Alzheimer Disease: Henderson VW

Henderson VW. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #15090555 links to  free full text

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Henderson VW, Hogervorst E. · No affiliation provided · Neurology. · Pubmed #14745046 No free full text.

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Knopman D, Henderson VW. · No affiliation provided · Neurology. · Pubmed #12682305 No free full text.

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Resnick SM, Henderson VW. · No affiliation provided · JAMA. · Pubmed #12413378 No free full text.

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Henderson VW. · Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, Stanford, California 94305-5405, USA. · Semin Reprod Med. · Pubmed #19401959 No free full text.

Abstract: Estrogen-containing hormone therapy initiated during late postmenopause does not improve episodic memory (an important early symptom of Alzheimer's disease), and it increases dementia risk. Cognitive consequences of exogenous estrogen exposures during midlife are less certain. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce risk of Alzheimer's disease later in life. However, there are concerns that observational findings may be systematically biased. Partial insight on this critical issue may be gleaned from results of ongoing clinical trials involving midlife postmenopausal women (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study). The effects of exogenous midlife estrogen exposures and Alzheimer risk can also be approached through better animal models, through carefully designed cohort studies, and through use of surrogate outcomes in randomized controlled trials in midlife women. Selective estrogen receptor modulators have the potential to affect cognitive outcomes and also merit additional study.

Henderson VW. · Departmentsof Health Research and Policy (Epidemiology), Stanford University, Stanford, California 94305-5405, USA. · Clin Obstet Gynecol. · Pubmed #18677155 No free full text.

Abstract: The natural menopause is not associated with substantial cognitive change. Limited clinical trial evidence suggests that estrogen-containing hormone therapy has little effect on cognition during midlife, but prompt initiation after surgical menopause may improve aspects of memory. Among older postmenopausal women, strong clinical trial evidence demonstrates that hormone initiation does not improve cognition. More limited clinical trial evidence indicates no improvement in Alzheimer symptoms, and the Women's Health Initiative Memory Study found an increase in dementia risk among older women. Observational findings of reduced Alzheimer risk may reflect early hormone use in younger women, or findings may be biased. Cognitive effects of selective estrogen receptor modulators are not yet well studied.

Henderson VW. · Department of Health Research and Policy, Stanford University, Stanford, California 94305-5405, United States. · Climacteric. · Pubmed #17882682 No free full text.

Abstract: Menopausal status and estrogen-containing hormone therapy may influence several neurological disorders, including Alzheimer's disease, epilepsy, migraine headache, multiple sclerosis, Parkinson's disease, sleep disorders, and stroke. For most of these illnesses, evidence on hormone therapy is insufficient to guide practice decisions. For stroke, clinical trial evidence indicates that hormone therapy increases risk of cerebral infarction. For women with Alzheimer's disease, estrogen treatment trials have tended to be small and of short duration. Most suggest that estrogen started after the onset of dementia symptoms does not meaningfully improve cognition or slow disease progression. Hormone therapy initiated after age 64 increased all-cause dementia in the Women's Health Initiative Memory Study. Many observational studies, however, report protective associations between hormone use and Alzheimer risk. Apparent risk reduction may represent a bias toward hormone therapy, since hormones are more often prescribed to healthier women. However, when compared to the Women's Health Initiative Memory Study, estrogen exposures in many observational studies reflect hormone initiation at a younger age, closer to the time of menopause. One intriguing hypothesis is that hormone therapy initiated or used during an early critical window may reduce later Alzheimer incidence. Public health implications of this hypothesis are important, but current data are inadequate to decide the issue.

Henderson VW. · Department of Health Research, Stanford University, Stanford, California 94305-5405, USA. · Neurologist. · Pubmed #16688016 No free full text.

Abstract: BACKGROUND: Menopause is a normal milestone experienced annually by 2 million American women each year, and many women are concerned about the relation between menopause and health. Associated hormonal changes have the potential to influence neurologic disease, as do hormonal therapies prescribed for menopausal symptoms or other conditions. The objective of this article is to increase neurologists' awareness of the relation between menopause and neurologic illness. REVIEW SUMMARY: This was a focused review of 4 common neurologic disorders potentially influenced by menopause or by estrogen-containing hormone therapy: stroke, epilepsy, Parkinson disease, and Alzheimer disease. Hormonal effects are germane to each illness, although clinical implications are clearer for stroke and Alzheimer disease than for epilepsy and Parkinson disease. For women with epilepsy, few clinical data directly address the role of menopause or estrogen-containing hormone therapy on seizure frequency. Relevant clinical research findings on Parkinson disease are inconsistent and provide an inadequate basis for practice guidelines. There is clinical trial evidence that hormone therapy does not reduce stroke incidence and may increase risk of ischemic stroke; hormone therapy cannot be recommended for stroke prevention. The natural menopausal transition is not characterized by objective memory loss. There is clinical trial evidence that hormone therapy should not be used for the postmenopausal woman age 65 years or older for the preservation of cognitive skills, prevention of dementia, or treatment of dementia due to Alzheimer disease. Long-term cognitive consequences of short-term hormone therapy used by younger women for menopausal symptoms remains an important area of uncertainty. CONCLUSIONS: Increased awareness of hormonal influences on neurologic illness is important for the practicing neurologist.

Henderson VW. · Department of Health Research and Policy (Epidemiology), Stanford University, CA 94305, USA. · Neuroscience. · Pubmed #16310963 No free full text.

Abstract: Estrogen has the potential to influence brain processes implicated in Alzheimer's disease pathogenesis. With the loss of ovarian estrogen production after menopause, estrogen-containing hormone therapy might be expected to influence the risk of Alzheimer's disease. Observational data link use of hormone therapy to reductions in Alzheimer risk, but experimental evidence from the Women's Health Initiative Memory Study trial demonstrates that oral estrogen, with or without a progestin, increases the incidence of dementia for postmenopausal women age 65 years or older. Mechanisms of harm in this setting are unknown. Bias and unrecognized confounding in observational research are leading candidates for discrepant results between observational studies and the Women's Health Initiative Memory Study trial. Studies are also distinguished by differences in outcome measures, hormone therapy formulations, prevalence of menopausal symptoms among study participants, and participant age. Finally, Women's Health Initiative Memory Study findings may not generalize to estrogen use by relatively young women during the menopausal transition or early postmenopause, a class of women who were ineligible for the Women's Health Initiative Memory Study trial. In observational studies, hormone therapy exposure often included use by younger women for menopausal vasomotor symptoms. Although there is no clinical trial evidence that hormone therapy at any age protects against Alzheimer's disease, it remains to be determined whether the age at which hormone exposure occurs or the timing of hormone therapy initiation in relation to the menopause (the critical window hypothesis) modifies treatment outcomes on dementia risk.

Henderson VW. · Department of Health Research and Policy (Epidemiology), Stanford University, 259 Campus Drive, Stanford, CA 94305-5405, USA. · Minerva Ginecol. · Pubmed #16306863 No free full text.

Abstract: The cessation of ovarian estrogen production occurring around the time of menopause has the potential to influence central nervous system function, as well as a number of neurological disorders that affect women during midlife and old age, including memory loss and mild cognitive impairment, ischemic stroke, Parkinson's disease, and Alzheimer's disease. During midlife, there is observational evidence that episodic memory is not substantially affected by natural menopause or by use of estrogen-containing hormone therapy, but short-term clinical trial evidence suggests hormone therapy might benefit verbal memory after surgical menopause. Clinical trial data indicate that hormone therapy does not reduce, and may increase, stroke incidence. Parkinson's disease and Alzheimer's disease are the 2 most common neurodegenerative illnesses. Estrogen influences dopaminergic pathways within the central nervous system. However, available observational evidence is limited and inconclusive regarding any role of hormone therapy in influencing risk or symptoms of Parkinson's disease, a disorder of dopaminergic neurons. Finally, clinical trial data indicate that hormone therapy should not be initiated in the late postmenopause with the goal of improving memory, preventing cognitive decline, reducing dementia risk, or improving Alzheimer's disease symptoms. An important priority for clinical investigation is to determine whether hormone therapy used during the menopausal transition and early postmenopause has long-term effects on cognition or dementia risk. The critical window hypothesis as applied to Alzheimer's disease conjectures that effects of early hormone therapy might differ from those of hormone therapy initiated in the late postmenopause, but convincing evidence is yet to be obtained.

Pinkerton JV, Henderson VW. · Department of Obstetrics and Gynecology, University of Virginia Health System, Midlife Health Center, 2955 Ivy Road Suite 104, Charlottesville, VA 22903, USA. · Semin Reprod Med. · Pubmed #15852203 No free full text.

Abstract: Cognitive aging is associated with decreases in memory, attention, and visual/motor performance and skills. Dementia consists of loss of memory and other cognitive abilities, associated with social or occupational impairment. Potential neuroprotective effects of estrogen include lowering beta-amyloid, enhancing cholinergic function, promoting synaptic plasticity and nerve process growth, reducing oxidative stress, and enhancing brain glucose transport. Observational and longitudinal studies suggest that hormone therapy may attenuate age-associated cognitive impairment or decrease Alzheimer's disease but this has not been confirmed by randomized clinical trials. A critical window of time may exist around the menopause when hormone therapy may delay or decrease cognitive changes; however, hormone therapy initiated in the late postmenopause does not improve global cognition and may increase dementia risk.

Henderson VW. · Donald W Reynolda Center on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. · Expert Opin Pharmacother. · Pubmed #14996635 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of dementia. After menopause, circulating levels of oestrogens decline markedly and oestrogen influences several brain processes predicted to modify AD risk. For example, oestrogen reduces the formation of beta-amyloid, a biochemical hallmark of AD. Oestrogen effects on oxidative stress and some effects on inflammation and the cerebral vasculature might also be expected to ameliorate risk. However, AD pathogenesis is incompletely understood and other oestrogen actions could be deleterious. Limited clinical trial evidence suggests that oestrogen therapy, begun after the onset of AD symptoms, is without substantial benefit or harm. Observational studies have associated oestrogen-containing hormone therapy with reduced AD risk. However, in the Women's Health Initiative Memory Study - a randomised, placebo-controlled trial of women 65 - 79 years of age - oral oestrogen plus progestin doubled the rate of dementia, with heightened risk appearing soon after treatment was initiated. Based on current evidence, hormone therapy is thus not indicated for the prevention of AD. Discrepancies between observational studies and the Women's Health Initiative clinical trial may reflect biases and unrecognised confounding factors in observational reports. Other explanations for divergent findings should be considered in future research, including effects of unopposed oestrogen or different hormone therapy preparations and the intriguing theoretical possibility that effects of hormone therapy on AD risk may be modified by the timing of use (e.g., initiation during the menopausal transition or early postmenopause versus initiation during the late postmenopause).

Henderson VW. · Department of Neurology, University of Southern California School of Medicine, Los Angeles 90089, USA. · Novartis Found Symp. · Pubmed #10965513 No free full text.

Abstract: The decline in circulating oestrogen concentrations that occurs after the menopause has the potential to impact Alzheimer's disease and other forms of dementia. Relevant actions include neurotrophic and neuroprotective effects; effects on acetylcholine and other neurotransmitters; and effects on proteins implicated in Alzheimer's disease pathogenesis. Since 1990, 14 case-control and cohort studies have considered the relation between postmenopausal oestrogen therapy and Alzheimer's disease. Most, but not all, report that oestrogen therapy is associated with a reduced Alzheimer risk of approximately one-half. Almost no epidemiological data address the potential link between oestrogen and other forms of dementia. Several small interventional trials have considered whether oestrogen might improve cognitive function of women with Alzheimer's disease. Data, however, are limited, and there is no compelling evidence that the short-term use of oestrogen monotherapy has a substantial impact on dementia symptoms. In summary, the use of oestrogen to reduce Alzheimer risk is biologically credible, and the preponderance of epidemiological evidence suggests that oestrogen therapy is indeed protective. This potentially important role of oestrogens for the primary prevention of Alzheimer's disease remains to be verified through well-designed randomized controlled trials.

Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, Ensrud K, Grady D. · Department of Psychiatry, University of California, San Francisco, Box 181, 4150 Clement St., San Francisco, CA 94121, USA. · Am J Psychiatry. · Pubmed #15800139 links to  free full text

Abstract: OBJECTIVE: This investigation examined whether raloxifene, a selective estrogen receptor modulator, affects the risk for Alzheimer's disease. METHOD: The Multiple Outcomes of Raloxifene Evaluation was a randomized, placebo-controlled trial among postmenopausal women with osteoporosis. The effect of raloxifene (60 or 120 mg/day) on vertebral fractures was the primary outcome. Development of mild cognitive impairment and dementia was a secondary outcome. Women were given clinical and cognitive evaluations at baseline and annually. After 3 years, among the 5,386 women enrolled at participating sites, those who had clinical symptoms of dementia or scored in the lowest 10th percentile on cognitive screening were evaluated by a blinded dementia specialist and had brain scans and laboratory tests to evaluate dementia etiology. Dementia was diagnosed by a blinded adjudication committee. RESULTS: Of the 5,386 women, 5,153 (95.7%) were classified as cognitively normal, 181 (3.4%) had mild cognitive impairment, and 52 (1.0%) had dementia, 36 with Alzheimer's disease. Compared to those taking placebo, women receiving 120 mg/day of raloxifene had a 33% lower risk of mild cognitive impairment (relative risk, 0.67; 95% confidence interval [CI], 0.46-0.98) and somewhat lower risks of Alzheimer's disease (relative risk=0.52, 95% CI=0.22-1.21) and any cognitive impairment (relative risk=0.73, 95% CI=0.53-1.01). Risks of mild cognitive impairment, Alzheimer's disease, and any impairment were not significantly different in the group taking 60 mg/day of raloxifene. CONCLUSIONS: Raloxifene at a dose of 120 mg/day, but not 60 mg/day, resulted in reduced risk of cognitive impairment in postmenopausal women.

Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, McCleary CA, Klein RA, Hake AM, Farlow MR. · Department of Neurology, University of Southern California, Los Angeles 90089, USA. · Neurology. · Pubmed #10668686 No free full text.

Abstract: BACKGROUND: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. METHODS: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. RESULTS: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. CONCLUSION: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

Henderson VW. · Departments of Health Research and Policy (Epidemiology) and of Neurology and Neurological Sciences, Stanford University, 259 Campus Drive, Stanford, CA 94305-5405, USA. · Menopause Int. · Pubmed #19237622 No free full text.

Abstract: Episodic memory is affected by cognitive ageing, and memory impairment beyond that expected on the basis of usual ageing may be an early indicator of Alzheimer's disease. Although memory complaints are common in midlife, it is reassuring that the natural menopausal transition is unaccompanied by objective memory loss. Less is known about memory after surgical menopause. Estrogen-containing hormone therapy initiated during the late postmenopause increases dementia risk and does not improve memory. It is unclear whether hormone use during the menopausal transition or early postmenopause affects Alzheimer risk. Observational studies imply a protective association consistent with the so-called critical window hypothesis, but these findings could be biased. Clinical practice implications are presented.

Kraut MA, Cherry B, Pitcock JA, Anand R, Li J, Vestal L, Henderson VW, Hart J. · Department of Radiology, Division of Neuroradiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Cogn Behav Neurol. · Pubmed #17356346 No free full text.

Abstract: BACKGROUND: Between 10% and 15% of patients with the amnestic variety of Mild Cognitive Impairment (MCI) convert to Alzheimer disease (AD) per year. OBJECTIVE: Characterize cognitive markers that may herald conversion from MCI to AD and directly assess semantic memory in patients meeting criteria for amnestic MCI. DESIGN: Thirty-five amnestic MCI patients and 121 healthy aging controls enrolled at an Alzheimer Disease Center received a battery of standard neuropsychologic tests, and the Semantic Object Retrieval Test (SORT), a test that we have developed for the assessment of semantic memory and subsequent name production, and that has been shown to be able to differentiate between normals and patients with AD. RESULTS: On the basis of normative data from the SORT, the MCI subjects could be divided into 2 groups: 10 patients (29%) with a significant semantic impairment (SI+) and 25 without a semantic memory deficit (SI-). There was a significant correlation between all SORT variables and performance on the Boston Naming Test. In this MCI population, significantly impaired SORT performance was associated with a relative decrease in performance on tests of frontal lobe functions, although disruption of thalamic-related processes cannot be excluded as an etiology for semantic memory impairment. CONCLUSIONS: The SORT is a specific test of semantic memory, and is a sensitive measure of semantic memory deficits in patients who otherwise meet criteria for amnestic MCI. Using this specific assessment tool, a significant number of MCI patients were found to have semantic memory deficits. As these patients may be early in the course of possible progression toward dementia, the SORT or other tests of semantic memory may provide important diagnostic or prognostic information in patients with MCI.

Kraut MA, Cherry B, Pitcock JA, Vestal L, Henderson VW, Hart J. · Department of Radiology, Division of Neuroradiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Cogn Behav Neurol. · Pubmed #17159612 No free full text.

Abstract: OBJECTIVE: To characterize performance on a test of semantic object retrieval (Semantic Object Retrieval Test-SORT) in healthy, elderly subjects and patients with Alzheimer disease (AD). BACKGROUND: Although the initial presentation of patients with AD often reflects impairment in delayed recall for verbally encoded memory, common complaints of patients with early AD are actually related to semantic memory impairment. DESIGN: Thirty-eight AD patients and 121 healthy aging controls enrolled in an Alzheimer's Disease Center received a battery of standard neuropsychologic tests including the SORT. RESULTS: Compared with normal controls, AD patients had SORT memory impairments with significantly more false positive memory errors, fewer correctly produced names, and more substitutions in the name production aspect of the test. SORT had robust test-retest reliability in normals. CONCLUSIONS: The SORT task provides a direct, specific assessment of semantic memory, and has now been administered to 121 healthy, aging controls for normative ranges of performance, and to AD patients. The task detected semantic memory deficits in approximately half of patients with mild-moderate AD, which is comparable to other studies assessing semantic deficits in AD with less specific measures.

Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA, Anonymous00054. · Stanford University School of Medicine, 259 Campus Drive, HRP Redwood Building, Stanford University, Stanford, CA 94305-5405, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #15608005 links to  free full text

Abstract: We examined the relation between oestrogen containing hormone therapy (HT) used for more than 6 months and Alzheimer's disease (AD) risk in 971 postmenopausal women (426 AD patients, 545 relatives without dementia). There was a significant interaction between age and HT use on AD risk (p = 0.03). In stratified analyses, a significant protective association was seen only in the youngest age tertile (50-63 years; odds ratio = 0.35, 95% confidence interval = 0.19 to 0.66). Results must be considered cautiously in light of recent clinical trial evidence that oestrogen plus progestin increases dementia incidence in older postmenopausal women. However, our observational findings are consistent with the view that HT may protect younger women from AD or reduce the risk of early onset forms of AD, or that HT used during the early postmenopause may reduce AD risk.

Hogervorst E, Bandelow S, Hart J, Henderson VW. · Department of Geriatrics, Donald W. Reynolds Center on Aging, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. · Int J Geriatr Psychiatry. · Pubmed #15352146 No free full text.

Abstract: BACKGROUND: Parallel versions of memory tasks are useful in clinical and research settings to reduce practice effects engendered by multiple administrations. We aimed to investigate the usefulness of three parallel versions of ten-item word list recall tasks administered by telephone. METHODS: A population based telephone survey of middle-aged and elderly residents of Bradley County, Arkansas was carried out as part of the Rural Aging and Memory Study (RAMS). Participants in the study were 1845 persons aged 40 to 95 years. Word lists included that used in the telephone interview of cognitive status (TICS) as a criterion standard and two newly developed lists. RESULTS: The mean age of participants was 61.05 (SD 12.44) years; 39.5% were over age 65. 78% of the participants had completed high school, 66% were women and 21% were African-American. There was no difference in demographic characteristics between groups receiving different word list versions, and performances on the three versions were equivalent for both immediate (mean 4.22, SD 1.53) and delayed (mean 2.35 SD 1.75) recall trials. The total memory score (immediate+delayed recall) was negatively associated with older age (beta = -0.41, 95%CI=-0.11 to -0.04), lower education (beta = 0.24, 95%CI = 0.36 to 0.51), male gender (beta = -0.18, 95%CI = -1.39 to -0.90) and African-American race (beta = -0.15, 95%CI = -1.41 to -0.82). CONCLUSIONS: The two RAMS word recall lists and the TICS word recall list can be used interchangeably in telephone assessment of memory of middle-aged and elderly persons. This finding is important for future studies where parallel versions of a word-list memory task are needed. (250 words).

Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J. · Department of Neurology, Alzheimer's Disease Center, University of California, Los Angeles, 710 Westwood Plaza, Room 2-238, Los Angeles, CA 90095-1769, USA. · Arch Neurol. · Pubmed #12633151 links to  free full text

Abstract: BACKGROUND: Imaging and postmortem studies suggest that frontal lobe white matter (FLWM) volume expands until about the age of 44.6 years and then declines. Postmortem evidence indicates that the structural integrity of myelin sheaths deteriorates during normal aging, especially in late myelinating regions such as the frontal lobes. OBJECTIVES: To assess the integrity of FLWM by magnetic resonance imaging and, thus, to provide an important index of brain aging and its relationship to Alzheimer disease (AD). DESIGN: Cross-sectional study. SETTING: Two metropolitan university hospitals and AD research centers. PARTICIPANTS: Two hundred fifty-two healthy adults (127 men and 125 women), aged 19 to 82 years, and 34 subjects with AD (16 men and 18 women), aged 59 to 85 years. MAIN OUTCOME MEASURE: Calculated transverse relaxation rate (R( 2)) of the FLWM (an indirect measure of the structural integrity of white matter). RESULTS: As expected from prior imaging data on FLWM volume, the quadratic function best represented the relationship between age and the FLWM R(2) (P<.001). In healthy individuals, the FLWM R(2) increased until the age of 38 years and then declined markedly with age. The R( 2) of subjects with AD was significantly lower than that of a group of healthy control subjects who were of similar age and sex (P<.001). CONCLUSIONS: The R(2) changes in white matter suggest that the healthy adult brain is in a constant state of change, roughly defined as periods of maturation continuing into middle age followed by progressive loss of myelin integrity. Clinically diagnosed AD is associated with more severe myelin breakdown. Noninvasive measures, such as the determination of the R(2), may have the potential to track prospectively the trajectory of deteriorating white matter integrity during normal aging and the development of AD and, thus, may be a useful marker for medication development aimed at the prevention of AD.

Cherry BJ, Buckwalter JG, Henderson VW. · Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA · Neuropsychologia. · Pubmed #11900735 No free full text.

Abstract: It is suggested that Alzheimer's disease (AD) patients are able to recall more items on the digit span task than on immediate free recall from a supraspan word list. Two experiments were undertaken to verify this assertion and to understand the basis of the putative span/supraspan discrepancy. The first experiment, involving 35 mildly or moderately demented AD patients, confirmed that digit span significantly exceeded immediate recall from a 10-item supraspan word list. Although digit span also exceeded supraspan recall in 38 elderly non-demented control subjects, the discrepancy was significantly greater within the AD group. In a second experiment, 19 AD cases and 20 controls were assessed with a word span task that used nouns matched by frequency and word length to nouns on the supraspan task. The magnitude of the span/supraspan discrepancy was reduced, indicating that part of the initial discrepancy was due to differences in stimulus items (digits versus common nouns). As before, AD subjects recalled more words on the span task than the supraspan task. However, in striking contrast, NC subjects recalled more words on the supraspan task, further indicating that AD patients are particularly impaired on supraspan recall. Using combined data from 106 subjects in both experiments, digit span performance correlated significantly with supraspan recall for NC but not AD subjects. Moreover, within the AD group the magnitude of the discrepancy was inversely related to a working memory measure derived from the backward digit span. The magnitude of the span/supraspan discrepancy correctly classified 88% of patients with mild dementia and 74% of controls. Results indicate that AD patients are specifically vulnerable to information overload inherent in the supraspan task, a view consistent with the perspective that AD is characterized by prominent disturbances in working memory.

Paganini-Hill A, Clark LJ, Henderson VW, Birge SJ. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. · J Am Geriatr Soc. · Pubmed #11527486 No free full text.

Abstract: OBJECTIVE: To test the hypothesis that performance on a clock-drawing test in a mailed survey to an older cohort is associated with known and potential risk and protective factors for Alzheimer's disease. DESIGN: The Leisure World Cohort Study is an ongoing study, begun in 1981, of nearly 14,000 older adults. In November 1992, the 8,406 living cohort members were mailed a follow-up questionnaire. SETTING: Leisure World Laguna Hills, a southern California retirement community. PARTICIPANTS: The study population is a predominantly white, well-educated, upper-middle-class community; approximately two-thirds are women. Data from 4,843 cohort members (mean age 80 years; range 52-101) were analyzed. MEASUREMENTS: The questionnaire included a clock-drawing task: a predrawn circle 3 1/4 inches (8.3 cm) in diameter was provided with instructions "In the circle below, draw in the numbers as on a clock face. Make no erasures." Clocks were scored on 7 items: all numbers 1-12 present without adding extra or omitting numbers, sequencing of numbers, position of numbers, orientation of numbers to circle, consistent number style (either Arabic or Roman), tilt of numbers, and superfluous marks. A total clock score was calculated by summing the number of correct individual items (0-7). We also classified individuals as cognitively impaired by a previously suggested method: individuals were affected if they did not have three numbers drawn in the upper left quadrant of the clock face. RESULTS: Ninety percent or more of the participants across all ages placed the numbers 1 to 12 on their clocks without omissions or additions; 35% completed the clock drawing without error. The mean total clock scores decreased with each successive 5-year age group in both men and women. Regression analysis indicated a significant effect for age (b = -0.15, P <.0001), education (b = 0.05, P =.0001), smoking (b = 0.13, P =.03), and female gender (b = -0.05, P =.05) and a marginally significant effect of nonrheumatoid arthritis (b = 0.05, P =.07) on total clock score. No other measured variable had a significant effect. Cognitively impaired individuals were more likely to be female and older. After adjusting for age and gender, they were also more likely to be hypertensive and to have taken blood pressure medication and less likely to be college graduates, have glaucoma or arthritis, and to have taken vitamin supplements. CONCLUSION: The clock-drawing task is an appealing measure of cognitive function for large epidemiological studies because it is a simple, self-administered test that is easily adapted to mail surveys and correlates with more-detailed and more-time-consuming cognitive screens. Although it is relatively free of influence by language, cultural, or ethnic factors, our study shows that even in a highly educated population, clock drawing is influenced by educational level and other known risk factors for Alzheimer's disease. Thus a clock-drawing task may help predict cognitive frailty and future disability in older people. Such determination can direct high-risk individuals to earlier diagnosis, potential therapies, and better management.

MacDonald MC, Almor A, Henderson VW, Kempler D, Andersen ES. · University of Southern California, Los Angeles 90089-2520, USA. · Brain Lang. · Pubmed #11412013 No free full text.

Abstract: Studies of language impairments in patients with Alzheimer's disease have often assumed that impairments in linguistic working memory underlie comprehension deficits. Assessment of this hypothesis has been hindered both by vagueness of key terms such as "working memory" and by limitations of available working memory tasks, in that many such tasks either seem to have little relationship to language comprehension or are too confusing or difficult for Alzheimer's patients. Four experiments investigated the usefulness of digit ordering, a new task assessing linguistic working memory and/or language processing skill, in normal adults and patients with probable Alzheimer's disease. The digit ordering task was shown to be strongly correlated with the degree of dementia in Alzheimer's patients. The task correlated with measures of language processing on which patients and normal controls performed differently. The results are interpreted as indicating that linguistic representations, linguistic processing, and linguistic working memory are intertwined, such that a deficit of one (e.g., working memory) cannot be said to "cause" a deficit in the other. The implications of this approach are explored in terms of task demands in comprehension and memory measures, and interpretation of previous results in the literature.

Smith CA, Henderson VW, McCleary CA, Murdock GA, Buckwalter JG. · Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA. · J Clin Exp Neuropsychol. · Pubmed #10923053 No free full text.

Abstract: The relation between anosognosia and dementia severity in Alzheimer's disease (AD) has been unclear. We constructed a measure that quantified the difference between the perceptions of deficits of patients with AD (n = 23) and ratings from a knowledgeable informant as a measure of anosognosia. There was no correlation between dementia severity and anosognosia. However, dementia severity was positively correlated with the degree of anosognosia after controlling for depressive symptomatology (p =.03). Post-hoc analyses, also controlling for depressive symptoms, indicated that higher levels of anosognosia were associated with lower performance on specific cognitive tasks. These results suggest depressive symptoms may confound the relationship between anosognosia and dementia severity.