Deborah B. Marin

The Caregiver Activity Survey (CAS): development and validation of a new measure for caregivers of persons with Alzheimer's disease

Background. Most instruments that measure the impairments associated with Alzheimers disease assess symptom severity. Little attention has been paid to the illnesss impact on the time formal and informal caregivers spend caring for Alzheimers individuals. A tool that measures the time spent caregiving would help to determine the economic impact of the illness. The Caregiver Activity Survey (CAS) was developed to measure the time caregivers spend aiding Alzheimers patients with their day‐to‐day activities.

Noncognitive Disturbances in Alzheimer's Disease: Frequency, Longitudinal Course, and Relationship to Cognitive Symptoms

OBJECTIVE: To investigate the frequency and longitudinal course of symptoms of depression, agitation, and psychosis in a longitudinally studied sample of patients with Alzheimers disease (AD).

CSF beta-amyloid, cognition, and APOE genotype in Alzheimer's disease.

Objectives: We examined the relationship between CSF amyloid beta peptide (Aβ) concentration and AD severity in 31 probable AD patients and explored whether APOE genotype modifies this relationship. Background: Aβ deposition in AD brains has been correlated with disease severity and with APOE-ε4 allele frequency. Few studies have examined the effects of APOE genotype on the relationship between CSF Aβ and disease severity in an antemortem sample. Methods: Patients carried the clinical diagnosis of probable AD and did not have serious medical illness, current or past diagnosis of mood disorder, schizophrenia or alcoholism, or current psychotic features. The Mini-Mental State Examination (MMSE) was administered to the patient within 3 months of CSF collection. CSF was analyzed for Aβ1-40 and Aβ1-42 by sandwich ELISAs, and APOE genotype was determined by PCR run from blood. Correlations were performed between MMSE score and Aβ1-40 and Aβ1-42 concentrations while controlling for potential confounding variables. Results: CSF measures of Aβ1-40 and Aβ1-42 concentrations were correlated with each other (r = 0.56, df = 28, p < 0.01). CSF Aβ1-40 and Aβ1-42 concentrations were positively correlated with MMSE score. The negative association between CSF Aβ measures and disease severity remained significant after controlling for age (Aβ1-40 and MMSE score: r = 0.46, df = 28, p = 0.01; Aβ1-42 and MMSE score: r = 0.35, df = 28, p = 0.05). Among the APOE-ε3/3 homozygotes there was a significant positive correlation only between Aβ1-42 and MMSE score (Aβ1-42, r = 0.94, p = 0.02; Aβ1-40, r = 0.79, p = 0.11). Conclusions: We hypothesize that an increased deposition of Aβ in plaques results in decreased CSF Aβ concentration. The stronger relationship between MMSE score and CSF Aβ, specifically in APOE-ε3/3 homozygotes, suggests that patients with APOE-ε3/3 genotype may have different pathogenic mechanisms than the other genotypes for Aβ deposition or clearance.

Elevated Serum Total and LDL Cholesterol in Very Old Patients with Alzheimer’s Disease

The relationships of serum lipids with Alzheimer’s disease (AD) and other dementias in very old patients are not clear. All residents of an academic nursing home were studied clinically for dementia and for serum lipids. All those autopsied over a 7.7-year period had apolipoprotein E (apoE) genotyping and detailed neuropathological examination. Those with pathologically defined criteria for AD (n = 84) were compared to all others who also had clinical dementia but did not show AD changes (n = 22). In contrast to most other reports of serum lipids in very old patients with AD, total cholesterol (TC) and low density lipoprotein cholesterol levels were each significantly higher for those with AD. The lipid-AD associations were progressively stronger with increasing pathological certainty of AD diagnosis. These relationships remained significant after adjustment for apoE genotype and for other known risk factors. The lipid-AD associations in a very old cohort, and prior evidence that elevated TC in middle life is a risk factor for later dementia, prompt consideration of factors associated with lipid metabolism in the development of Alzheimer’s dementia.

The relationship between apolipoprotein E, dementia, and vascular illness

The purpose of this study was to concurrently assess the relationship of Apolipoprotein E (APOE) with both dementias and vascular illnesses in the very old. Nine hundred and fifty nine subjects (mean age 85 years) in a long-term care facility were genotyped and cognitively tested with the Mini Mental State Exam. All subjects were studied for the relationship of APOE with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. Four hundred fifty individuals met criteria for inclusion into one of the following groups: Alzheimers disease (n = 318), vascular dementia (n = 49), or not demented controls (n = 83) and were investigated for the relationship between APOE and these diagnostic categories. APOE epsilon4 was not associated with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. The APOE epsilon3 allele was more common in men with atherosclerotic heart disease. In contrast, the APOE epsilon4 allele was more common in patients with Alzheimers disease (22%) and vascular dementia (26%) than in not demented controls (7%). APOE epsilon4 is associated with dementias in the very old, whereas its relationship with either peripheral or central nervous system vascular disease without dementia is not as robust.

A Pilot Study of Prednisone in Alzheimer's Disease

Preliminary to a multicenter trial, an open-label study was conducted of prednisone treatment in Alzheimers disease. Prednisone was given at an initial dose of 10 mg (part 1) or 20 mg (part 2) and tapered over 7 weeks. There were no serious adverse events attributed to the medication, and there were no significant changes in either mean cognitive or behavioral assessment scores with treatment during either part. Serum levels of the acute phase proteins alpha-1-antichymotrypsin and C-reactive protein did not change significantly during part 1, but were suppressed by the higher dose given in part 2. Thus, a prednisone regimen with an initial dose of 20 mg is tolerable and results in suppression of the acute phase response in Alzheimers disease.

The impact of behavioral impairment of functional ability in Alzheimer's disease

This study sought to determine the relationship between behavioral disturbance and functional status in a longitudinally studied sample of patients with Alzheimers disease (AD). One hundred and forty‐nine patients meeting NINCDS–ADRDA criteria for probable AD were followed for an average of 37.3 months, with follow‐up assessments every 6 months. Subjects were seen at the Alzheimers Disease Research Center clinics at the Mt Sinai Medical Center, New York, and the Veterans Affairs Medical Center, Bronx, New York. Measures included the Physical and Self‐Maintenance Scale (PSMS) and Instrumental Activities of Daily Living Scale (IADLS) of Lawton and Brody and the cognitive and non‐cognitive subscales of the Alzheimers Disease Assessment Scale (ADAS). For each patient the assessment at which they had their most severe non‐cognitive symptoms as measured by the non‐cognitive part of the ADAS (ADAS‐NC) was determined. ADAS‐NC scores at that assessment were correlated with IADLS and PSMS scores at the same assessment and at the next assessment 6 months later. While there was some modest association of ADAS‐NC scores with functional impairment using pairwise correlation coefficients, none of the correlations remained significant when the severity of cognitive impairment was controlled statistically. Findings were not significantly changed when drug status was controlled. These results suggest that behavioral disturbance, while very troubling to caregivers and patients, does not substantially worsen functional ability beyond the contribution of cognitive impairment in AD. Together with previous results indicating that non‐cognitive symptoms in AD are episodic and fluctuating rather than progressive, the present data suggest that interventions for non‐cognitive disturbances in AD should be viewed as ways to increase patient comfort, safety and ease of care and not as ways to improve functional autonomy. The latter can be achieved only by improving the progressive cognitive deficits of AD. Copyright

Impact of Rivastigmine on Costs and on Time Spent in Caregiving for Families of Patients With Alzheimer's Disease

BACKGROUND Alzheimers disease (AD) places a significant burden on health care systems worldwide. As new treatments are developed, their cost-effectiveness is often assessed to help health care professionals make informed decisions. In addition to the more common practice of assessing direct medical costs, indirect costs, including time spent in caregiving, should be evaluated. METHODS This study examined the potential effects of the dual cholinesterase inhibitor rivastigmine (Exelon) on caregivers of patients with AD. Results from two 26-week, placebo-controlled trials have demonstrated the clinically relevant and statistically significant efficacy of rivastigmine (6-12 mg/day) compared to placebo, on cognition, activities of daily living, and global functioning. By delaying progression of AD, significant savings in caregiver burden are anticipated, as measured by time spent caregiving and its related costs. Data collected in a prospective, observational study of AD patients and their caregivers were used to establish the relationship between disease severity (based on Mini-Mental State Examination [MMSE] score) and time spent caregiving (according to the 5-item Caregivers Activity Survey score). A significant correlation was observed between the two scores (N = 43, r = -.56, p < .0001), demonstrating that more time for supervision from caregivers is required as the disease progresses. This finding was used to estimate the reduced caregiver burden resulting from the delay in disease progression that was demonstrated with use of rivastigmine. RESULTS Over a 2-year period, the reduction in time spent in caregiving reached 691 hours for caregivers of patients with mild AD (MMSE score 21-30), resulting in a total savings of approximately 11,253 dollars. Treatment of patients with moderately severe AD was also evaluated. The trend was similar but the impact was less, suggesting an economic benefit to early therapy. CONCLUSION Early diagnosis and a pharmacologic intervention that allows the patients to remain at home longer by delaying disease progression would have a beneficial impact on patients, caregivers, and payers, and should therefore be encouraged through initiatives designed to identify and treat patients early in the course of disease.

Genetic epidemiological study of maternal and paternal transmission of alzheimer's disease

Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission.

l-Deprenyl and physostigmine for the treatment of Alzheimer's disease

The present study evaluated the safety of and obtained preliminary data on the cognitive effects of L-deprenyl and physostigmine in patients with Alzheimers Disease. Seventeen outpatients with Alzheimers Disease participated in a double-blind crossover study in which they received 4 weeks of L-deprenyl at a dose of 10 mg p.o., q.d., and 4 weeks of placebo in random order. During both the L-deprenyl and placebo periods, patients received cognitive assessments during physostigmine (0.5 mg) and placebo infusions separated by 2 days. The cognitive effects of these agents alone and in combination were measured with digit span, verbal fluency, list learning, praxis, delayed recall, and delayed recognition tasks. Fifteen patients completed the study. The two drugs, used alone or in combination, were safe and well tolerated. Analyses of variance demonstrated that neither physostigmine nor L-deprenyl, whether given alone or in combination, significantly improved cognition, when compared with the double placebo condition.