In this randomized trial involving patients with mild cognitive impairment, vitamin E did not reduce the rate of progression to Alzheimer's disease. Although an initial benefit of donepezil was ...observed during the first year, over the course of the three-year study the rate of progression to Alzheimer's disease was similar in patients treated with donepezil and those treated with placebo. The side effects of donepezil included diarrhea, nausea, muscle cramps, and insomnia.
In patients with mild cognitive impairment, vitamin E did not reduce the rate of progression to Alzheimer's disease. Over the course of the three-year study the rate of progression to Alzheimer's disease was similar in patients treated with donepezil and those treated with placebo.
Mild cognitive impairment represents a transitional state between the cognitive changes of normal aging and the earliest clinical features of Alzheimer's disease.
1
Amnestic mild cognitive impairment refers to the subtype that has a primary memory component, either alone (single domain) or in conjunction with other cognitive-domain impairments (multiple domain), but of insufficient severity to constitute dementia.
2
–
6
Previous research has shown that the rate of progression to clinically diagnosable Alzheimer's disease is 10 to 15 percent per year among persons who meet the criteria for the amnestic form of mild cognitive impairment, in contrast to a rate of 1 to . . .
CONTEXT Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even ...in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B6 and B12. Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline. OBJECTIVE To determine the efficacy and safety of B vitamin supplementation in the treatment of AD. DESIGN, SETTING, AND PATIENTS A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B6, and vitamin B12 supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B12, and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States. INTERVENTION Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements 5 mg/d of folate, 25 mg/d of vitamin B6, 1 mg/d of vitamin B12 and 40% treated with identical placebo); duration of treatment was 18 months. MAIN OUTCOME MEASURE Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). RESULTS A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean SD, −2.42 3.35 in active treatment group vs −0.86 2.59 in placebo group; P < .001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, −0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements. CONCLUSION This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00056225
Immunization of patients with Alzheimer's disease (AD) with synthetic amyloid-beta peptide (Abeta(42)) (AN1792) was previously studied in a randomized, double-blind, placebo-controlled phase 2a ...clinical trial, Study AN1792(QS-21)-201. Treatment was discontinued following reports of encephalitis. One year follow-up revealed that AN1792 antibody responders showed improvements in cognitive measures as assessed by the neuropsychological test battery (NTB) and a decrease in brain volume compared with placebo.
A follow-up study, Study AN1792(QS-21)-251, was conducted to assess the long-term functional, psychometric, neuroimaging, and safety outcomes of patients from the phase 2a study 4.6 years after immunization with AN1792. The results were analyzed by comparing patients originally identified as antibody responders in the AN1792 phase 2a study with placebo-treated patients.
One hundred and fifty-nine patients/caregivers (30 placebo; 129 AN1792) participated in this follow-up study. Of the 129 AN1792-treated patients, 25 were classified in the phase 2a study as antibody responders (anti-AN1792 titers > or = 1:2,200 at any time after the first injection). Low but detectable, sustained anti-AN1792 titers were found in 17 of 19 samples obtained from patients classified as antibody responders in the phase 2a study. No detectable anti-AN1792 antibodies were found in patients not classified as antibody responders in the phase 2a study. Significantly less decline was observed on the Disability Assessment for Dementia scale among antibody responders than placebo-treated patients (p=0.015) after 4.6 years. Significant differences in favor of responders were also observed on the Dependence Scale (p=0.033). Of the small number of patients who underwent a follow-up MRI, antibody responders showed similar brain volume loss during the follow-up period subsequent to the AN1792 phase 2a study compared with placebo-treated patients.
Approximately 4.6 years after immunization with AN1792, patients defined as responders in the phase 2a study maintained low but detectable, sustained anti-AN1792 antibody titers and demonstrated significantly reduced functional decline compared with placebo-treated patients. Brain volume loss in antibody responders was not significantly different from placebo-treated patients approximately 3.6 years from the end of the original study. No further cases of encephalitis were noted. These data support the hypothesis that Abeta immunotherapy may have long-term functional benefits.
With the increasing life expectancy in developed countries, the incidence of Alzheimer’s disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the ...pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non-AD dementias would not benefit from an AD-specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored. Although there currently is no ideal biomarker that would fulfill all these requirements, there is increasing evidence that a combination of currently existing neuroimaging and cerebrospinal fluid (CSF) and blood biomarkers can provide important complementary information and thus contribute to a more accurate and earlier diagnosis of AD. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is exploring which combinations of these biomarkers are the most powerful for diagnosis of AD and monitoring of treatment effects.
The Alzheimer's disease neuroimaging initiative Mueller, Susanne G; Weiner, Michael W; Thal, Leon J ...
Neuroimaging clinics of North America,
11/2005, Volume:
15, Issue:
4
Journal Article
Peer reviewed
Open access
With increasing life expectancy in developed countries, the incidence of Alzheimer's disease (AD) and its socioeconomic impact are growing. Increasing knowledge of the mechanisms of AD facilitates ...the development of treatment strategies aimed at slowing down or preventing neuronal death. AD treatment trials using clinical outcome measures require long observation times and large patient samples. There is increasing evidence that neuroimaging and cerebrospinal fluid and blood biomarkers may provide information that may reduce sample sizes and observation periods. The Alzheimer's Disease Neuroimaging Initiative will help identify clinical, neuroimaging, and biomarker outcome measures that provide the highest power for measurement of longitudinal changes and for prediction of transitions.
Patients with autopsy-confirmed frontotemporal dementia (FTD;
n
= 16) and Alzheimer's disease (AD;
n
= 32) were compared on first-letter and semantic category fluency tasks. Despite being matched on ...age, education, and dementia severity, FTD patients performed worse overall and showed similar impairment in letter and semantic category fluency, whereas AD patients showed greater impairment in semantic category than letter fluency. A measure of the disparity between letter and semantic category fluency (the semantic index) was effective in differentiating FTD from AD patients, and this disparity increased with increasing severity of dementia. These unique patterns of letter and semantic category fluency deficits may be indicative of differences in the relative contribution of frontal-lobe-mediated retrieval deficits and temporal-lobe-mediated semantic deficits in FTD and AD.
Full text
Available for:
CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ
CONTEXT Several reports from small clinical trials have suggested that estrogen
replacement therapy may be useful for the treatment of Alzheimer disease (AD)
in women. OBJECTIVE To determine whether ...estrogen replacement therapy affects global, cognitive,
or functional decline in women with mild to moderate AD. DESIGN The Alzheimer's Disease Cooperative Study, a randomized, double-blind,
placebo-controlled clinical trial conducted between October 1995 and January
1999. SETTING Thirty-two study sites in the United States. PARTICIPANTS A total of 120 women with mild to moderate AD and a Mini-Mental State
Examination score between 12 and 28 who had had a hysterectomy. INTERVENTIONS Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25
mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew
after randomization but before receiving medication; 97 subjects completed
the trial. MAIN OUTCOME MEASURES The primary outcome measure was change on the Clinical Global Impression
of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome
measures included other global measures as well as measures of mood, specific
cognitive domains (memory, attention, and language), motor function, and activities
of daily living; compared by the combined estrogen groups vs the placebo group
at 2, 6, 12, and 15 months of follow-up. RESULTS The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants
taking placebo worsened (P = .48). Secondary outcome
measures also showed no significant differences, with the exception of the
Clinical Dementia Rating Scale, which suggested worsening among patients taking
estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for
placebo; P = .01). CONCLUSIONS Estrogen replacement therapy for 1 year did not slow disease progression
nor did it improve global, cognitive, or functional outcomes in women with
mild to moderate AD. The study does not support the role of estrogen for the
treatment of this disease. The potential role of estrogen in the prevention
of AD, however, requires further research.
The existence of multipotent progenitor populations in the adult forebrain has been widely studied. To extend this knowledge to the adult spinal cord we have examined the proliferation, distribution, ...and phenotypic fate of dividing cells in the adult rat spinal cord. Bromodeoxyuridine (BrdU) was used to label dividing cells in 13- to 14-week-old, intact Fischer rats. Single daily injections of BrdU were administered over a 12 d period. Animals were killed either 1 d or 4 weeks after the last injection of BrdU. We observed frequent cell division throughout the adult rodent spinal cord, particularly in white matter tracts (5-7% of all nuclei). The majority of BrdU-labeled cells colocalized with markers of immature glial cells. At 4 weeks, 10% of dividing cells expressed mature astrocyte and oligodendroglial markers. These data predict that 0.75% of all astrocytes and 0.82% of all oligodendrocytes are derived from a dividing population over a 4 week period. To determine the migratory nature of dividing cells, a single BrdU injection was given to animals that were killed 1 hr after the injection. In these tissues, the distribution and incidence of BrdU labeling matched those of the 4 week post injection (pi) groups, suggesting that proliferating cells divide in situ rather than migrate from the ependymal zone. These data suggest a higher level of cellular plasticity for the intact spinal cord than has previously been observed and that glial progenitors exist in the outer circumference of the spinal cord that can give rise to both astrocytes and oligodendrocytes.
CONTEXT: Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory ...drugs (NSAIDs) may favorably influence the course of the disease. OBJECTIVE: To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. SETTING: Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. PARTICIPANTS: Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. INTERVENTIONS: Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). RESULTS: The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 8.0) or rofecoxib (7.6 7.7) was not significantly different from the change in participants treated with placebo (5.7 8.2). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. CONCLUSION: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.
Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in ...about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.
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