To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD).
An autopsy series of 102 patients with dementia and ...pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD cases were stratified according to their last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations.
Most (87%) of the NCs had allocortical NFTs, whereas only a minority (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In contrast, none of the NCs exhibited neocortical NFTs, except one case with a single ST tangle. However, neocortical NFTs were not detected in even 10% of the patients with AD and, in particular, were absent in nearly 50% of those with mild disease at death. Thus, their sensitivity as a marker of AD was lower than that of NPs, which, conversely, were found in all patients with AD. Comparing NCs and patients with mild AD, significant differences were found for numbers of NPs only. Across the AD groups, in contrast, although NP and NFT density increased with dementia severity, significant differences consistently emerged for NFTs alone.
Deterioration in Alzheimer disease appears to be driven by neuritic plaques and neurofibrillary tangles at different stages of the disease. The significant increase in neuritic plaques, but not neurofibrillary tangles, in patients with even mild Alzheimer disease at death compared with normal control subjects suggests that only neuritic plaques are associated with the earliest symptoms of Alzheimer disease.
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.
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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.
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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 . . .
To define and investigate key issues in the management of dementia and to make literature-based treatment recommendations.
The authors searched the literature for four clinical questions: 1) Does ...pharmacotherapy for cognitive symptoms improve outcomes in patients with dementia? 2) Does pharmacotherapy for noncognitive symptoms improve outcomes in patients with dementia? 3) Do educational interventions improve outcomes in patients and/or caregivers? 4) Do other nonpharmacologic interventions improve outcomes in patients and/or caregivers?
Cholinesterase inhibitors benefit patients with AD (Standard), although the average benefit appears small; vitamin E likely delays the time to clinical worsening (Guideline); selegiline, other antioxidants, anti-inflammatories, and estrogen require further study. Antipsychotics are effective for agitation or psychosis in patients with dementia where environmental manipulation fails (Standard), and antidepressants are effective in depressed patients with dementia (Guideline). Educational programs should be offered to family caregivers to improve caregiver satisfaction and to delay the time to nursing home placement (Guideline). Staff of long-term care facilities should also be educated about AD to minimize the unnecessary use of antipsychotic medications (Guideline). Behavior modification, scheduled toileting, and prompted voiding reduce urinary incontinence (Standard). Functional independence can be increased by graded assistance, skills practice, and positive reinforcement (Guideline).
Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid ...pathology.
To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain.
The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects.
Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation.
Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.
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.
To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB).
Pathologic diagnosis of DLB mandates Lewy bodies but also allows for AD ...pathology in the form of plaques and tangles. Because clinical diagnostic accuracy of DLB remains low, the authors questioned whether the severity of AD pathology in the form of tangles might affect the clinician's ability to correctly diagnose DLB in life.
Ninety-eight subjects with autopsy-proven DLB who had been evaluated annually at the University of California San Diego AD Research Center were identified. The clinical diagnosis used was the last diagnosis before death. Pathologic diagnosis of DLB was made according to Consensus guidelines, and Braak staging was used to assess the degree of neurofibrillary AD pathology. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined.
Only 27% of the subjects with DLB demonstrated both visual hallucinations and spontaneous extrapyramidal signs (EPS). The low Braak stage (0 to 2, n = 24) subjects had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher (3 to 6, n = 66) Braak stages (33%, p = 0.008), and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039).
The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.
The APOE epsilon4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in beta-amyloid senile plaques (SPs) and neuritic ...plaques (NPs). Whether it affects neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains controversial. In contrast, the epsilon2 allele has been reported to decrease the risk for AD. However, its effect on neuropathologic and neurochemical markers of disease is unclear.
To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD.
In an autopsy series of 296 patients with AD, APOE genotype was determined in blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal (MF), inferior parietal (IP), and superior temporal (ST) cortices and the hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF, IP, and ST cortices.
Compared with patients with no epsilon4 alleles, epsilon4 carriers (patients with either one or two epsilon4 alleles) did not differ significantly with regard to any pathologic or neurochemical measures, except for increased ST NPs. However, when cases were stratified into three groups according to the number of epsilon4 alleles, patients with two epsilon4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no epsilon4 alleles. The association of the epsilon4/4 genotype with neocortical pathologic severity remained significant even after adjusting for age at onset or age at death. In contrast, there were no significant group differences with regard to neocortical ChAT activity. When pathologic and neurochemical measures were compared between patients with the epsilon2 allele and those without, a strong relationship emerged between the epsilon2 allele and decreased NPs in all neocortical regions.
The epsilon4 allele does not predict cholinergic decline in AD. Although the presence of a single epsilon4 allele appears to have no effect, the presence of two epsilon4 alleles is an important determinant of both NP and NFT accumulation. A putative protective role for the epsilon2 allele in AD may be mediated by reduced plaque burden.
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.
To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer's disease.
A multicenter, randomized, placebo-controlled clinical ...trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer's Disease Cooperative Study. Subjects with Alzheimer's disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin.
Private homes and long-term care facilities.
157 individuals were recruited by 36 Alzheimer's disease research centers. Subjects with a diagnosis of Alzheimer's disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver.
Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data.
No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups.
Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease.
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.
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