MMSE Change Research Articles

Enhanced soluble CD40 ligand and Alzheimer's disease: Evidence of a possible pathogenetic role

It has been suggested that cerebrovascular factors contribute to Alzheimer's disease. Soluble CD40 ligand (sCD40L) is directly involved in the development of vascular damage. We tested the hypothesis that sCD40L may be enhanced in Alzheimer's disease and predictive of its clinical course. Plasma sCD40L levels were evaluated in three groups of 40 consecutive patients each referring for mild or moderate or severe Alzheimer's disease, as assessed by the Clinical Dementia Rating (CDR), and in 40 healthy subjects. Seventy-seven patients with mild or moderate disease were re-evaluated after 2 years. Cross-sectional comparisons revealed higher plasma sCD40L levels in Alzheimer's disease patients than in controls (9.3 ± 4.7 ng/mL versus 3.4 ± 1.3 ng/mL, p < 0.0001). Circulating sCD40L levels significantly increased through the three CDR stages ( p = 0.0011 or less) and were correlated with MMSE ( r = −0.574, p < 0.0001) and ADAS-cog subscale ( r = 0.538, p < 0.0001) scores. Longitudinal evaluation identified sCD40L as an independent predictor of MMSE ( β = −0.157, t = −3.650, p = 0.0005) and ADAS-cog subscale ( β = 0.484, t = 3.890, p = 0.0002) score changes after 2 years. Patients with plasma sCD40L level ≥ 6.0 ng/mL, identified by ROC curve analysis as the best discriminating value for disease progression, had a three-fold increase in the risk of progression toward a worse CDR stage (odd ratio: 3.0, C.I. 95% 1.2–8.1). In conclusion, circulating sCD40L is enhanced in patients with Alzheimer's disease and independently associated with the severity and progression of the disease. These data might suggest a pathogenetic role for sCD40L in Alzheimer's disease.

P2-096: Ischemic lesion determines dementia outcome in Alzheimer’s disease with mixed pathology

Alzheimer's disease (AD) and vascular dementia (VaD) behave differently in neuropsychology and disease progression. However, cerebral ischemic pathology commonly coexists in AD, and studies suggest the cognitive profile in mixed dementia resembles VaD rather than AD. The impact of ischemic lesion on the clinical progression of AD with mixed pathology is unclear. To define the role of ischemic lesion in dementia progression in AD patients with mixed pathology. A retrospective observational study on consecutive AD, mixed dementia and VaD patients seen in a multidisciplinary memory clinic of a tertiary hospital from 1 Jan 1999 to 30 Jun 2004. Mixed dementia and AD patients were reclassified according to the published radiology operational NINDS–AIREN criteria for VaD into AD–N, no ischemic lesion on CT or MRI; AD–I, presence of ischemic lesion but not fulfilled the operational criteria; and AD–V, fulfilled operational criteria. A radiologist blinded to clinical diagnosis reviewed the imaging findings. Patients followed for more than 1 year were included in the study. Need for institution care and loss of self independence as indicated by score 3 in clinical dementia rating (CDR) were used as composite endpoints for poor outcome. One hundred seventy–three patients were included in the study. Their mean age was 76.3, 38.7% was male. The initial MMSE was 15.8±0.4, and the average duration of follow up was 29.7 months. Forty–three patients were diagnosed VaD, 53, 42 and 35 patients had AD–N, AD–I and AD–V respectively. There was no difference in the rate of change in MMSE among 4 groups of patients. Grouping patients with and without operational VaD criteria showed a significant worse performance on outcome endpoint in those with operational VaD criteria (VaD + AD–V), regardless on the clinical diagnosis of AD or VaD (figure 1). Presence of operational VaD criteria remained the only significant independent risk factor in the Cox–regression proportional hazard model after controlling for age, sex and ChEI treatment, the hazard ratio was 1.9 (1.1–3.3). Kaplan–Meier curve after regrouping patients according to the presence of radiological criteria for VaD. Log rank χ2 5.28, df=1, p value– 0.02.

Verbal repetition in patients with Alzheimer's disease who receive donepezil

Current outcome measures for Alzheimer's disease (AD) drugs have been criticized as insufficiently patient-centred. One commonly unmeasured goal of patients and caregivers is verbal repetition. We examined how often reducing repetition (of questions, statements or stories) was set as treatment goal, whether and when it responded, and how change in repetition correlated with change in other domains. This is a secondary analysis of the open-label Atlantic Canada Alzheimer's Disease Investigation of Expectations study of donepezil for mild-moderate AD in 100 community-dwelling people. Goal Attainment Scaling, an individualized account of the goals of treatment, was the primary outcome measure. Reducing repetition was a treatment goal in 46%, who were not systematically different from others. Of 18 patients in whom repetition improved for 9 months, 83% (15) showed a response at 3 months. Early (3-month) response correlated best with the overall level of goal attainment (r = 0.74) and changes in leisure activities (r = 0.69) and social interactions (r = 0.68) compared with changes in cognition (r = 0.44) or behaviour (r = 0.11). Correlations with the ADAS-Cog and MMSE change scores remained only modest (at 12 months = -0.25 and 0.19, respectively). Correlations with the CIBIC-Plus were higher (-0.47 at 3 months and -0.43 at 12 months). Diminution of repetition is common, and appears to mark response to cholinesterase inhibition in some patients. Responders generally also show improved cognition and function, perhaps as an aspect of improved executive function.

Impact of chemotherapy (CT) related anemia on functional/cognitive capacity in elderly non-small cell lung cancer (NSCLC) patients

8176 Background: In elderly cancer patients (≥ 65 years) no trial defines exactly the impact of CT on functional status and cognitive functions of these patients. AIM: Considering that anemia is a common finding in this setting of cancer patients and its prevalence increases after 65 years, we performed this study to find whether any association exists between haemoglobin level (Hb) and Comprehensive Geriatric Assessment (CGA) variables. (Mini Mental State Examination [MMSE], Activities of Daily Living [ADL]/Instrumental Activity Daily Living [IADL], Geriatric Depression Scale [GDS], Cumulative Illness Rating Scale [CIRS]). Patients and Methods: We enrolled 42 consecutive NSCLC elderly patients (male/female = 31/11, median age = 77, PS 0/1/2/3 = 14/20/7/1, stage III/IV disease = 20/22) undergoing CT (platinum based CT: 55% of cases). After the baseline evaluation (V0), all patients were interviewed after each cycle of CT (Vx) receiving multidisciplinary CGA at least till cycle 2. Hb was checked weekly and its association with these indexes was expressed using Spearman’s non-parametric coefficient r. Results: Mental and functional capacity, depression and comorbidities were found to be associated to Hb value; Spearman’s r calculated over all visits (V0-V5) was: MMSE and Hb +0.52 (p < 0.0001), ADL and Hb: +0.55 (p < 0.0001), IADL and Hb: +0.27 (p < 0.0003), GDS and Hb: -0.50 (p < 0.0001), CIRS and Hb: -0.33 (p < 0.0001). For all visits since V1, ADL, MMSE and CIRS changes from V0 were related with concomitant Hb changes, Spearman’s r being +0.54 (p < 0.0001) for ADL, +0.47 (p < 0.0001) for MMSE, and -0.45 (p< 0.0001) for CIRS. In 14 patients given erythropoietin in the interval V0-V2, mean Hb increased from 9.2 to 10.8 g/dL, and ADL (+0.57), MMSE (+3.4), CIRS (-1.7) mean values were improved. On the contrary, in 18 patients not given erythropoietin Hb varied from 13.0 to 11.2 g/dL and a parallel worsening in ADL (-0.94), MMSE (-3.3) and CIRS (+6,2) has been observed. Conclusion: Chemotherapy related anemia is associated with reduction of ADL, MMSE and increase of CIRS. In elderly cancer patients anemia correction or maintenance could be useful to preserve or improve functional independency and mental decay. No significant financial relationships to disclose.

A follow-up study of change in quality of life among persons with dementia residing in a long-term care facility.

Dementia is a major public health problem. Increased attention is being paid to the quality of life (QOL) of people with this chronic disease. There have been no longitudinal studies of QOL change in dementia. Longitudinal study of a cohort of 47 persons with dementia residing in a long-term care facility. The QOL of participants was assessed at baseline using the Alzheimer's Disease Related Quality of Life (ADRQL) scale. At this time participants were also assessed on a series of other clinical measures. QOL was reassessed on the ADRQL scores two years later. There was small but significant mean decline in ADRQL over the two-year study interval. However, for 49% of participants, ADRQL scores did not change or improved. Small but significant declines occurred in all ADRQL domains, with the exception of 'feelings and mood'. Of the baseline variables assessed, only a lower baseline ADRQL score was associated with greater decline in ADRQL score at follow-up. There was no association between sociodemographic variables, baseline ratings of dementia severity (MMSE), ADL impairment, behavioral impairment, and depression, or MMSE change during follow-up and ADRQL decline. Among long-term care residents with dementia there is a small decline in QOL ratings over two years. However, for nearly half, QOL ratings stay the same or improve. The ADRQL is a sensitive measure of change in QOL and is appropriate for use as an outcome measure in intervention studies. The predictors of QOL change are complex and require further study.

Treatment with donepezil in Alzheimer patients with and without cerebrovascular disease

Donepezil, a selective acetylcholinesterase inhibitor, is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). In a post-marketing surveillance (PMS) study in Germany, patients under routine treatment conditions were observed while treatment was switched from other antidementia drugs (i.e., nootropics) to donepezil. A total of 913 patients were enrolled (60.1% female, mean±S.D. age 73.4±8.6 years, mean Mini-Mental Status Examination [MMSE] 18.0±5.3), and were treated with donepezil (5 or 10 mg/day according to recommended dosing). 709/913 (77.1%) of patients had been pretreated with other antidementive drugs (piracetam, memantine, ginkgo, and others). In 29.6% of patients, investigators documented concomitant cerebrovascular disease (CVD+) according to their clinical judgment. Observation period was 3 months for the individual patient. Efficacy parameters were changes in MMSE, global clinical (investigators) judgment of efficacy, and a clinical judgment about the patients' quality of life (QoL). Adverse events were also analyzed. The objective of the present investigation was to compare—in a “real-life” setting—the differential efficacy and tolerability of donepezil in AD patients with and without concomitant cerebrovascular disease. After 3 months, patients had improved by a mean MMSE change from baseline of 2.2 points (CVD+: 2.4 pts, CVD−: 2.1 pts). QoL was judged “improved” in 70.0% of patients (CVD+: 72.5%, CVD−: 69.6%). Adverse events were reported in 85/913 (9.3%) of patients (CVD+: 11.2%, CVD−: 7.9%). Reported adverse events were substantially less than reported previously in controlled clinical trials. This suggests that donepezil therapy is effective and well tolerated in AD patients, both with and without concomitant cerebrovascular disease.

Cognitive Functions and Depression as Predictors of Poor Outcome 15 Months after Stroke

The prognostic predictors of poor outcome, as defined by death between 3 and 15 months and dependent living at 15 months, were examined in the Helsinki Stroke Aging Memory (SAM) study cohort. Death between 3 and 15 months was registered from the whole study group of 486 consecutive patients aged 55–85 years. Altogether 286 of the 486 patients went through a detailed follow-up examination both 3 and 15 months after stroke, including structured measures of emotion (Beck’s Depression Inventory, BDI), cognition (Mini-Mental State Examination, MMSE), dementia assessment according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and handicap (Rankin scale, RS). The only independent correlate of death between 3 and 15 months was dependent living at 3 months (OR 2.6, 95% CI 1.2–5.8), which also had the most powerful association with dependent living at 15 months (OR 5.8, 95% CI 2.6–13.1). Also, both worsening in cognition (change in MMSE, OR for each point of worsening 1.2, 95% CI 1.1–1.3) and worsening of depression (change in BDI, OR for each point of worsening 1.1, 95% CI 1.02–1.12), between 3 and 15 months follow-up, had an independent effect on dependent living 15 months after ischemic stroke. This challenges the care and rehabilitation of these items even at the stable period after stroke.

Lack of change in average age and MMSE in newly diagnosed AD patients over the last 10 years

Sleep disturbance is a symptom shared by all neurodegenerative, dementing illnesses, such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and its presence frequently precipitates decisions to seek institutional care for patients. Although the sleep disturbances of AD and DLB are qualitatively similar, they appear to be more prominent in patients with DLB. Disturbance of the circadian rhythm has been noted and is a potential factor underlying the nocturnal sleep fragmentation and daytime sleepiness observed in these patients. We studied the circadian variation of core-body temperature and motor activity in a total of 32 institutionalized patients with probable AD by NINCDS-ADRDA criteria, 9 of whom also met pathologic criteria for DLB. Eight, healthy, elderly male controls were studied on a clinical research unit designed to simulate the hospital environment where the dementia patients were studied. Circadian variables generally had greater deviations from normal associated with increasing AD pathology, as measured by postmortem-determined Braak stage, supporting the hypothesis that central changes mediate circadian disturbances in AD and DLB. Patients with a postmortem diagnosis of DLB manifested greater disturbances of locomotor activity circadian rhythms than patients with AD, possibly reflecting the greater sleep disturbances seen in this population, but the differences from normal in the circadian rhythms of the AD and DLB patients were qualitatively similar.

Inheritance of the ApoE ε4 Allele Increases the Rate of Brain Atrophy in Dementia Patients

We investigated the influence of the apolipoprotein (ApoE) ε4 allele on the rate of brain atrophy in patients with clinical dementia and in subjects at risk for dementia. Eighty-one subjects, consecutively referred to a memory clinic due to symptoms of dementia, went through a comprehensive examination, including cerebral magnetic resonance imaging. After an initial investigation these subjects were divided into one of six diagnostic groups; Alzheimer’s disease (AD, n = 23), objective cognitive impairment (OCI, n = 27), subjective cognitive impairment (SCI, n = 17), vascular dementia (VaD), frontotemporal dementia (FTD) and unspecified dementia (USD). The last three groups were joined into one diagnostic group designated ‘other dementia’ (OD, altogether n = 14). In order to study the progression of cognitive impairment as well as the rate of atrophy in different brain regions all subjects were reinvestigated after an average period of 16 monhts. Interest was focused on investigating if those subjects with one or two ε4 alleles differed in either dementia progression or rate of brain atrophy compared to those without the ε4 allele. We found that the ApoE ε4 carriers had a statistically significantly larger increase in ventricular volume as compared with the ApoE ε4 noncarriers. In all diagnostic groups the ApoE ε4 carriers showed a greater rate of ventricular volume increase, as compared to the noncarriers. However, this difference was statistically significant only for the OD subjects. No statistical significant changes over time were seen for whole brain volume or volume of the temporal lobes and the medial temporal lobes. The diagnostic groups differed in dementia progression with the AD subjects having the most pronounced reduction in MMSE scores as compared to subjects at risk for AD (OCI and SCI subjects). The presence of ApoE ε4 allele did not influence the change in MMSE in any of the diagnostic groups.

Mortality and temporal course of probable Alzheimer's disease: a 5-year prospective study.

Alzheimer's disease (AD) is associated with an increased mortality in comparison with aged control populations. The relationship between the clinical and the temporal course of AD has not been well studied over significant intervals. Community-residing patients with probable AD (N = 103, 42 men, mean age = 70.2 +/- 8.0 years) were studied at baseline on demographic and clinical variables, including measures of global deterioration (Global Deterioration Scale; GDS), mental status and cognition (e.g., Mini-Mental State Examination; MMSE), and functional impairment (Functional Assessment Staging; FAST). Baseline characteristics included a GDS range of Stage 4, 5, or 6 (38.8%, 39.8%, and 21.4%, respectively) and a mean MMSE score of 15.4 +/- 5.6. The mean follow-up interval was 4.6 +/- 1.4 years. Follow-ups were done blind to baseline measures and when necessary were conducted in residential and nursing home settings. Of locatable subjects (n = 95, 92%), 30 (31.6%) were decreased. Survivors (n = 65) had a mean GDS stage of 6.2 +/- 0.9 and a mean MMSE score of 5.1 +/- 6.9; 51% had MMSE scores of 0. Increased age and male gender, but not baseline clinical dementia variables, increased the risk of death (ps < .01). Change in clinical variables correlated significantly with time elapsed (r = .32, p < .05, for MMSE change, to r = .48, p < .001, for GDS change). Significant variance in temporal change (i.e., time elapsed) was accounted for by change in two of the five clinical measures studied (i.e., GDS and FAST; multiple r = .53). The results support previous estimates of mean duration of the GDS and FAST stages. For subjects with probable AD followed over approximately 5 years, clinical variables changed significantly over time in survivors. However, the majority of temporal variance in the course of AD remains unexplained.