Alzheimer's Severity Research Articles

Frequency power and coherence of electroencephalography are correlated with the severity of Alzheimer's disease: A multicenter analysis in Taiwan

Slowing of average electroencephalography (EEG) frequency in Alzheimer's disease (AD) is well established, but whether EEG changes are able to reflect the severity of AD is uncertain. We attempt to establish quantitative EEG parameters that are suitable for evaluating AD in clinical practice. Ninety-five patients with newly diagnosed AD at different stages from four neurologic institutes were enrolled for the study. Standard scalp resting EEG data were collected for quantitative analysis. Global band power ratio and interhemispheric alpha band coherence were calculated. Patients with advanced AD had a greater slow-to-fast wave power ratio. Among several power ratio parameters, global theta and delta to alpha and beta band power ratio showed the best correlation with stages of AD (p < 0.05 between any two patient groups). Patients with advanced AD had decreased coherence in multiple brain regions. The phenomenon was most prominent in the centroparietal region (p < 0.05 between any two patient groups). Increased global slow-to-fast power ratio and decreased centroparietal interhemispheric alpha band coherence are strongly correlated with disease progress in AD patients. These two quantitative EEG parameters may help evaluate AD patients in daily clinical practice. Global power ratio changes may suggest a shift of dominant frequency, and decreased interhemispheric alpha band coherence may suggest functional disconnection and corpus callosum abnormalities in AD patients.

In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease

Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.

Inflammatory Proteins in Plasma Are Associated with Severity of Alzheimer’s Disease

Markers of Alzheimer’s disease (AD) are being widely sought with a number of studies suggesting blood measures of inflammatory proteins as putative biomarkers. Here we report findings from a panel of 27 cytokines and related proteins in over 350 subjects with AD, subjects with Mild Cognitive Impairment (MCI) and elderly normal controls where we also have measures of longitudinal change in cognition and baseline neuroimaging measures of atrophy. In this study, we identify five inflammatory proteins associated with evidence of atrophy on MR imaging data particularly in whole brain, ventricular and entorhinal cortex measures. In addition, we observed six analytes that showed significant change (over a period of one year) in people with fast cognitive decline compared to those with intermediate and slow decline. One of these (IL-10) was also associated with brain atrophy in AD. In conclusion, IL-10 was associated with both clinical and imaging evidence of severity of disease and might therefore have potential to act as biomarker of disease progression.

Efficacy of increasing donepezil in mild to moderate Alzheimer's disease patients who show a diminished response to 5 mg donepezil: a preliminary study

With the recent approval of several new drugs, pharmacological management of Alzheimer's disease has become more complicated in Japan. The efficacy and safety of increasing the dose of donepezil to 10 mg daily were assessed in an open-label study of patients with mild to moderate Alzheimer's disease who were showing a diminished response to 5 mg daily. The subjects included 27 patients with mild to moderate probable Alzheimer's disease whose primary caregivers had confirmed progression of symptoms during treatment with donepezil 5 mg daily. The dose of donepezil was increased to 10 mg daily, and the Alzheimer's disease assessment scale-cognitive subscale (Japanese version), Neuropsychiatric Inventory, and Zarit caregiver burden interview scores were compared before and after dose escalation. Adverse events were also investigated. Efficacy was evaluated in 24 patients; three dropped out because of adverse reactions. The Alzheimer's disease assessment scale score showed significant improvement after dose escalation of donepezil (P = 0.006). The total score of the Neuropsychiatric Inventory and the Zarit score showed no significant changes. However, the anxiety score of the Neuropsychiatric Inventory showed a significant increase (P = 0.028). Safety assessment revealed that the dropout rate was 11.1% and adverse reactions occurred in 40.7%. Nausea (29.6%) and loss of appetite (22.2%) were common adverse reactions. Because cognitive function showed improvement after increasing the dose of donepezil, the dosage of this drug should probably be adjusted based on the overall severity of Alzheimer's disease as well as the progression of cognitive dysfunction.

Antedependence models for nonstationary categorical longitudinal data with ignorable missingness: likelihood‐based inference

Time index-ordered random variables are said to be antedependent (AD) of order (p1 ,p2 , … ,pn ) if the kth variable, conditioned on the pk immediately preceding variables, is independent of all further preceding variables. Inferential methods associated with AD models are well developed for continuous (primarily normal) longitudinal data, but not for categorical longitudinal data. In this article, we develop likelihood-based inferential procedures for unstructured AD models for categorical longitudinal data. Specifically, we derive maximum likelihood estimators (MLEs) of model parameters; penalized likelihood criteria and likelihood ratio tests for determining the order of antedependence; and likelihood ratio tests for homogeneity across groups, time invariance of transition probabilities, and strict stationarity. We give closed-form expressions for MLEs and test statistics, which allow for the possibility of empty cells and monotone missing data, for all cases save strict stationarity. For data with an arbitrary missingness pattern, we derive an efficient restricted expectation-maximization algorithm for obtaining MLEs. We evaluate the performance of the tests by simulation. We apply the methods to longitudinal studies of toenail infection severity (measured on a binary scale) and Alzheimer's disease severity (measured on an ordinal scale). The analysis of the toenail infection severity data reveals interesting nonstationary behavior of the transition probabilities and indicates that an unstructured first-order AD model is superior to stationary and other structured first-order AD models that have previously been fit to these data. The analysis of the Alzheimer's severity data indicates that the antedependence is second order with time-invariant transition probabilities, suggesting the use of a second-order autoregressive cumulative logit model.

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.

TheMTHFR677T Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer’s Disease in an Egyptian Population

Objective. We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimer's disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Methods. Forty-three Alzheimer's cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. Results. No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls (P = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; P = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. Conclusions. The MTHFR 677C>T polymorphism—especially the presence of one copy of the T allele—appears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker.

Correction: Analyzing Gene Expression from Whole Tissue vs. Different Cell Types Reveals the Central Role of Neurons in Predicting Severity of Alzheimer’s Disease

Correction: Analyzing Gene Expression from Whole Tissue vs. Different Cell Types Reveals the Central Role of Neurons in Predicting Severity of Alzheimer’s Disease

Development of an instrument to measure attitudes of physical therapy providers working with people with dementia.

This study investigated the factor structure of an instrument to measure attitudes and beliefs of how physical therapist (PT) practitioners perceive working with people with a dementia disorder. A survey was mailed to every skilled nursing facility in Indiana (n = 495) for completion by a PT or physical therapist assistant. The survey was developed and included whether the severity of Alzheimer's disease (AD) impacts the attitudes of physical therapy practitioners. Of the 12 attitudinal questions, 11 were significant (P < .001) concerning how the severity of a diagnosis of AD (early, middle, and late) impacts attitudes of people in physical therapy practice. Principal component analysis identified 3 factors with Eigen values of 3.3 or higher accounting for 43% of the cumulative variance. These factors include professional competence, resources, and conscientiousness. This brief instrument could serve as an assessment tool to determine whether PT practitioners exhibit therapeutic nihilism when working with people with a dementia disorder.

P4‐363: The medical food Souvenaid preserves functional brain network organisation in patients with mild Alzheimer's disease

clinical evaluation was complex; but for our purpose we have used MMSE, grouping the patients into stages: mild (MMSE score 21-26), mild to moderate (MMSE score 15-20), moderate (MMSE score 10-14) and severe (MMSE score Below 10).For evaluating their socioeconomic and clinical status the Centre’s standard questionnaire was used; care costs were included (for medications, use of professional services, use of community support services by caregivers and lay carers.Caregiver burden was also determined by specific scales, using the human capital method. Descriptive statistics and regression models were used.Assessment of costs was made considering existing costs at 1st of January, 2010 as applicable to a discounting rate of 6%. Results: A total of 64 claims were reviewed. The average total cost of AD per patient per a 12-month period was ,V6072. The proportion of cost attributable to caregivers was the main component of burden 61% in AD.The annual societal cost of care per patient increased with severity of Alzheimer’s disease. The cost per patient was estimated to be 5.378V 8V for mild disease, 6.259V for mild to moderate disease, 6.343V for moderate disease and 6.407V for severe disease. Poorer functional status was associated with higher total and care giving costs. For subjects living in the community, unpaid caregiver time was the greatest components of cost and increased with disease severity. Conclusions: Health care costs for AD are substantial. The societal cost of care of Alzheimer’s disease increases with increasing disease severity. Informal cost is responsible for the largest cost component

Serum brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 levels in dementia

The aim of this study is to measure serum levels of neurotropic factor (NF) in patients with dementia. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) were determined in Alzheimer's dementia patients without medication (AD; n: 22), Alzheimer's dementia patients receiving cholinesterase inhibitor (CEI) treatment (AD+CEI; n: 32) and vascular dementia patients receiving CEI treatment (VaD+CEI; n: 27) and the age-matched control group (n: 20). NGF levels were detected to be significantly higher in the control group than in AD group (P<0.001). BDNF and NT-3 levels in AD group were not significantly different from control group's levels. NGF levels in AD+CEI group were significantly higher than in AD group (P<0.05). There was also no significant difference in serum neurotrophic factor levels between AD+CEI and VaD+CEI group. A positive correlation between BDNF and Mini Mental State Examination (MMSE) scores (r: 0.422, P<0.01) in AD group and a negative correlation between BDNF and MMSE scores in the AD+CEI group (r: -0.357, P<0.005) were obtained. In conclusion, our results suggest that while serum NGF levels are associated with the presence of dementia, serum BDNF levels may be associated with the severity of Alzheimer's dementia. However, future studies are required to determine the importance of NFs.

A biomarker for severity of Alzheimer’s disease: 1H-NMR resonances in cerebrospinal fluid correlate with performance in mini-mental-state-exam

Context: There is no valid biomarker for severity of Alzheimer’s disease (AD) available until now.Objective: Therefore, we investigated 1H-NMR spectroscopy for specific resonances as biomarkers for severity of AD.Materials and methods: Cerebrospinal fluid (CSF) of patients with diagnosed AD and healthy control subjects was analysed by one-dimensional water-suppressed 1H-NMR spectroscopy. The resonances were correlated with the cognitive performance of the patients and controls.Results: Specific 1H-NMR resonances showed higher intensities in AD patients than in control subjects. Mini-mental-state-exam scores correlated with 1H-NMR resonances in AD patients.Discussion and conclusion: 1H-NMR resonances of CSF are obviously valid biomarker for severity of AD, despite the lack of knowledge of the underlying molecular structure. Successful isolation and identification of these substances will most likely provide details to the pathophysiology of AD.

Association of HDL cholesterol level with the severity of Alzheimer's disease and improvement following exercise

Association of HDL cholesterol level with the severity of Alzheimer's disease and improvement following exercise

The relationship between motor cortex excitability and severity of Alzheimer's disease: A transcranial magnetic stimulation study

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have been limited to test motor cortical excitability. The aim of this study was to investigate the inhibitory circuits of the motor cortex and to relate these to measures of cognitive function in AD patients. Results were compared with those of a control group of healthy subjects matched for age, sex and education. Forty-five AD patients and 37 healthy volunteers were included in the study. Each participant received a neurological evaluation, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR). Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), motor evoked potential (MEP), cortical silent period (CSP), and transcallosal inhibition (TI). AD patients showed significantly reduced rMT, aMT and shorter MEP onset latency; in addition there was a prolongation of both CSP and TI. There was a significant positive correlation between the MMSE and CDR, on the one hand, and aMT and rMT, on the other hand, whereas the correlation was negative with CSP and TI durations. AD is associated with hyperexcitability of the motor cortex, which supports the hypothesis that changes in GABAb and glutamate function are important factors in cognitive impairment.

78. Genetic influences of sigma-1 receptor and apolipoprotein E on the severity of Alzheimer’s disease

78. Genetic influences of sigma-1 receptor and apolipoprotein E on the severity of Alzheimer’s disease

Relationship Between Proteolytically Cleaved Gelsolin and Levels of Amyloid-β Protein in the Brains of Down Syndrome Subjects

Gelsolin plays an important role in the fibrillogenesis of amyloid-β (Aβ). It binds to Aβ and inhibits its fibrillization. Gelsolin also gets proteolytically cleaved under apoptotic conditions. We recently reported a correlation between proteolytic product of gelsolin (carboxyl-terminal fragment of gelsolin, gelsolin-CTF) and severity of Alzheimer's disease. In this study, we report that gelsolin is cleaved in the brains of adult individuals (age, 43-63 years) with Down syndrome (DS), and that levels of gelsolin-CTF are significantly increased in the frontal cortex of adult DS subjects as compared to age-matched control subjects. Gelsolin-CTF was not observed in frontal cortex of young DS (age 0.5-23 years) and age-matched control subjects. In addition, the levels of both soluble and total Aβ40 and Aβ42 were significantly increased in the frontal cortex of adult DS patients as compared to age-matched control subjects. A positive relationship was observed between gelsolin-CTF in frontal cortex of DS, and the levels of soluble Aβ40 (r2= 0.7820, p < 0.01) and Aβ42 (r2 = 0.8179, p < 0.01). Experiments with recombinant full-length gelsolin and its N-terminal and C-terminal fragments showed that similar to gelsolin, proteolytic fragments of gelsolin can also interact with soluble synthetic Aβ. The post-translational modification of gelsolin proteins may not be essential as these proteins (overexpressed in Escherichia coli) were able to form complexes with Aβ. These results suggest that there may be a relationship between proteolytic cleavage of gelsolin and increased Aβ in the brain. Since soluble non-fibrillar forms of Aβ are neurotoxic, they may be involved in apoptosis and proteolysis of gelsolin.

PND20 PERCEIVED CAREGIVER BURDEN AND HEALTH RELATED QUALITY OF LIFE IN ALZHEIMER'S CAREGIVERS

PND20 PERCEIVED CAREGIVER BURDEN AND HEALTH RELATED QUALITY OF LIFE IN ALZHEIMER'S CAREGIVERS

Caregiver depression is associated with a low sense of coherence and health-related quality of life

Objectives: The main objective is to examine the sense of coherence (SOC) of spouse caregivers. The aim was further investigate the association of SOC, health-related quality of life (HRQoL), depressive symptoms, distress and how severity of Alzheimer's disease (AD) affects SOC. Method: 17O patient–spouse caregiver dyads in which the patient has recently diagnosed mild AD. Caregivers completed SOC scale (SOC-29), HRQoL (15D), Beck depression and general health questionnaire scale. The assessment of AD-related symptoms was made using mini mental state examination, clinical dementia rating, neuropsychiatric inventory and functional performance using activities of daily living (ADCS-ADL) scale. Results: Male caregivers’ SOC was significantly higher than female caregivers. The main predictor for low SOC was depression, with 37% of spousal caregivers reporting depressive symptoms. Women reported more depressive symptoms and distress. Caregivers’ HRQoL was as high as 0.8714, and a significant correlation was found between SOC and depression, r = −0.632 and distress r = −0.579. Furthermore, significant correlations were found between HRQoL and depression (r = −0.572) and distress (r = −0.568). The main predictors for high HRQoL were female gender and low distress. Conclusion: Spouse caregivers with low SOC seem to be a vulnerable group of caregivers. The many negative effects of perceived health accumulate in these caregivers during the very early phases of the caregiving process. Vulnerable caregivers need to be recognized at the time of AD diagnosis so that they can receive psychological support and counselling in addition to prevent morbidity in these caregivers.

A large-scale retrospective study of closing-in behavior in Alzheimer’s disease

The frequency and characteristics of closing-in behavior (CIB) were examined in 797 patients with Alzheimer's disease (AD), 132 of whom were followed up longitudinally. The frequency of CIB increased with the complexity of the graphic copying task and with the severity of Alzheimer's disease. Regression analyses suggested that attentional deficits are critical factors for the appearance of CIB, but that visuospatial impairments also play an important role in the emergence of severe forms of CIB.

Independent Effects of Intra- and Extracellular Aβ on Learning-Related Gene Expression

Alzheimer's disease is characterized by numerous pathological abnormalities, including amyloid beta (Abeta) deposition in the brain parenchyma and vasculature. In addition, intracellular Abeta accumulation may affect neuronal viability and function. In this study, we evaluated the effects of different forms of Abeta on cognitive decline by analyzing the behavioral induction of the learning-related gene Arc/Arg3.1 in three different transgenic mouse models of cerebral amyloidosis (APPPS1, APPDutch, and APP23). Following a controlled spatial exploration paradigm, reductions in both the number of Arc-activated neurons and the levels of Arc mRNA were seen in the neocortices of depositing mice from all transgenic lines (deficits ranging from 14 to 26%), indicating an impairment in neuronal encoding and network activation. Young APPDutch and APP23 mice exhibited intracellular, granular Abeta staining that was most prominent in the large pyramidal cells of cortical layer V; these animals also had reductions in levels of Arc. In the dentate gyrus, striking reductions (up to 58% in aged APPPS1 mice) in the number of Arc-activated cells were found. Single-cell analyses revealed both the proximity to fibrillar amyloid in aged mice, and the transient presence of intracellular granular Abeta in young mice, as independent factors that contribute to reduced Arc levels. These results provide evidence that two independent Abeta pathologies converge in their impact on cognitive function in Alzheimer's disease.