Moderate-severe Alzheimer's Disease Research Articles

Novel Pathogenic Mechanism of Late-onset Alzheimer's Disease by Deficiency of NMDA Receptor Subunit GluN3A

Late-onset Alzheimer’s disease (AD) and related dementia (ADRD) are serious neurodegenerative disorders among aging populations. The progress of AD/ADRD cultivates over years to decades in humans and several months in animal models. Ca<sup>2+</sup> homeostasis is a core function of neurons where the N-methyl-D-aspartate (NMDA) receptor plays a major role in excitatory neuronal activities. The Ca<sup>2+</sup> hypothesis of AD proposes that even slight but sustained Ca<sup>2+</sup> dyshomeostasis in the brain is a critical pathophysiology or pathogenesis of AD. However, instigating factors like the trigger and time/duration of the Ca<sup>2+</sup> dysregulation in AD progression have been largely obscure, while β-amyloid (Aβ) peptides are often indicated as the trigger. Hyperactivities of excitatory neurons and NMDARs have been implicated in AD as a main mediating mechanism caused by AD pathologies such as Aβ deposition. NMDAR overactivation is restrained by the unique regulatory GluN3 subunits (GluN3A and GluN3B; previously known as NR3A and NR3B). Expression of GluN3A in the receptor complex reduces NMDAR currents and Ca<sup>2+</sup> influx, while deletion of GluN3A causes larger NMDA currents and elevated intracellular Ca<sup>2+</sup>. Significant GluN3A levels are detected in both rodent and human adult/aging brains. We hypothesized that the “gatekeeper” role of GluN3A is constantly required for Ca<sup>2+</sup> homeostasis and normal aging; its deficiency can lead to slowly evolved “degenerative excitotoxicity”. Our in vitro, ex vivo, and in vivo studies using GluN3A knockout (KO) mice of young and older ages revealed neuronal hyperactivity, moderate but sustained elevation of cytosolic Ca<sup>2+</sup>, chronic inflammation, neuronal loss/apoptosis, synaptic impairments and progressive cognitive deficits. The AD hallmarks of Aβ and tau pathology were identified after, but not before, cognition decline. In the “gain of function” experiment, expression of GluN3A in the GluN3A KO brain prevented AD progression. Specific regional knockdown of GluN3A in the cortex and hippocampus of wild-type mice at the adult age (3 months old) resulted in similar AD/ADRD phenotypic alterations in the following 3-6 months. The NMDAR antagonist memantine (MEM) is approved by FDA as a symptomatic treatment for moderate-severe AD patients. According to the chronic neurohyperactivity in AD progression and the modified Ca<sup>2+</sup> hypothesis that Ca<sup>2+</sup> dysregulation is an early and “life-long” pathogenesis, the maintenance of NMDAR normal activity by MEM or other safe NMDAR antagonists could be a disease-modifying early treatment in preclinical/prodromal stages. This prediction is endorsed by clinical trials using MEM and other NMDAR antagonists in mild cognitive impairment (MCI) and early AD patients, showing beneficial effects of maintaining cognitive functions. Consistently, we showed that, in GluN3A KO mice and 5xFAD mice, early and chronic MEM treatment (started at 3-month of age and lasted for 3-6 months) prevented or attenuated AD phenotypes. Meanwhile, the chronic MEM therapy in mice showed preconditioning effect of neuroprotection against ischemic stroke that strikes over 50% AD patients. Large clinical trials of long-term and more systematic examinations on AD/ADRD progression and the comorbidity of stroke are warranted for this innovative therapy. Our results support the modification of Ca<sup>2+</sup> hypothesis of AD with the novel amyloid-independent mechanism. Specifically, the deficiency of GluN3A alone causes lifelong Ca<sup>2+</sup>-related progression of AD pathophysiology and amyloid pathology. The long-term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for late-onset AD/ ADRD.

Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer's Disease.

Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer's disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region's plasticity response in AD.

The effects of the glycaemic control on the severity of the delirium in the advanced phase of Alzheimer's disease.

Behavioral and psychological symptoms of dementia (BPSD) and delirium are common in advanced phases of Alzheimer's disease (AD). Thirty-eight moderate-severe AD patients were enrolled (n=16 affected by type 2 diabetes). Each patient received a comprehensive geriatric assessment (CGA) (including evaluation of BPSD and frailty), and a complete metabolic evaluation (including the measurement of the glycated hemoglobin, HbA1c). Both the hyper- and hypo-glycemic extremes of the glycemic spectrum worsened BPSD, but delirium was more susceptible to hypoglycemic events. The severity of delirium was significantly related to cognitive function (r = -0.585, p<0.001) and frailty (r = +0.440, p<0.05). The measurement of HbA1c was useful for evaluating the risk of delirium in relationship to glycemic control and nutritional status.

The effects of the glycaemic control on the severity of the delirium in the advanced phase of Alzheimer’s disease

Background: Behavioral and psychological symptoms of dementia (BPSD) and delirium are common in advanced phases of Alzheimer’s disease (AD). Methods: Thirty-eight moderate-severe AD patients were enrolled (n=16 affected by type 2 diabetes). Each patient received a comprehensive geriatric assessment (CGA) (including evaluation of BPSD and frailty), and a complete metabolic evaluation (including the measurement of the glycated hemoglobin, HbA1c). Results: Both the hyper- and hypo-glycemic extremes of the glycemic spectrum worsened BPSD, but delirium was more susceptible to hypoglycemic events. The severity of delirium was significantly related to cognitive function (r = -0.585, p<0.001) and frailty (r = +0.440, p<0.05). Conclusions: The measurement of HbA1c was useful for evaluating the risk of delirium in relationship to glycemic control and nutritional status.

Trough Melatonin Levels Differ between Early and Late Phases of Alzheimer Disease.

ObjectiveMelatonin has been considered to have an essential role in the pathophysiology of Alzheimer’s disease (AD) for its regulatory function on circadian rhythm and interaction with glutamate for the modulation of learning and memory. Previous studies revealed that melatonin levels decreased in patients with AD. However, melatonin supplement didn’t show promising efficacy for AD. This study compared trough melatonin levels among elderly people with different severities of cognitive deficits.MethodsWe enrolled 270 elder individuals (consisting four groups healthy elderly, amnestic mild cognitive impairment [MCI], mild AD, and moderate-severe AD) in the learning cohort. Trough melatonin levels in plasma were measured using ELISA. Cognitive function was evaluated by Clinical Dementia Rating Scale (CDR) and Mini-Mental State Examination (MMSE). An independent testing cohort, also consisting of four groups, was enrolled for ascertainment.ResultsIn the learning cohort, trough melatonin levels decreased in the MCI group but elevated in the mild and moderate to severe AD groups. Trough melatonin levels were associated with CDR and MMSE in MCI or AD patients significantly. In the testing cohort, the results were similar to those in the learning cohort.ConclusionThis study demonstrated that trough melatonin levels in the peripheral blood were decreased in MCI but increased with the severity of AD. The finding supports the trials indicating that melatonin showed efficacy only in MCI but not in AD. Whether trough melatonin level has potential to be a treatment response biomarker for AD, especially its early phase needs further studies.

The effects of the glycaemic control on the severity of the delirium in the advanced phase of Alzheimer's disease.

Behavioural and psychological symptoms of dementia (BPSD) and delirium are common in advanced phases of Alzheimer's disease (AD). Thirty-eight moderate-severe AD patients were enrolled (n=16 affected by type 2 diabetes). Each patient received a comprehensive geriatric assessment (CGA) (including evaluation of BPSD and frailty), and a complete metabolic evaluation (including the measurement of the glycated haemoglobin, HbA1c). Both the hyper- and hypo-glycaemic extremes of the glycaemic spectrum worsened BPSD, but delirium was more susceptible to hypoglycaemic events. The severity of delirium was significantly related to cognitive function (r = -0.585, p<0.001) and frailty (r = +0.440, p<0.05). The measurement of HbA1c was useful for evaluating the risk of delirium in relationship to glycaemic control and nutritional status.

PND108 Understanding the Evolution of Patient Burden across the Severity Stages of Alzheimer's Disease Using Online Social MEDIA

Spontaneous online conversations by patients and caregivers across the clinical severity stages of Alzheimer’s Disease (AD) were used to inform how to tailor patient-centric diagnostic, disease and lifestyle management approaches over the course of disease. We used Natural Language Processing (NLP) to analyze Social, Physical, Emotional, Cognitive, and Role Activity (SPEC-R) issues extracted from patient and caregiver narratives over 84 public social media sites to evaluate patient burden in Mild Cognitive Impairment due to AD (MCI-AD), Early-AD (E-AD) and Moderate-Severe AD (MS-AD). 112,464 narratives from 692 patients and 10,174 caregivers were qualified into the final analytic sample with 333 patients clinically diagnosed for MCI-AD and 359 for E-AD. No individuals with MS-AD were captured over the social media forums. Of the caregivers, 971 were caring for patients with MCI-AD, 3,776 for patients with E-AD, and 5,427 for patients with MS-AD. Among patients with MCI-AD and their caregivers, 95.5% patients and 83.0% caregivers discussed cognitive issues, e.g. memory impairments. 61.1% patients and 51.4% caregivers shared emotional issues, e.g. anxiety and depression. Among patients with E-AD and their caregivers, emotional issues were the most frequently discussed by both patients (93.6%) and caregivers (53.5%), e.g. anxiety, depression and other emotional experiences. Cognitive issues followed, and shared by 86.9% patients and 39.6% caregivers. Among caregivers for patients with MS-AD, 42.7% reported on emotional issues and 20.7% on physical issues, e.g. fatigue and agitation. Individuals with MCI-AD or E-AD were active on social media to share their experiences and challenges while those with MS-AD appeared to no long participate in online communications relating to their illness. Caregivers were active on social media across disease severity stages. However, frequencies of caregiver reporting on prominent patient challenges differed from that of patient self-reporting.

Multiple Visual Rating Scales Based on Structural MRI and a Novel Prediction Model Combining Visual Rating Scales and Age Stratification in the Diagnosis of Alzheimer's Disease in the Chinese Population.

Objective: To explore the value of multiple visual rating scales based on structural MRI in the diagnosis of Alzheimer's disease (AD) in the Chinese population.Materials and Methods: One hundred patients with AD and 100 age- and gender- matched cognitively normal controls were enrolled in this study. All the participants underwent neuropsychological tests and a structural MRI scan of the brain, among them, 42 AD cases and 47 cognitively normal controls also underwent 3D-T1 weighted sequence used for the analysis of voxel-based morphometry (VBM). The AD cases were divided into mild and moderate–severe groups according to the mini-mental state examination. Each participant was evaluated by two trained radiologists who were blind to the clinical information, according to the six visual rating scales, including for medial temporal lobe atrophy (MTA), posterior atrophy (PA), anterior temporal (AT), orbitofrontal (OF) cortex, anterior cingulate (AC), and fronto-insula (FI). Finally, we estimated the relationship between the visual rating scales and the volume of corresponding brain regions, using correlation analysis, and evaluated the specificity and sensitivity of every single scale and combination of multiple scales in the diagnosis of AD, using a receiver operating characteristic (ROC) curve and establishing a logistic regression model.Results: The optimal cutoff of all six visual rating scales for distinguishing AD cases from normal controls was 1.5. Using automated classification based on all six rating scales, the accuracy for distinguishing AD cases from healthy controls ranged from 0.68 to 0.80 (for mild AD) and 0.77–0.90 (for moderate–severe AD), respectively. A diagnostic prediction model with a combination of MTA and OF results was made as follows: Score = BMTA(score) + BOF(score) −1.58 (age < 65 years); Score = BMTA(score) + BOF(score) −4.09 (age ≥65 years). The model was superior to any single visual rating scale in the diagnosis of mild AD (P < 0.05).Conclusion: Each of the six visual rating scales could be applied to the diagnosis of moderate-severe AD alone in the Chinese population. A prediction model of the combined usage of MTA, OF, and age stratification for the early diagnosis of AD was preliminarily established.

Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers.

Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

Frequency and subgroups of neuropsychiatric symptoms in mild cognitive impairment and different stages of dementia in Alzheimer's disease.

Neuropsychiatric symptoms (NPS), such as depression, apathy, agitation, and psychotic symptoms are common in mild cognitive impairment (MCI) and dementia in Alzheimer's disease (AD). Subgroups of NPS have been reported. Yet the relationship of NPS and their subgroups to different stages of cognitive impairment is unclear. Most previous studies are based on small sample sizes and show conflicting results. We sought to examine the frequency of NPS and their subgroups in MCI and different stages of dementia in AD. This was a cross-sectional study using data from a Norwegian national registry of memory clinics. From a total sample of 4,571 patients, we included those with MCI or AD (MCI 817, mild AD 883, moderate-severe AD 441). To compare variables across groups ANOVA or χ 2-test was applied. We used factor analysis of Neuropsychiatric Inventory Questionnaire (NPI-Q) items to identify subgroups of NPS. The frequency of any NPS was 87.2% (AD 91.2%, MCI 79.5%; p < 0.001) and increased with increasing severity of cognitive decline. The most frequent NPS in MCI was depression. Apathy was the most frequent NPS in AD across different stages of severity. The factor analysis identified three subgroups in MCI and mild AD, and a fourth one in moderate-severe AD. We labelled the subgroups "depression," "agitation," "psychosis," and "elation." The frequency of NPS is high in MCI and AD and increases with the severity of cognitive decline. The subgroups of NPS were relatively consistent from MCI to moderate-severe AD. The subgroup elation appeared only in moderate-severe AD.

Memantine for Alzheimer's Disease: An Updated Systematic Review and Meta-analysis.

The clinical benefit of memantine for Alzheimer's disease (AD) remains inconclusive. We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. Thirty studies (n = 7,567; memantine versus placebo: N = 11, n = 3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: N = 17, n = 4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD) = -0.24, 95% confidence intervals (95% CIs) = -0.34, -0.15, p < 0.00001, I2 = 35% ] and BD (SMD = -0.16, 95% CIs = -0.29, -0.04, p = 0.01, I2 = 52%) compared with placebo. In the sensitivity analysis including only patients with moderate-severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD = -0.20, 95% CIs = -0.34, -0.07, p = 0.003, I2 = 36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD = -0.20, 95% CIs = -0.36, -0.03, p = 0.02, I2 = 77%) and a trend of CF improvement (SMD = -0.11, 95% CIs = -0.22, 0.01, p = 0.06, I2 = 56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMD = -0.11, 95% CIs = -0.21, -0.01, p = 0.04, I2 = 40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD = -0.18, 95% CIs = -0.31, -0.05, p = 0.006, I2 = 49%). No differences were detected in all-cause discontinuation between the groups. The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs.

Efficacy and tolerance of Memantine monotherapy and combination therapy with Reinhartdt And Sea Cucumber Capsule on agitation in moderate to severe Alzheimer disease

Objective: To explore the efficacy and tolerance of Memantine combined Reinhartdt And Sea Cucumber Capsule (R.S.C) on treating agitation in patients with moderate-severe Alzheimer disease (AD). Methods: One hundred and fifty-eight moderate-sever AD patients from Sep.2013 to Sep.2014 in Zhejiang Provincial People's Hospital were randomly divided into two groups: group of Memantine combined R. S.C and group of single Memantine. Then Mini-Mental Sate Examination (MMSE) and Neuropsychiatric Inventory (NPI) were used to evaluate cognition symptom, behavioral and psychological symptoms of dementia (BPSD) and agitation symptom at the baseline and the end of 24 weeks.The Treatment Emergent Symptom Scale (TESS) was used to assess adverse reaction and tolerance.At last, the data was analyzed by chi-square test, t-test and covariance test. Result: At the terminal of experience, the total NPI scores and agitation factor decreased markedly in both of the two groups (P<0.05). Among the patients who had agitation symptom at the baseline, the total NPI scores and agitation factor (18±5, 3.7±2.6) in group of Memantine combined R. S.C were notably lower than those in the group of single Memantine (21±6, 5.3±2.5) (P<0.05). The incidence of adverse reaction between the two groups had no significant difference (combined treatment group was 27.7%, single treatment group was 23.2%). One patient dropped out because of skin allergy, and most adverse reactions were tolerant. Conclusions: Both two groups are effective in agitation and BPSD, and Memantine combined R. S.C is better than single treatment.R.S.C dose not aggravate adverse reaction and can be well tolerated.

BRYOSTATIN-1 IMPROVES COGNITION AND DAILY LIVING TASKS IN MODERATE TO SEVERE ALZHEIMER’S DISEASE: PRELIMINARY REPORT OF A PHASE 2 STUDY

In preclinical studies, the PKCε activator bryostatin-1 induces growth of mature synapses, prevents neuronal death, and influences amyloid plaques and tau tangles. We report the first safety and efficacy study of repeated doses of bryostatin in Alzheimer's disease (AD). Adults with moderate–severe AD (MMSE-2: 4–15 inclusive) received biweekly infusions of placebo or bryostatin-1 (20 or 40μg) for 12 weeks. Endpoints included the Severe Impairment Battery (SIB) and an Activities of Daily Living Inventory-Severe Impairment Version (ADCS-ADL-SIV) at baseline, weeks 5,9,13, and 30d after last infusion. Safety evaluations included routine blood tests and treatment emergent adverse events (TEAEs). A mixed-model for repeated measures was used to assess change from baseline to week 13 (Δ13) between each bryostatin group and placebo (1-tailed α=0.10 and power=80%) in predefined populations of the Full Analysis Set (≥1 post-baseline efficacy assessment) and Completer AnalysisSet (completed week 13 visit). Randomization was stratified by MMSE-2 4–9 vs. 10–15. Bryostatin-1 was provided by the National Cancer Institute. 147 adults were randomized in 28 centers with n=135 in the Full Analysis Set and n=113 in the Completer Analysis Set. Full Analysis Set mean(sd) age=71.6(7.9), MMSE-2=10.2(3.4), and 51.9% females with no imbalances among arms. 83.0% used acetylcholinesterase inhibitors, 67.4% memantine, and 58.5% both. The Δ13 (80%CI) in SIB was 1.9(-0.3,4.2) for 20μg and 0.8(-1.4,4.0) for 40μg in the Full Analysis Set, and this finding was strengthened when analyses were confined to the Completer Analysis Set (2.6 [0.4,4.9] for 20μg and 1.5[-0.7,3.8] for 40μg). Subjects who completed the 30d followup had sustained benefit. In the FAS, Δ13 for the ADCS-ADL-SIV was 1.4(0.0,2.8) for 20μg and 0.8 (-0.6,2.3) for 40μg group. TEAE rates were 58% in placebo, 65% in 20μg and 83% in the 40μg groups. TEAEs >placebo in both arms included diarrhea, while the 40μg arm also included fatigue, weight loss and myalgia. 20μg of bryostatin-1 every other week for 12 weeks appeared safe and benefited cognition and activities of daily living in moderate to severe AD. These results suggest acceptable safety and clinical benefits for the 20 μg group and support further development of bryostatin-1.

Angiotensin converting enzyme serum activities: Relationship with Alzheimer’s disease

ObjectiveTo determine serum activities of angiotensin-converting enzyme (ACE) as a marker in diagnosis and determine the severity of Alzheimer's disease (AD), MethodsWe measured serum ACE activities in 59 moderate-severe AD, 19 mild AD, 45 amnestic mild cognitive impairment (aMCI) and 39 controls. ResultsWe found that patients in moderate-severe AD stages showed significantly higher ACE in comparison to aMCI and controls (ANOVA, LSD post hoc test: p: 0.02 and p: 0.01, respectively). Logistic regression analysis showed that if ACE activities added 200 U/L, the superiority of AD risk was 1.18 times higher than before compared with the control group (OR 1.18, 95% CI 1.01–1.74; P=0.49). By means of multivariate linear regression analysis, we found that age (β coefficient: 7.77; P: 0.01) was significantly associated with ACE activities. However, ACE activities were found to be significantly negatively associated with measures of orientation and immediate recall among the AD patients (r<0, P<0.05), whereas ACE activities were not associated with any MMSE scores among the non-AD groups (P > 0.05).uuuu ConclusionsACE serum activity that correlates with age is likely to constitute a potential risk factor for the development of AD. ACE serum activity might be a useful biomarker for disease status with increasingly high ACE from mild stage to moderate-severe stage. Moreover, patients with aMCI could take ACE inhibitor (ACEI) to decrease the incidence of AD, and patients with AD could take ACEI to retard cognitive decline in early AD.

Double negative (IgG+IgD-CD27-) B cells are increased in a cohort of moderate-severe Alzheimer's disease patients and show a pro-inflammatory trafficking receptor phenotype.

Alzheimer's disease (AD) is a progressive, irreversible, and debilitating disease for which no effective preventive or disease modifying therapies or treatments have so far been detected. The crucial step in AD pathogenesis is the production of amyloid-β42 peptide, which causes chronic inflammation. Activated cells in the central nervous system (CNS) produce pro-inflammatory mediators that lead to the recruitment of myeloid or lymphocytic cells. As a consequence, the communication between the CNS and peripheral blood of AD subjects could influence the lymphocyte distribution and/or the expression of phenotypic markers. In the present paper, we show a significant decrease in total CD19+ B lymphocytes and a remodeling of the B cell subpopulations in moderate-severe AD patients, compared with their coeval healthy controls and mild AD subjects. In particular, we report a significant reduction in naïve B cells (IgD+CD27-) and a simultaneous increase in double negative (DN, IgD-CD27-) memory B lymphocytes. We have also evaluated the expression of the pro-inflammatory chemokine receptors CCR6 and CCR7 in total and naïve/memory B cells from mild and moderate-severe AD patients, with the aim to detect a possible relationship between the trafficking profile and the stage of the disease. Our results demonstrate that both the amount and the trafficking profile of B cells are related to the severity of AD. The results discussed in this paper suggest a well-selected antibody panel should be used as an additional test for the identification of early AD.

Association between white matter hyperintensity and medial temporal atrophy at various stages of Alzheimer's disease.

Whilst there is evidence implicating small vessel cerebrovascular disease in the pathogenesis of Alzheimer's disease (AD), its specific contribution to the pathophysiology of AD remains unclear. The burden of small vessel cerebrovascular disease visualized as white matter hyperintensity (WMH) and its association with medial temporal atrophy (MTA) at different stages of AD was studied. One hundred and sixty-five cognitively normal (CN) community controls, 103 mild cognitive impairment (MCI) patients, 141 mild AD patients and 68 moderate-severe AD patients were studied. Clinical, cognitive and risk factor data were collected, and WMH and MTA were quantified by trained raters. The Jonckheere-Terpstra test for ordered alternatives was used to study the association between WMH and MTA in different stages of AD. The burden of total WMH increased significantly with increasing severity of AD, even after correcting for confounders. The proportion of CN, MCI, mild AD and moderate-severe AD subjects with severe burden of WMH was 6.7%, 9.7%, 28.4%, and 39.7%, respectively. A strong positive association between WMH severity and MTA was evident amongst MCI (P = 0.011) and mild AD (P = 0.003) subjects, but not in CN (P = 0.953) and moderate-severe AD subjects (P = 0.301). The burden of WMH increased significantly from the stage of CN to MCI to AD. The association between WMH and MTA was greatest at the stage of MCI and mild AD. This has implications on the strategy to slow the progression of AD, where measures to reduce WMH, including control of vascular risk factors, need to be optimized at the stage of MCI and mild AD.

CSF lactate levels, τ proteins, cognitive decline: a dynamic relationship in Alzheimer's disease

ObjectivesTo investigate, in patients with Alzheimer's Disease (AD), the possible interplay linking alteration of neuronal energy metabolism, as measured via cerebrospinal fluid (CSF) lactate concentration, to severity of AD neurodegenerative...

Double negative (CD19+IgG+IgD−CD27−) B lymphocytes: A new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer's disease patients

Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD−CD27− (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (α-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate–severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.

Alzheimer disease: sleep, orexin and cognitive decline

Introduction In Alzheimer’s disease (AD) several networks including regions regulating the sleep-wake rhythm are altered. Orexin-A is an hypothalamic neuropeptide contributing to the regulation of the sleep-wake cycle. The aim of our study was to investigate the possible involvement of the orexinergic system in the AD neurodegenerative processes and its relationship with sleep impairment. Materials and methods We included 48 consecutive untreated AD patients and 29 healthy controls. Based on MMSE, AD patients were divided in 2 groups: mild AD (MMSE ⩾ 21; 21 subjects) and moderate-severe AD (MMSE 21; 27 subjects). We quantified orexin CSF levels in AD patients and controls, and examined potential links to the established AD markers CSF levels, as tau, phospho-tau (ptau), and beta-amyloid1–42 (A β 1–42). Moreover, AD patients underwent a full nocturnal polysomnography (PSG). Finally, CSF results were correlated with sleep structure parameters and MMSE. Results Regarding CSF data, control subjects showed orexin CSF levels not significantly different with AD patients as well as with mild AD subjects. However, moderate-severe AD patients showed increased orexin CSF levels in respect to both mild AD patients and controls. Regarding PSG parameters, moderate–severe AD patients, compared to mild AD subjects, showed a significant reduction in sleep efficiency (SE) and a significant increase in wakefulness after sleep onset (WASO) and in REM latency. Moreover, in AD patients the orexin CSF levels were negatively correlated with REM sleep, slow wave sleep (SWS) and SE, whereas were positively correlated with WASO and sleep latency. Furthermore, it appeared to exist a positive correlation between the increase of orexin and tau CSF levels in AD patients. A β 1–42 CSF levels were negatively correlated with WASO whereas were positively correlated with REM sleep. Tau CSF levels were negatively correlated with SWS. The decrease of MMSE correlated with the impairment of SE and REM sleep and the increase of WASO. Conclusion Our study shows that in AD cognitive decline is linked to a parallel sleep deterioration, which appears to be related to an increase of the CSF orexin levels. In conclusion, our results demonstrate that the orexinergic system is not impaired in AD, but its output and function appears to be overexpressed along the progression of neurodegenerative processes, possibly due to an unbalance of the neurotransmitters networks regulating the wake-sleep cycle towards the systems promoting wakefulness. Acknowledgements We are grateful to Ms. Alessandra Nitti for technical support, Dr. Francesca Izzi for acquisition of data, Prof. Nicola Biagio Mercuri for study supervision and Prof. Giuseppe Sancesario and Dr. Alessandro Martorana for acquisition of data and study supervision.

Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer’s Disease: A Review of Clinical Trials

Background. Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.