Severe Alzheimer's Disease Patients Research Articles

TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer's disease patients.

TDP-43 proteinopathy in Alzheimer's disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism. We have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments. TDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs. TTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease.

Alpha Rhythm Wavelength of Electroencephalography Signals as a Diagnostic Biomarker for Alzheimer's Disease.

To explore changes in the alpha rhythm wavelength of background electroencephalography in Alzheimer's disease patients with different degrees of dementia in a resting state; examine their correlation with the degree of cognitive impairment; determine whether the alpha rhythm wavelength can distinguish mild Alzheimer's disease patients, moderately severe Alzheimer's disease patients, and healthy controls at the individual level; and identify a cut-off value to differentiate Alzheimer's disease patients from healthy controls. Quantitative electroencephalography signals of 42 patients with mild Alzheimer's disease, 42 patients with moderately severe Alzheimer's disease, and 40 healthy controls during rest state with eyes closed were analyzed using wavelet transform. Electroencephalography signals were decomposed into different scales, and their segments were superimposed according to the same length (wavelength and amplitude) and phase alignment. Phase averaging was performed to obtain average phase waveforms of the desired scales of each lead. The alpha-band wavelengths corresponding to the ninth scale of the background rhythm of different leads were compared between groups. The average wavelength of the alpha rhythm phase of the whole-brain electroencephalography signals in Alzheimer's disease patients was prolonged and positively correlated with the severity of cognitive dysfunction (P < 0.01). The ninth-scale phase average wavelength of each lead had high diagnostic efficacy for Alzheimer's disease, and the diagnostic efficacy of lead P3 (area under the receiver operating characteristic curve = 0.873) was the highest. The average wavelength of the electroencephalography alpha rhythm phase may be used as a quantitative feature for the diagnosis of Alzheimer's disease, and the slowing of the alpha rhythm may be an important neuro-electrophysiological index for disease evaluation.

The Effectiveness and Safety of Chemical Drugs Combined with Acupuncture for Alzheimer's Disease: A Systematic Review and Meta-Analysis

Introduction: Acupuncture has been applied with chemical drugs to treat Alzheimer's disease (AD) in the clinic. Whether such combination is effective and safe should be studied although it is recommended by some researchers.&lt;br/&gt; Methods: To explore the effectiveness and safety of acupuncture combined with chemical drugs for AD, databases like PubMed, Web of Science were searched to retrieve randomized controlled trials (RCTs) on AD treated with acupuncture and chemical drugs to perform meta-analysis. The risk of bias in each study was assessed using the Cochrane risk of bias tool. Meta- analysis was performed using RevMan 5.3.&lt;br/&gt; Results: Five studies were included in which only donepezil combined with acupuncture was evaluated. Acupuncture combined with donepezil showed a significant difference in effectiveness rate [RR=1.45, 95% CI (1.19, 1.77), P =0.0002] compared with donepezil. On the comparison of mini-mental state examination (MMSE) score and Alzheimer's disease assessment scale cognitive subscale (ADAS-Cog) score there was no difference. However, after one trial with severe AD patients was removed, acupuncture combined with donepezil showed better effect than donepezil alone.&lt;br/&gt; Conclusion: Acupuncture combined with donepezil could work on AD at the early stage or being mild, implying that acupuncture could be a complementary therapy for AD at the early stage or being mild. Besides, scalp acupuncture seems to be more effective on improving cognitive function. However, this conclusion must be considered cautiously, given the small sample size and lack of trials with high quality. Therefore, more high-quality, multicenter, prospective RCTs with large sample sizes are needed to further clarify the effect of acupuncture combined with chemical drugs for AD.

Inter-band Bispectral Analysis of EEG Background Activity to Characterize Alzheimer's Disease Continuum.

The aim of this study was to characterize the EEG alterations in inter-band interactions along the Alzheimer's disease (AD) continuum. For this purpose, EEG background activity from 51 healthy control subjects, 51 mild cognitive impairment patients, 50 mild AD patients, 50 moderate AD patients, and 50 severe AD patients was analyzed by means of bispectrum. Three inter-band features were extracted from bispectrum matrices: bispectral relative power (BispRP), cubic bispectral entropy (BispEn), and bispectral median frequency (BispMF). BispRP results showed an increase of delta and theta interactions with other frequency bands and the opposite behavior for alpha, beta-1, and beta-2. Delta and theta interactions, along with the rest of the spectrum, also experimented a decrease of BispEn with disease progression, suggesting these bands interact with a reduced variety of components in advanced stages of dementia. Finally, BispMF showed a consistent reduction along the AD continuum in all bands, which is reflective of an interaction of the global spectrum with lower frequency bands as the disease develops. Our results indicate a progressive decrease in inter-band interactions with the severity of the disease, especially those involving high frequency components. Since inter-band coupling oscillations are related to complex and multi-scaled brain processes, these alterations likely reflect the neurodegeneration associated with the AD continuum.

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

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

Extracellular Vesicles of Alzheimer's Disease Patients as a Biomarker for Disease Progression.

Alzheimer's disease (AD) is a progressive neurodegenerative brain pathology and the most common form of dementia. Evidence suggests that extracellular vesicles (EVs) containing cytokines and microRNA are involved in inflammation regulation. The current study aimed to explore a potential impact of AD patients' EVs on disease progression. Blood samples were collected after obtaining signed informed consent (No. 0462-14-RMB) from 42 AD patients at three stages of disease severity and from 19 healthy controls (HC). EV size and concentration were studied by nanotracking analysis. EV membrane antigens were defined by flow cytometry and Western blot; EV protein contents were screened by protein array; the miRNA content was screened by nanostring technology and validated by RT-PCR. HC and AD patients' EVs consisted of a mixture of small (< 100nm) and larger vesicles. The myelin oligodendrocyte glycoprotein (MOG) expression on EVs correlated with disease severity. EVs of patients with moderate and severe AD had significantly higher levels of MOG, compared with mild AD patients. Levels of EVs expressing the axonal glycoprotein CD171 were significantly higher in severe AD patients than in HC. Increase in endothelial EVs was observed in AD patients. An above twofold increase was found in the content of inflammatory cytokines and > 50% decrease in growth factors in AD patients' EVs compared with HC-EVs. Levels of let-7g-5p, miR126-3p, miR142-3p, miR-146a-5p, and mir223-3p correlated with disease severity. Neural damage, specific miRNA downregulation, and inflammatory cytokine upregulation, found in patients' EVs, might be used as a biomarker reflecting AD severity.

The application of weighted gene co-expression network analysis in identifying key modules and hub genes associated with disease status in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative condition that affects more than 15 million individuals globally. However, a predictive molecular biomarker to distinguish the different stages of AD patients is still lacking. A weighted gene co-expression network analysis (WGCNA) was employed to systematically identify the co-expressed gene modules and hub genes connected with AD development based on a microarray dataset (GSE1297) from the Gene Expression Omnibus (GEO) database. An independent validation cohort, GSE28146, was utilized to assess the diagnostic efficiency for distinguishing the different stages of AD. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting analysis were applied to examine the mRNA and protein level of GRIK1, respectively, in AD mice established with the expression of mutant amyloid precursor protein and wild type mice. The morphology of neurons was investigated using phalloidin staining. We identified 16 co-expressed genes modules, with the pink module showing significant association with all three disease statuses [neurofibrillary tangle (NFT), BRAAK, and mini-mental state examination (MMSE)]. Enrichment analysis specified that these modules were enriched in phosphatidylinositol 3-kinase (PI3K) signaling and ion transmembrane transport. The validation cohort GSE28146 confirmed that six hub genes in the pink module could distinguish severe and non-severe AD patients [area under the curve (AUC) >0.7]. These hub genes might act as a biomarker and help to differentiate diverse pathological stages for AD patients. Finally, one of the hubs, GRIK1, was validated by an animal AD model. The mRNA and protein level of GRIK1 in the AD hippocampus was increased compared with the control group (NC) hippocampus. Phalloidin staining showed that dendritic length of the GRIK1 pCDNA3.1 group was shorter than that of the NC group. In summary, we systematically recognized co-expressed gene modules and genes related to AD stages, which gave insight into the fundamental mechanisms of AD progression and revealed some probable targets for the treatment of AD.

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.

Impairment of Several Immune Functions and Redox State in Blood Cells of Alzheimer's Disease Patients. Relevant Role of Neutrophils in Oxidative Stress.

Since aging is considered the most risk factor for sporadic Alzheimer’s Disease (AD), the age-related impairment of the immune system (immunosenescence), based on a chronic oxidative-inflammatory stress situation, could play a key role in the development and progression of AD. Although AD is accompanied by systemic disturbance, reflecting the damage in the brain, the changes in immune response and redox-state in different types of blood cells in AD patients have been scarcely studied. The aim was to analyze the variations in several immune functions and oxidative-inflammatory stress and damage parameters in both isolated peripheral neutrophils and mononuclear blood cells, as well as in whole blood cells, from patients diagnosed with mild (mAD) and severe AD, and of age-matched controls (elderly healthy subjects) as well as of adult controls. The cognitive decline of all subjects was determined by Mini-Mental State Examination (MMSE) test (mAD stage was established at 20 ≤ MMSE ≤ 23 score; AD stage at <18 MMSE; elderly subjects >27 MMSE). The results showed an impairment of the immune functions of human peripheral blood neutrophils and mononuclear cells of mAD and AD patients in relation to healthy elderly subjects, who showed the typical immunosenescence in comparison with the adult individuals. However, several alterations were only observed in severe AD patients (lower chemotaxis, lipopolysaccharide lymphoproliferation, and interleukin (IL)-10 release; higher basal proliferation, tumor necrosis factor (TNF)-α release, and IL-10/TNF-α ratio), others only in mAD subjects (higher adherence), meanwhile others appeared in both mAD and AD patients (lower phytohemaglutinin lymphoproliferation and higher IL-6 release). This impairment of immune functions could be mediated by: (1) the higher oxidative stress and damage also observed in blood cells from mAD and AD patients and in isolated neutrophils [lower glutathione (GSH) levels, high oxidized glutathione (GSSG)/GSH ratio, and GSSG and malondialdehyde contents], and (2) the higher release of basal pro-inflammatory cytokines (IL-6 and TNF-α) found in AD patients. Because the immune system parameters studied are markers of health and rate of aging, our results supported an accelerated immunosenescence in AD patients. We suggest the assessment of oxidative stress and function parameters in peripheral blood cells as well as in isolated neutrophils and mononuclear cells, respectively, as possible markers of AD progression.

Partial improvement in performance of patients with severe Alzheimer's disease at an early stage of fornix deep brain stimulation.

Deep brain stimulation is a therapy for Alzheimer's disease (AD) that has previously been used for mainly mild to moderate cases. This study provides the first evidence of early alterations in performance induced by stimulation targeted at the fornix in severe AD patients. The performance of the five cases enrolled in this study was scored with specialized assessments including the Mini-Mental State Examination and Clinical Dementia Rating, both before and at an early stage after deep brain stimulation. The burden of caregivers was also evaluated using the Zarit Caregiver Burden Interview. As a whole, the cognitive performance of patients remained stable or improved to varying degrees, and caregiver burden was decreased. Individually, an improved mental state or social performance was observed in three patients, and one of these three patients showed remarkable improvement in long-term memory. The conditions of another patient deteriorated because of inappropriate antipsychotic medications that were administered by his caregivers. Taken together, deep brain stimulation was capable of improving some cognitive aspects in patients with severe AD, and of ameliorating their emotional and social performance, at least at an early stage. However, long-term effects induced by deep brain stimulation in patients with severe AD need to be further validated. More research should focus on clarifying the mechanism of deep brain stimulation. This study was registered with ClinicalTrials.gov (NCT03115814) on April 14, 2017.

The value of whole-brain CT perfusion imaging and CT angiography using a 320-slice CT scanner in the diagnosis of MCI and AD patients.

To validate the value of whole-brain computed tomography perfusion (CTP) and CT angiography (CTA) in the diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Whole-brain CTP and four-dimensional CT angiography (4D-CTA) images were acquired in 30 MCI, 35 mild AD patients, 35 moderate AD patients, 30 severe AD patients and 50 normal controls (NC). Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and correlation between CTP and 4D-CTA were analysed. Elevated CBF in the left frontal and temporal cortex was found in MCI compared with the NC group. However, TTP was increased in the left hippocampus in mild AD patients compared with NC. In moderate and severe AD patients, hypoperfusion was found in multiple brain areas compared with NC. Finally, we found that the extent of arterial stenosis was negatively correlated with CBF in partial cerebral cortex and hippocampus, and positively correlated with TTP in these areas of AD and MCI patients. Our findings suggest that whole-brain CTP and 4D-CTA could serve as a diagnostic modality in distinguishing MCI and AD, and predicting conversion from MCI based on TTP of left hippocampus. • Whole-brain perfusion using the full 160-mm width of 320 detector rows • Provide clinical experience of 320-row CT in cerebrovascular disorders of Alzheimer's disease • Initial combined 4D CTA-CTP data analysed perfusion and correlated with CT angiography • Whole-brain CTP and 4D-CTA have high value for monitoring MCI to AD progression • TTP in the left hippocampus may predict the transition from MCI to AD.

Clinical management and associated costs for moderate and severe Alzheimer's disease in urban China: a Delphi panel study.

BackgroundHealthcare resource utilisation for Alzheimer’s disease (AD) in China is not well understood. This Delphi panel study aimed to describe the clinical management pathways for moderate and severe AD patients in urban China and to define the amount and cost of healthcare resources used.MethodsA panel of 11 experts was recruited from urban China to participate in two rounds of preparatory interviews. In the first round, 9 physicians specialised in dementia gave a qualitative description of the clinical management of AD patients. In the second round, 2 hospital administrators were asked about the cost of AD management and care. Results from the interviews were discussed by the experts in a Delphi panel meeting, where consensus was reached on quantitative aspects of AD management, including the rate of healthcare resource utilisation, the respective unit costs and caregiving time.ResultsInterviewees reported that mild AD is under-recognised in China; most patients are diagnosed with moderate to severe AD. Loss of independence and agitation/aggression are the main drivers for healthcare resource utilisation and contribute to a heavier caregiver burden. It was estimated that 70 % moderate AD patients are independent/non-aggressive at the time of diagnosis, 15 % are independent/aggressive, 10 % are dependent/non-aggressive, and 5 % are dependent/aggressive. Dependent/aggressive AD patients are more likely to be hospitalised (70–90 %) than accepted in a nursing home (0–20 %), while the opposite is true for dependent/non-aggressive patients (5–35 % for hospitalisation vs. 80 % for nursing home). Independent AD patients require 1–3 hours/day of caregiver time, while dependent patients can require up to 12–15 hours/day. Experts agreed that AD complicates the management of age-related comorbidities, found in 70–80 % of all AD patients, increasing the frequency and cost of hospitalisation.ConclusionsThe Delphi panel approach was an efficient method of gathering data about the amount of healthcare resources used and associated costs for moderate and severe AD patients in urban China. The results of this study provide a useful source of information for decision makers to improve future healthcare policies and resource planning, as well as to perform economic evaluations of AD therapies.

Memantine Treatment in Patients with Alzheimer's Disease already Receiving Donepezil

Alzheimer's Disease (AD) is a neurological disorder in which the death of brain cells causes memory loss and cognitive decline. There are three stages of AD: - preclinical; mild cognitive impairment and dementia. Many surveys showed that people of age 65years or more are usually diagnosed with AD. The main treatment of AD includes Donezepil, Alantimine, Rivastigmine and Tacrine which belong to cholinesterase inhibitors. Memantine is an N-methyl-D-aspartate-receptor inhibitor which works by blocking excess activity of glutamate in brain and helps reduce the symptoms of AD. Memantine is a first and only member of a new class of medication showing clinical benefit and good tolerability in AD. Memantine has also exhibited efficacy and safety in a placebo-controlled trial. This review is about the many theories proposed for the administration of memantine to AD patients receiving stable donezepil therapy would result in clinical benefit and are safe and well tolerated which has been researched. Many clinical trials are still ongoing. This review is based on study on two groups of AD patients where one group is given placebo withdonezepil and other group is given 20mg memantine with donezepil; then both the groups are compared. Many clinical trial results are based on the comparative study of both the group of patients where the patients (40%) receiving memantine added to donezepil significantly outperformed those patients (52%) receiving placebo with donezepil. Therefore many clinical trials had produced positive results when the drugs memantine and donezepil were concomitantly administered. Based on the studies the patients receiving antiglutamatergic treatment showed an improvement in the cognition scores for moderate to severe AD patients.

Discontinuation of antidementia medications in extremely severe Alzheimer's disease patients: A 12-week, randomized, multicenter trial

Discontinuation of antidementia medications in extremely severe Alzheimer's disease patients: A 12-week, randomized, multicenter trial

Complexity extraction of electroencephalograms in Alzheimer's disease with weighted-permutation entropy.

In this paper, weighted-permutation entropy (WPE) is applied to investigating the complexity abnormalities of Alzheimer's disease (AD) by analyzing 16-channel electroencephalograph (EEG) signals from 14 severe AD patients and 14 age-matched normal subjects. The WPE values are estimated in the delta, the theta, the alpha, and the beta sub-bands for each channel with an overlapped sliding window. WPE is modified from the permutation entropy (PE), which has been recently suggested as a measurement to extract the complexity of the EEG signals. The advantage of WPE over PE is verified by both the model simulated and the experimental EEG signals. Although the results show that both the average PE and WPE of AD patients are decreased in contrast with the normal group in these four sub-bands, especially in the theta band, WPE can exhibit a better performance in distinguishing the AD patients from the normal controls by the more significant differences in the four sub-bands, which may be attributed to the brain dysfunction. Thus, it suggests that WPE may become a probable useful tool to detect brain dysfunction in AD and it seems to be promising to disclose the abnormalities of brain activity for other neural disease.

Is there correlation between cognition and functionality in severe dementia? the value of a performance-based ecological assessment for Alzheimer's disease.

Besides significant cognitive decline, patients in later stages of Alzheimer's disease (AD) also present global functional impairment, usually reported by their caregivers. This study searched for preserved activities of daily living by investigating correlations among specific instruments for severe dementia with a performance-based functional scale. A sample of 95 moderate to severe AD patients and their caregivers underwent a neuropsychological battery consisting of screening tools, the Functional Assessment Staging Test (FAST), the Severe Mini-Mental State Examination (MMSEsev) and a performance-based ecological scale, the Performance Test of Activities of Daily Living (PADL). Consistent findings emerged from the comparisons among tests. PADL showed significant statistical correlation with MMSEsev (ρ<0.001), according to FAST subdivisions. Upon suspicion of unreliable caregiver reports, ecological scales may be useful for disease staging. Variable degrees of functionality and cognition may be present even in later stages of AD, requiring proper assessment.

Increased Susceptibility to Oxidative Death of Lymphocytes from Alzheimer Patients Correlates with Dementia Severity

We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer's disease (AD) patients when exposed to hydrogen peroxide (H2O2)-induced oxidative stress and an increased resistance to death in those of patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling cell death is deregulated in opposite directions in Alzheimer's disease (AD) and cancer, to explain the inverse association observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates with the degree of dementia severity. Peripheral lymphocytes from 23 AD patients, classified using the Clinical Dementia Rating (CDR) into severe dementia (CDR 3, n=10) and mild-to-moderate dementia (CDR 1- 2, n=13), and 15 healthy controls (HC) (CDR 0), were exposed to H2O2 for 20 hours. Lymphocyte death was determined by flow cytometry and propidium iodide staining. The greatest susceptibility to H2O2-induced death was observed for lymphocytes from severe dementia patients, whereas those with mild-to-moderate dementia exhibited intermediate values, compared to healthy controls. A significant increase in the apoptosis/necrosis ratio was found in AD patients. Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibition significantly protected from H2O2-induced death of lymphocytes, whereby a lower degree of protection was observed in severe AD patients. Moreover, inhibition of PARP-1 abolished the differences in apoptosis/necrosis ratios observed between the three groups of patients. These results support the notion that AD is a systemic disorder, whereby enhanced susceptibility to H2O2-induced death in peripheral lymphocytes correlates with dementia severity and enhanced death in AD patients is attributable to a PARP-dependent increase in the apoptosis/necrosis ratio.

Three-Dimensional Quantitative Imaging of Telomeres in Buccal Cells Identifies Mild, Moderate, and Severe Alzheimer's Disease Patients

Using three-dimensional (3D) telomeric analysis of buccal cells of 82 Alzheimer's disease (AD) patients and cognitively normal age and gender-matched controls, we have for the first time examined changes in the 3D nuclear telomeric architecture of buccal cells among levels of AD severity based on five 3D parameters: i) telomere length, ii) telomere number, iii) telomere aggregation, iv) nuclear volume, and v) a/c ratio, a measure of spatial telomere distribution. Our data indicate that matched controls have significantly different 3D telomere profiles compared to mild, moderate, and severe AD patients (p < 0.0001). Distinct profiles were also evident for each AD severity group. An increase in telomere number and aggregation concomitant with a decrease in telomere length from normal to severe AD defines the individual stages of the disease (p < 0.0001).

Evaluation of an 8-item Severe Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study

The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB - the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity. A post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini-Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated. Assessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24. In this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD.

The cell survival kinase SGK1 and its targets FOXO3a and NDRG1 in aged human brain

Serum- and glucocorticoid-inducible kinase 1 (SGK1) protects neuronal cells from injury stimuli in vitro, and exerts anti-apoptotic effects via downstream targets including the forkhead-like transcription factor FOXO3a. SGK1 is a homolog of Akt, a related survival kinase that is up-regulated in Alzheimer's disease (AD). Here we aimed to examine the expression pattern of SGK1 and FOXO3a in aged human cerebral cortex. Cortical tissue from aged donors without brain disease (aged controls, AC, n = 19) and from severe AD patients (Braak stage V-VI; n = 14) were examined by immunohistochemistry and immunoblot analysis. SGK1 was present in all samples (detected by immunohistochemistry and immunoblotting). Large cortical neuronal cells were strongly positive for SGK1, with predominantly nuclear labelling. Some astrocytes and oligodendrocytes were also labelled. SGK1 was not seen in nerve tracts (axons or myelin) and rarely seen in CD68-positive cells (microglia, perivascular macrophages) or vascular cells (myocytes or endothelia). The fraction of large cortical neurones with nuclear FOXO3a was lower in AD cases relative to AC (54%, 70%, respectively, P < 0.001). In immunoblots no difference in SGK1 abundance was detected between AC and AD tissues. Phosphorylation of NDRG1 (an SGK1-specific target) was greater in AD, relative to AC cases (approximately twofold, P = 0.023). Neuronal expression of SGK1 in aged human brain and its nuclear compartmentalization suggest a possible neuroprotective role. FOXO3a and NDRG1 data suggest augmented SGK1 activity (as reported for Akt) in severe AD. Increased intracellular SGK1 may complement enhanced Akt, with a distinct subcellular localization.