cohort showed normal values of daytime sleepiness (median EES score 5 [3, 8]), while nycturia (89.1%) and snoring (71.1%) were the most common symptoms. Participants with severe OSA included a higher proportion of older men, were associated with snoring and sedentariness. No significant differences in cognitive assessment were found between patients with and without severe OSA in any of the domains. The prevalence of APOE ε4 was not significantly different between patients with and without severe OSA. There was a high prevalence of OSA in patients with mild-moderate AD. OSA was not associated with sleepiness or worse cognitive function. APOE ε4 was not related to the presence or severity of OSA. Further longitudinal studies will be required to evaluate whether OSA impairs cognitive evolution in AD patients.

Galantamine protects against synaptic, axonal, and vision deficits in experimental neurotrauma

Our goal was to investigate the neuroprotective effects of galantamine in a mouse model of blast-induced indirect traumatic optic neuropathy (bITON). Galantamine is an FDA-approved acetylcholinesterase inhibitor used to treat mild-moderate Alzheimer's disease. We exposed one eye of an anesthetized mouse to repeat bursts of over-pressurized air to induce traumatic optic neuropathy. Mice were given regular or galantamine-containing water (120 mg/L) ad libitum, beginning immediately after blast and continuing for one month. Electroretinograms and visual evoked potentials were performed just prior to endpoint collection. Histological and biochemical assessments were performed to assess activation of sterile inflammation, axon degeneration, and synaptic changes. Galantamine treatment mitigated visual function deficits induced by our bITON model via preservation of the b-wave of the electroretinogram and the N1 of the visual evoked potential. We also observed a reduction in axon degeneration in the optic nerve as well as decreased rod bipolar cell dendritic retraction. Galantamine also showed anti-inflammatory and antioxidant effects. Galantamine may be a promising treatment for blast-induced indirect traumatic optic neuropathy as well as other optic neuropathies.

RELATIONSHIP OF CARDIOPULMONARY EXERCISE TESTING AND FIELD WALKING TESTS IN MILD-MODERATE ALZHEIMER’S DEMENTIA

The purpose of this study was to investigate relationships among peak exercise parameters on 6-minute walk (6MWT) and shuttle walk tests (SWT), and laboratory-based cardiopulmonary exercise testing (CPET). These relationships have been established in cardiopulmonary patient populations, but not in community-dwelling older adults with mild-moderate Alzheimer’s dementia (AD). This study is a cross-sectional analysis of the baseline data of 6MWT, SWT, and CPET from the FIT-AD Trial (n=88: 49 males [76.6 {7.0} years and MMSE 21.5{3.5}] and 39 females [77.3 {6.5} years and MMSE 22.1 {3.4}]). Peak values for each test included heart rate (HR), systolic blood pressure (SBP), and rating of perceived exertion (RPE). Peak oxygen assumption (VO2) was measured in the CPET. Peak walking distance (PWD) was measured for the 6MWT and SWT. CPET produced significantly higher peak HR (118.7 [17.5] vs. 106 [22.8] vs. 106 [18.8] bpm), RPE (16 [2.1] vs. 12 [2.3] vs. 11 [2.1]) and SBP (182 [23.7] vs. 156 [18.9] vs. 150 [16.9] mmHg) compared to the SWT and 6MWT respectively. PWD on SWT (240.4 [128.1] m) and 6MWT (364.3 [108.5] m) significantly correlated with peak VO2 (17.0 [4.3]ml/kg/min) on CPET (r=.44 and r=.43) respectively. Correlations of peak VO2 and PWD on SWT in persons with AD are considerably lower than what is seen for persons with cardiopulmonary diseases. This lower correlation seen in our sample may be due to shorter PWD on walking tests. Future research should focus how mobility affects correlation of peak values on these tests.

98 Use of Drgs with Anticholinergic Properties in People Living with Alzheimer’s Disease: Data from NILVAD

Abstract Background Prolonged exposure to anticholinergic medication, particularly in midlife, is associated with increased risk of cognitive impairment/dementia. Less well explored is the ongoing use of drugs with anticholinergic properties in patients with Alzheimer’s Disease (AD), where the potential to accelerate cognitive decline may be greatest. Methods We analysed medication data from the NILVAD trial, a clinical trial examining the efficacy of Nilvadapine in mild-moderate Alzheimer’s Disease (AD). Drgs were coded based on their Anatomical Therapeutic Chemical (ATC) classification and Anticholinergic Burden Scale (ABS) applied to each participant’s medication list. Logistic and linear regression were used to model predictors of potential anticholinergic medication use/total ABS score. Results Of 510 participants with AD (mean age 72.8 +/-8.3 years; 62% female), just over one-quarter (N = 134, 26.27%) were prescribed a drug with potential/definite anticholinergic properties. Half of these had an anticholinergic burden score of 3 or greater (N = 67, 13.4%). The most frequent definite anticholinergics prescribed included quetiapine (N=27) oxybutynin (N = 22), paroxetine (N=14) and amitriptyline (N=8). Usage did not significantly differ by country or study arm. Overall, 88.43% of patients were prescribed a cholinesterase inhibitor. On multivariate analysis of potential/definite anticholinergic usage, age (p=0.044; OR 1.03, 1.01-1.06), total number of medications (p=0.001, OR 1.3, 1.18-1.41) as well as a greater dementia severity rated using the Alzheimer’s Disease Assessment Scale (ADAS-Cog) (p=0.008; 1.04 1.01-1.07) were associated with likelihood of anticholinergic use. Conclusion Over one-quarter of community-dwelling older patients with AD are prescribed a drug with potential or definite anticholinergic properties. Use of drugs with potential/definite anticholinergic properties were associated with total medication burden in addition to greater dementia severity at baseline. This is particularly pertinent given the deleterious cognitive effects of anticholinergic medication. Further attention to reducing total anticholinergic burden in patients with dementia is warranted.

Somatosensory Temporal Discrimination Threshold in Patients with Cognitive Disorders.

The temporal processing of sensory information can be evaluated by testing the somatosensory temporal discrimination threshold (STDT), which is defined as the shortest interstimulus interval needed to recognize two sequential sensory stimuli as separate in time. The STDT requires the functional integrity of the basal ganglia and of the somatosensory cortex (S1). Although there is evidence that time processing is impaired in patients with Alzheimer's disease (AD), no study has yet investigated STDT in patients with various degree of cognitive impairment. The aim of our study was to understand how cognition and attention deficits affect STDT values in patients with cognitive abnormalities. We enrolled 63 patients: 28 had mild-moderate AD, 16 had mild cognitive impairment (MCI), and the remaining 19 had subjective cognitive deficit (SCD). A group of 45 age-matched healthy subjects acted as controls. Paired tactile stimuli for STDT testing consisted of square-wave electrical pulses delivered with a constant current stimulator through surface electrodes over the distal phalanx of the index finger. STDT values were higher in AD and MCI patients than in SCD subjects or healthy controls. Changes in the STDT in AD and MCI were similar in both conditions and did not correlate with disease severity. STDT alterations in AD and MCI may reflect a dysfunction of the dopaminergic system, which signals salient events and includes the striatum and the mesocortical and mesolimbic circuits.

Challenges to and Facilitators of Recruitment to an Alzheimer’s Disease Clinical Trial: A Qualitative Interview Study

Background:Low participation in clinical trials is a major challenge to advancing clinical Alzheimer’s disease (AD) research and care. Factors influencing recruitment to AD trials are not fully understood.Objective:To identify barriers to, and facilitators of, recruitment in a UK multi-center, secondary care AD trial (Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR) trial) and implications for improving recruitment to AD trials.Methods:Semi-structured qualitative telephone interviews with a purposive sample of 17 trial site staff explored the RADAR trial recruitment pathway and views and experiences of recruitment. Interviews were analyzed thematically.Results:Diagnostic and care pathways hindered identifying patients with mild-moderate AD, with a lack of up-to-date patient records and data access problems affecting screening. Research is not routinely embedded in AD care but facilitated recruitment when it was. Clinicians’ and patients’ favorable view of the trial purpose facilitated recruitment, although the complexity of participant information sheets and requirement for study companion created challenges.Conclusion:These findings have important implications for the design of future AD trials and for planning how to best interface with clinical commitments to ensure sufficient and timely recruitment. Challenges to AD trial recruitment can occur at care pathway, clinician, and patient and companion levels. Recruitment can be facilitated by: improving diagnostic processes and systems for recording and sharing patient information, embedding research into routine patient care, collaborating with a range of services to identify and approach eligible patients, training and engaging trial staff, and providing patients with clear and concise study information.

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.

Oxidative Stress in Elderly with Different Cognitive Status: My Mind Project.

Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training ("My Mind Project"). A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable. We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM. Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias.

Simultaneous resting-state FDG-PET/fMRI in Alzheimer Disease: Relationship between glucose metabolism and intrinsic activity

Simultaneously evaluating resting-state brain glucose metabolism and intrinsic functional activity has potential to impact the clinical neurosciences of Alzheimer Disease (AD). Indeed, integrating such combined information obtained in the same physiological setting may clarify how impairments in neuroenergetic and neuronal function interact and contribute to the mechanisms underlying AD. The present study used this multimodality approach to investigate, by means of a hybrid PET/MR scanner, the coupling between glucose consumption and intrinsic functional activity in 23 patients with AD-related cognitive impairment ranging from amnestic mild cognitive impairment (MCI) to mild-moderate AD (aMCI/AD), in comparison with a group of 23 healthy elderly controls. Between-group (Controls > Patients) comparisons were conducted on data from both imaging modalities using voxelwise 2-sample t-tests, corrected for partial-volume effects, head motion, age, gender and multiple tests. FDG-PET/fMRI relationships were assessed within and across subjects using Spearman partial correlations for three different resting-state fMRI (rs-fMRI) metrics sensitive to AD: fractional amplitude of low frequency fluctuations (fALFF), regional homogeneity (ReHo) and group independent component analysis with dual regression (gICA-DR). FDG and rs-fMRI metrics distinguished aMCI/AD from controls according to spatial patterns analogous to those found in stand-alone studies. Within-subject correlations were comparable across the three rs-fMRI metrics. Correlations were overall high in healthy controls (ρ = 0.80 ± 0.04), but showed a significant 17% reduction (p < 0.05) in aMCI/AD patients (ρ = 0.67 ± 0.05). Positive across-subject correlations were overall moderate (ρ = 0.33 ± 0.07) and consistent across rs-fMRI metrics. These were confined around AD-target posterior regions for metrics of functional connectivity (ReHo and gICA-DR). In contrast, FDG/fALFF correlations were distributed in the frontal gyrus, thalami and caudate nuclei. Taken together, these results support the presence of bioenergetic coupling between glucose utilization and rapid transmission of neural information in healthy ageing, which is substantially reduced in aMCI/AD, suggesting that abnormal glucose utilization is in some way linked to communication breakdown among brain regions impacted by the underlying pathological process.

Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer's Disease: A Prospective Cohort Study.

An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized. We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer's disease (AD) in the presence of vascular or genetic risk factors. 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome. Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT. pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.

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.

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin.

Background:Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer’s disease (AD) treated with plasma exchange (PE) with albumin replacement.Objective:To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial.Methods:Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline.Results:42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls.Conclusions:Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.

IDALOPIRDINE, A 5-HT6 ANTAGONIST, AS ADJUNCTIVE THERAPY TO ACETYLCHOLINESTERASE INHIBITORS IN PATIENTS WITH MILD-MODERATE ALZHEIMER’S DISEASE: KEY OUTCOMES FROM THE STAR PHASE III PROGRAM

Idalopirdine is a novel, selective, 5-HT6 receptor antagonist tested as adjunctive to acetylcholinesterase-inhibitors (AChEIs) for the treatment of mild-moderate Alzheimer's disease (AD). In a Phase II study in patients with moderate AD (MMSE 12–19), idalopirdine 90mg/day (30mg TID) added to stable donepezil treatment produced significant improvement in cognitive performance relative to donepezil monotherapy (Lancet Neurol. 2014;13:1092–9). Here, we present data from a large phase III program designed to establish the efficacy and safety of idalopirdine 10–60mg/day adjunctive to AChEI in mild-moderate AD. The phase III program consisted of three 24-week, double-blind, parallel group, placebo-controlled, multi-national, multi-center, fixed-dose (10, 30, and 60mg QD) studies of idalopirdine as adjunctive to AChEIs in patients aged ≥50 years with mild-moderate AD (MMSE 12–22) (NCT01955161; NCT02006641; NCT02006654). The primary endpoint in all studies was change from Baseline to Week-24 in ADAS-cog total score; key secondary endpoints were change from Baseline to Week-24 in ADCS-ADL23 total and ADCS-CGIC scores. Endpoints were analyzed using an MMRM approach. Dose-group efficacy required a significant benefit over placebo for the primary endpoint and at least one key secondary endpoint. 2525 patients (n=933, 858, 734) (mean age 74 years; mean Baseline ADAS-cog score 26; 62–65% female) were randomized across three studies. None of the doses met the prespecified efficacy criteria in the studies. A priori defined strata analyses suggested some indication of efficacy for 60mg/day in the moderate MMSE stratum (MMSE 12–18, ∼60% of patients); although these were not replicated by endpoints across studies. The proportion of patients reporting treatment-emergent adverse events was comparable between idalopirdine and placebo groups across studies. Transient, dose-dependent increases in liver enzymes and vomiting were infrequently observed (<5%). Study completion rates were high (89–91%), as was roll-over to the ongoing open-label extension study (NCT02079246; 90–92%). The 24-week efficacy of 10–60mg/day idalopirdine as adjunctive to AChEI in mild-moderate AD was not demonstrated in a large phase III program. Idalopirdine 10–60mg/day was safe and well-tolerated. The phase III program did not replicate phase II efficacy results performed in a moderate stage population with idalopirdine 90 mg (30mg TID) dose.

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity-A Functional MRI Study in the Awake Rat.

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. 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 brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

Utility of the Neuropsychiatric Inventory Questionnaire (NPI-Q) in the assessment of a sample of patients with Alzheimer's disease in Chile.

The Neuropsychiatric Inventory Questionnaire (NPI-Q) is an informant-based instrument that measures the presence and severity of 12 Neuropsychiatric Symptoms (NPS) in patients with dementia, as well as informant distress.ObjectiveTo measure the psychometric properties of the NPI-Q and the prevalence of NPS in patients with Alzheimer's disease (AD) in Chile.Methods53 patients with AD were assessed. Subjects were divided into two different groups: mild AD (n=26) and moderate AD (n=27). Convergent validity was estimated by correlating the outcomes of the NPI-Q with Neuropsychiatric Inventory (NPI) scores and with a global cognitive efficiency test (Addenbrooke's Cognitive Examination - Revised - ACE-R). Reliability of the NPI-Q was analysed by calculating its internal consistency. Prevalence of NPS was estimated with both the NPI and NPI-Q.ResultsPositive and significant correlations were observed between the NPI-Q, the NPI, and the ACE-R (r=0.730; p<0.01 and 0.315; p<0.05 respectively). The instrument displayed an adequate level of reliability (Cronbach's alpha=0.783). The most prevalent NPS were apathy/indifference (62.3%) and dysphoria/depression (58.5%).ConclusionThe NPI-Q exhibited acceptable validity and reliability indicators for patients with AD in Chile, indicating that it is a suitable instrument for the routine assessment of NPS in clinical practice.

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.

Loss of precuneus dendritic spines immunopositive for spinophilin is related to cognitive impairment in early Alzheimer's disease

Precuneus (PreC) cortex is affected with amyloid plaques early in Alzheimer's disease (AD), and this pathology may be associated with alterations in PreC synapses and cognitive impairment. We quantified the spinophilin-immunoreactive (ir) dendritic spine density and the intensity of spinophilin immunofluorescence, the latter as a measure of relative protein levels of spinophilin, in PreC lamina III from 33 subjects with clinical diagnoses of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or severe AD (sAD). Both measures of spinophilin were lower in mAD and sAD compared with NCI. The MCI group had higher protein levels of spinophilin compared with mAD and sAD, and higher spinophilin-ir dendritic spine density compared with sAD. Lower spinophilin-ir dendritic spine density and relative protein levels of spinophilin were associated with greater amyloid beta (Aβ) plaque burden, detected with a derivative of Pittsburgh compound-B (6-CN-PiB), and worse cognitive performance. Clinical onset of AD is marked by the loss of PreC spinophilin-ir dendritic spines that is related to Aβ pathology and may contribute to cognitive symptoms early in the disease.

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer\u2019s disease

BackgroundTreatment of mild-moderate Alzheimer’s disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores.MethodsFor this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples.ResultsCompared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels.ConclusionsCollectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders.Trial registrationClinicalTrials.gov NCT01504854