Alzheimer Disease: Corey-Bloom J

Yaari R, Corey-Bloom J. · Department of Neurosciences and the Alzheimer's Disease Research Center, University of California, San Diego, La Jolla, California 92161, USA. · Semin Neurol. · Pubmed #17226739 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Currently, 4.5 million individuals in the United States are estimated to have AD, and that number is projected to increase to at least 14 million by the year 2050. AD is a major cause of disability and mortality, and its impact on health care costs, including direct and indirect medical and social service costs, is estimated to be greater than $100 billion per year. AD typically presents with an insidious decline in memory that progresses to affect language, visuospatial perception, calculations, and executive functioning. Behavioral and psychiatric symptoms are also frequent in AD. Diagnosis is determined clinically, as there is currently no laboratory test to confirm AD in life. The neuropathologic hallmarks of AD are neuritic plaques and neurofibrillary tangles. Currently available medical therapies have demonstrated modest benefits but likely do not alter disease progression. Caregivers play a large role in managing the patient and should be encouraged to seek out adult day care centers, home health services, respite care, and additional social support.

Polich J, Corey-Bloom J. · Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. · Curr Alzheimer Res. · Pubmed #16375655 No free full text.

Abstract: Early stage Alzheimer disease patients and matched elderly unaffected controls (n = 16/group) were evaluated with the P300 event-related brain potential (ERP). All subjects performed four oddball tasks that varied systematically in task difficulty and were each presented in the auditory and visual modalities. P300 amplitude was smaller and peak latency longer for the Alzheimer patients compared to elderly control subjects across tasks and modalities. P300 differences between Alzheimer patients and controls were largest for the relatively easy tasks, with little influence of stimulus modality observed. The results suggest that the P300 brain potential is sensitive to Alzheimer's disease processes during its early stages, and that easily performed stimulus discrimination tasks are the clinically most useful. Theoretical and practical implications are reviewed.

Corey-Bloom J. · Department of Neurosciences, University of California, La Jolla, California, USA. · Int J Clin Pract. · Pubmed #12723727 No free full text.

Abstract: Dementia has the potential to become a major public health concern during this century due to increasing life expectancy and growth in the ageing population. The commonest types of dementia include Alzheimer's disease (AD), vascular dementia (VaD), and dementia with cerebrovascular components. Galantamine is the only acetylcholinesterase inhibitor that exhibits a dual mechanism of action--inhibition of acetylcholinesterase and nicotinic receptor modulation. Clinical studies demonstrate the efficacy and safety of galantamine in patients with AD, VaD, and AD with cerebrovascular components. Galantamine shows beneficial effects on cognition, global function, activities of daily living and behaviour. Adverse events observed with galantamine use are generally mild to moderate in severity, transient and gastrointestinal in nature. The dose of galantamine should be escalated to 16 and 24 mg/day at four-week intervals to achieve maximal tolerability. Because of its unique mechanism of action, galantamine may have potential benefits over conventional enzyme-inhibiting agents.

Corey-Bloom J. · Neurology Service, UCSD School of Medicine, San Diego, California 92161, USA. · Int Psychogeriatr. · Pubmed #12636180 No free full text.

Abstract: Cognitive decline, commonly first recognized as memory impairment, is a typical feature of Alzheimer's disease (AD). Neuropathological changes in the cerebral cortex and limbic system lead to deficits in learning, memory, language, and visuospatial skills. The precise nature of cognitive dysfunction reflects the distribution of pathological changes in AD. These will vary along the disease severity continuum and may also depend on where the disease sits in the spectrum of dementia. For example, AD-related disorders such as Lewy body dementia (LBD) and Parkinson's disease dementia (PDD) also show symptoms of cognitive decline and share several pathological features, including degeneration of cortical cholinergic and striatal dopaminergic neurons. In vascular dementia (VaD), there is often an unequal distribution of cognitive deficit, with severe impairment in some functions and relative sparing of others. Cholinesterase (ChE) inhibitors, which help restore acetylcholine levels in the brain, are licensed for the symptomatic treatment of AD and have shown additional benefit in related dementias. Physiological correlates of cholinergic function/dysfunction in the brain include regional cerebral blood flow, glucose metabolism, and cerebrospinal fluid levels of ChE enzymes. These variables represent valuable markers of the clinical efficacy of ChE inhibitors. However, direct assessment of cognitive improvement, stabilization or decline is usually considered the key efficacy parameter in clinical studies of ChE inhibitors in AD and related dementias. Large-scale, placebo-controlled clinical studies of ChE inhibitors have demonstrated efficacy in treating the cognitive impairments associated with AD. Randomized comparative studies of ChE inhibitors are now under way to directly compare symptomatic efficacy and effects on disease progression. Clinical trial data of the cognitive effects of ChE inhibitors in AD, LBD, PDD, and VaD are discussed in detail in this article. The benefits of long-term treatment on symptomatic improvement in cognition and further potential disease-modifying effects are highlighted.

Cooke JR, Loredo JS, Liu L, Marler M, Corey-Bloom J, Fiorentino L, Harrison T, Ancoli-Israel S. · Department of Medicine, University of California, San Diego, California, USA. · Drugs Aging. · Pubmed #16872233 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Studies suggest that some acetylcholinesterase inhibitors (AChEIs) increase rapid eye movement (REM) sleep and nightmares in patients with Alzheimer's disease (AD) but few have studied their effect on other sleep parameters. The objective of this study was to examine differences in sleep architecture in AD patients taking different AChEIs. METHODS: 76 participants (51 men, 25 women) [mean age = 78.2 years; SD = 7.7] with mild to moderate AD underwent medication history screening as well as polysomnography to determine the percentage of each sleep stage. Participants were divided into groups based on AChEI used: donepezil (n = 41), galantamine (n = 15), rivastigmine (n = 8) or no AChEI (n = 12). General univariate linear model analyses were performed. RESULTS: AChEI therapy had a significant effect on the percentage of stage 1 (p = 0.01) and stage 2 (p = 0.03) sleep. Patients in the donepezil group had a significantly lower percentage of stage 1 sleep than patients in the galantamine group (mean = 17.3%, SD = 11.7 vs 29.2%, SD = 15.0, respectively; p = 0.01), but there was no significant difference between the donepezil group and the rivastigmine (mean = 25.0%, SD = 12.3) or no AChEI groups (mean = 27.6%, SD = 17.7) in this respect. No significant differences in percentage of stage 1 between other groups were seen. Patients in the donepezil group also had a significantly higher percentage of stage 2 sleep than patients in the no AChEI group (mean = 63.6%, SD = 14.4 vs 51.4%, SD = 16.9, respectively; p = 0.04), but there was no significant difference between the donepezil group and either the galantamine group (mean = 56.5%, SD = 8.7) or the rivastigmine group (mean = 59.9%, SD = 8.4). There were no significant differences between groups in terms of percentage REM sleep or other sleep parameters. CONCLUSION: Subgroups of AD patients (classified according to AChEI treatment) in this study differed with respect to the amount of stage 1 and stage 2 sleep experienced, with the donepezil-treated group having the lowest percentage of stage 1 sleep and the highest percentage of stage 2 sleep. There was no significant difference in the amount of REM sleep between the groups. Our data suggest that sleep architecture may be affected by the use of donepezil in patients with AD. Although not elicited in this study because of the small sample size, there may be a class effect of AChEIs on sleep architecture. Double-blind, placebo-controlled studies are needed to better understand causality and the effect of each AChEI on sleep architecture in patients with AD.

Brodaty H, Corey-Bloom J, Potocnik FC, Truyen L, Gold M, Damaraju CR. · University of New South Wales, Sydney, Australia. · Dement Geriatr Cogn Disord. · Pubmed #15990426 No free full text.

Abstract: The primary objective of this study was to evaluate the efficacy and tolerability of a flexible dosing regimen (16 or 24 mg/day) of galantamine prolonged-release capsule (PRC) compared with placebo in subjects with mild to moderate Alzheimer's disease (AD). This phase III, double-blind, placebo- and active-controlled, parallel-group trial randomized 971 patients to treatment for 6 months. Efficacy endpoints included change in the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog/11), Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Neuropsychiatric Inventory (NPI) scores. Galantamine was associated with significant improvements in the ADAS-cog/11 score but not in the CIBIC-plus or NPI scores. Galantamine PRC was associated with significant improvement in ADCS-ADL scores. Galantamine PRC had similar tolerability and safety profiles compared with twice-daily galantamine, and when administered as a once-daily flexible dosing regimen of 16 or 24 mg/day, was demonstrated to be as safe and effective for the treatment of mild to moderate AD.

Lineweaver TT, Salmon DP, Bondi MW, Corey-Bloom J. · Department of Psychology, Butler University, Indianapolis, Indiana 46208, USA. · J Int Neuropsychol Soc. · Pubmed #15686606 No free full text.

Abstract: The ability to spatially rotate a mental image was compared in patients with Alzheimer's disease (AD; n = 18) and patients with Huntington's disease (HD; n = 18). Compared to their respective age-matched normal control (NC) group, the speed, but not the accuracy, of mental rotation abnormally decreased with increasing angle of orientation for patients with HD. In contrast, the accuracy, but not the speed, of rotation abnormally decreased with increasing angle of orientation for patients with AD. Additional analyses showed that these unique patterns of performance were not attributable to different speed/accuracy trade-off sensitivities. This double dissociation suggests that the distinct brain regions affected in the two diseases differentially contribute to speed and accuracy of mental rotation. Specifically, the slowing exhibited by HD patients may be mediated by damage to the basal ganglia, whereas the spatial manipulation deficit of AD patients may reflect pathology in parietal and temporal lobe association cortices important for visuospatial processing.

Ancoli-Israel S, Gehrman P, Martin JL, Shochat T, Marler M, Corey-Bloom J, Levi L. · Department of Psychiatry 116A, University of California, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · Behav Sleep Med. · Pubmed #15600135 No free full text.

Abstract: Sleep in the nursing home environment is extremely fragmented, possibly in part as a result of decreased light exposure. This study examined the effect of light on sleep and circadian activity rhythms in patients with probable or possible Alzheimer's disease. Results showed that both morning and evening bright light resulted in more consolidated sleep at night, as measured with wrist actigraphy. Evening light also increased the quality of the circadian activity rhythm, as measured by a 5-parameter extended cosine model (amplitude, acrophase, nadir, slope of the curve, and relative width of the peak and trough). Increasing light exposure throughout the day and evening is likely to have the most beneficial effect on sleep and on circadian rhythms in patients with dementia. It would behoove nursing homes to consider increasing ambient light in multipurpose rooms where patients often spend much of their days.

Bondi MW, Houston WS, Salmon DP, Corey-Bloom J, Katzman R, Thal LJ, Delis DC. · VA San Diego Healthcare System, San Diego, California 92161, USA. · J Int Neuropsychol Soc. · Pubmed #12901784 links to  free full text

Abstract: The profiles of neuropsychological deficits associated with Alzheimer's disease (AD) in Young-Old (M age and 70) and Very-Old (M age > 80) patients were compared, along with possible modifying effects of apolipoprotein E (APOE) genotype on these profiles. A comprehensive battery of neuropsychological tests was administered to the two AD patient groups (Young-Old: n = 33; Very-Old: n = 48) and their respective age-matched normal control (NC) groups who remained free of dementia on follow-up examinations over a 1 to 10 year period (Young-Old: n = 43; Very-Old: n = 36). AD and NC groups did not differ in education levels or gender distributions. Young-Old AD and Very-Old AD groups were comparable in education, gender, dementia severity, and disease duration. Results showed that both AD groups achieved comparable raw scores on all the neuropsychological measures. However, when scores were standardized on the basis of performance of their respective NC groups (i.e., age-corrected z scores), Very-Old AD patients significantly outperformed Young-Old AD patients on tests of executive functions, visuospatial skills, and delayed memory. Furthermore, the relationship between age and memory and executive function deficits in AD was modified by APOE genotype. These data suggest that the profile of neuropsychological deficits associated with AD in the Very-Old lacks the disproportionate saliency of episodic memory and executive function deficits typical of the Young-Old.

Ancoli-Israel S, Martin JL, Gehrman P, Shochat T, Corey-Bloom J, Marler M, Nolan S, Levi L. · Department of Psychiatry, University of California, San Diego, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA. · Am J Geriatr Psychiatry. · Pubmed #12611749 No free full text.

Abstract: OBJECTIVE: Preliminary data suggest that morning bright light might improve symptoms of agitation, a serious problem in patients with dementia. The authors expand on an earlier pilot study by evaluating the effect of bright light therapy on agitated behavior in a large sample of patients with severe dementia. METHODS: Ninety-two patients were randomly assigned to morning bright light, morning dim red light, or evening bright light. Agitation was rated by research staff who observed the patients every 15 minutes throughout the treatment period and by caregivers at one time-point before and one time-point after treatment. RESULTS: Morning bright light delayed the acrophase of the agitation rhythm by over 1.5 hours. Bright light was associated with improved caregivers' ratings but had little effect on observational ratings of agitation. CONCLUSION: Although the result that light shifted the peak of the agitated behavior might be generalizable to patients with milder forms of AD, the fact that agitation was not ameliorated might not be. Because the suprachiasmatic nucleus (SCN) of patients with severe AD is likely to be more degenerated, and the circadian activity rhythms deteriorate as the disease progresses, it is still possible that patients with more intact SCNs, that is, patients with mild or moderate AD, might benefit from light treatment even more than those with severe AD.

Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. · Department of Psychiatry, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. · Am J Geriatr Psychiatry. · Pubmed #19155748 No free full text.

Abstract: OBJECTIVES: Patients with Alzheimer dementia often display both agitated behavior and poor sleep. Given that the disease is often associated with low endogenous levels of melatonin, exogenous melatonin administration may lead to improvements in sleep and agitation. DESIGN: Randomized, placebo-controlled study. SETTING: Nursing homes in San Diego, CA, metropolitan area. PARTICIPANTS: Subjects were patients with probable Alzheimer disease. INTERVENTION: Melatonin (8.5 mg immediate release and 1.5 mg sustained release) (N = 24) or placebo (N = 17) administered at 10:00 P.M. for 10 consecutive nights. The protocol consisted of baseline (3 days), treatment (10 days), and posttreatment (5 days) phases. MEASUREMENTS: Sleep was measured continuously using actigraphy. Agitation was rated using both the Agitated Behavior Rating Scale and the Cohen-Mansfield Agitation Inventory. Treatment effects were examined both across the 24-hr day and separately by nursing shift. RESULTS: There were no significant effects of melatonin, compared with placebo, on sleep, circadian rhythms, or agitation. CONCLUSION:: This study failed to find a beneficial effect of exogenous melatonin, consistent with a number of other studies. The lack of efficacy may be related to the absence of a true treatment effect or to the superphysiologic dose of melatonin used.

Ancoli-Israel S, Palmer BW, Cooke JR, Corey-Bloom J, Fiorentino L, Natarajan L, Liu L, Ayalon L, He F, Loredo JS. · Departments of Psychiatry, University of California, San Diego, La Jolla, California, USA. · J Am Geriatr Soc. · Pubmed #18795985 No free full text.

Abstract: OBJECTIVES: To examine whether treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) in patients with Alzheimer's disease (AD) results in better cognitive function. DESIGN: Randomized double-blind placebo-controlled trial. Participants were randomized to therapeutic CPAP for 6 weeks or placebo CPAP for 3 weeks followed by therapeutic CPAP for 3 weeks. SETTING: General clinical research center. PARTICIPANTS: Fifty-two men and women with mild to moderate AD and OSA. INTERVENTION: CPAP. MEASUREMENTS: A complete neuropsychological test battery was administered before treatment and at 3 and at 6 weeks. RESULTS: A comparison of subjects randomized to 3 weeks of therapeutic versus placebo CPAP suggested no significant improvements in cognition. A comparison of pre- and posttreatment neuropsychological test scores after 3 weeks of therapeutic CPAP in both groups showed a significant improvement in cognition. The study was underpowered to make definitive statements about improvements within specific cognitive constructs, although exploratory post hoc examination of change scores for individual tests suggested improvements in episodic verbal learning and memory and some aspects of executive functioning such as cognitive flexibility and mental processing speed. CONCLUSION: OSA may aggravate cognitive dysfunction in dementia and thus may be a reversible cause of cognitive loss in patients with AD. OSA treatment seems to improve some cognitive functioning. Clinicians who care for patients with AD should consider implementing CPAP treatment when OSA is present.

Fine EM, Delis DC, Wetter SR, Jacobson MW, Hamilton JM, Peavy G, Goldstein J, McDonald C, Corey-Bloom J, Bondi MW, Salmon DP. · Psychology Service (116B)-Delis Lab, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · J Clin Exp Neuropsychol. · Pubmed #18415887 No free full text.

Abstract: The present study compared the performance of individuals with Huntington's disease (HD) and Alzheimer's disease (AD) on three types of California Verbal Learning Test-Second Edition (CVLT-II) recognition discriminability indices (RDI): Source, Novel, and Total. The HD and AD groups did not differ significantly on Source RDI (all 16 targets versus the 16 previously presented, List B, distractors). However, HD patients performed significantly better than AD patients on Total RDI (all 16 targets versus all 32 distractors) and Novel RDI (all 16 targets versus 16 new distractors). Implications of these findings on the differentiation of the memory disorders associated with HD and AD are discussed.

Doody RS, Corey-Bloom J, Zhang R, Li H, Ieni J, Schindler R. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Drugs Aging. · Pubmed #18257603 No free full text.

Abstract: BACKGROUND: Donepezil is licensed for the treatment of mild-to-moderate Alzheimer's disease (AD) at doses of 5-10 mg/day and has recently been approved in the US for severe AD. Multiple studies have suggested that donepezil 10 mg/day provides additional cognitive and functional benefits over the 5 mg/day dose. Higher doses of donepezil, if safe and well tolerated, might provide further benefits for patients with AD. OBJECTIVE: To evaluate the safety and tolerability of donepezil at doses of 15 and 20 mg/day. METHOD: A 24-week, randomized, double-blind, placebo-controlled, pilot study conducted at two investigational sites in the US. Enrolled patients (male and female; aged 50-86 years) had a diagnosis of probable AD at the mild-to-moderate stage (Mini-Mental State Examination [MMSE] score 10-26). All patients had been treated with donepezil 10 mg/day for 12-30 months prior to enrolment. Patients (n = 31) were randomized 1 : 1 to receive either a standard dose of donepezil (donepezil 10 mg/day plus placebo 5 mg/day for weeks 1-12; donepezil 10 mg/day plus placebo 10 mg/day for weeks 13-24) or a higher dose of donepezil (donepezil 15 mg/day for weeks 1-12; donepezil 20 mg/day for weeks 13-24). Primary outcome measures were tolerability (as determined by monitoring of discontinuations, dose modifications and adverse events) and safety (as determined by adverse event monitoring, physical examinations, clinical laboratory tests and ECGs). Psychometric measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog], MMSE and Clinician's Interview-Based Impression of Change with caregiver information [CIBIC+]) and pharmacokinetic/pharmacodynamic parameters were secondary outcomes. RESULTS: No patients withdrew from the study and there were no serious adverse events or deaths. By week 24, 15 of 16 patients in the higher-dose group tolerated the maximum 20 mg/day dose; one patient had a permanent dose reduction to donepezil 15 mg/day. In the standard-dose group, 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study; one patient had a permanent dose reduction to donepezil 10 mg/day plus placebo 5 mg/day. Temporary dose reductions occurred in two patients (one from each group). Adverse events reported were as expected for donepezil and were all mild to moderate in intensity. Adverse events considered to be possibly or probably related to treatment were reported for three patients in the standard-dose group and six patients in the higher-dose group. One patient in the higher-dose group had weight loss reported as possibly or probably treatment related. Mean changes on ECGs were not clinically significant in either group, and the incidence of bradycardia was comparable. No treatment difference on any of the psychometric measures was observed between the groups. Pharmacokinetic analyses showed that an increased donepezil dose was associated with an increase in donepezil plasma concentrations from baseline. CONCLUSION: In this small pilot study of patients with mild-to-moderate AD already stabilized on donepezil 10 mg/day, doses of 15 and 20 mg/day of donepezil appeared safe and well tolerated. These results justify initiation of larger clinical trials designed to investigate the efficacy and safety of doses of donepezil higher than 10 mg/day in patients with AD.

Cooke JR, Liu L, Natarajan L, He F, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, Greenfield D, Ancoli-Israel S. · Department of Medicine, University of California, San Diego, Veterans Affairs San Diego Healthcare System, CA, USA. · Behav Sleep Med. · Pubmed #17083302 No free full text.

Abstract: Patients with Alzheimer's disease (AD) commonly have poor sleep and a high reported incidence of sleep-disordered breathing (SDB). This study examined how the presence of SDB affected sleep stages in AD patients. Sixty-six volunteers with mild - moderate AD underwent home polysomnography. Results showed that patients with SDB spent less of the night in REM sleep than those with no SDB, but there were no differences in other sleep stages. The findings suggest that the decreased amount of REM sleep may be due to the presence of AD and SDB. Treating these patients' SDB may increase their amount of REM sleep, which may result in improved daytime functioning. Controlled trials of SDB treatment in AD are needed to answer this question.

Chong MS, Ayalon L, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, Liu L, Ancoli-Israel S. · Department of Psychiatry, Univeristy of California at San Diego, San Diego, CA 92161, USA. · J Am Geriatr Soc. · Pubmed #16696743 No free full text.

Abstract: OBJECTIVES: Studies have reported that 33% to 70% of patients with Alzheimer's disease (AD) have sleep-disordered breathing (SDB). Continuous positive airway pressure (CPAP) treatment has been shown to reduce daytime sleepiness and improve health-related quality of life in nondemented older people with SDB. The effect of therapeutic CPAP treatment on daytime sleepiness in patients with mild-moderate AD with SDB was assessed. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Patients' home and the University of California San Diego, General Clinical Research Center, J. Christian Gillin Laboratory of Sleep and Chronobiology. PARTICIPANTS: Thirty-nine community-dwelling elderly patients with mild-moderate probable AD with SDB. INTERVENTION: Patients were randomly assigned to receive 6 weeks of therapeutic CPAP or 3 weeks of sham CPAP followed by 3 weeks of therapeutic CPAP. MEASUREMENTS: Epworth Sleepiness Scale (ESS) was administered at baseline, 3 weeks, and 6 weeks. Changes in daytime sleepiness in subjects who received optimal therapeutic CPAP were compared with changes in the sham CPAP group. RESULTS: Within the therapeutic CPAP group, ESS scores were reduced from 8.89 during baseline to 6.56 after 3 weeks of treatment (P=.04) and to 5.53 after 6 weeks of treatment (P=.004). In the sham CPAP group, there was no significant difference after 3 weeks of sham CPAP but a significant decrease from 7.68 to 6.47 (P=.01) after 3 weeks of therapeutic CPAP. CONCLUSION: These data provide evidence of the effectiveness of CPAP in reducing subjective daytime sleepiness in patients with AD with SDB.

Ayalon L, Ancoli-Israel S, Stepnowsky C, Marler M, Palmer BW, Liu L, Loredo JS, Corey-Bloom J, Greenfield D, Cooke J. · Department of Psychiatry, University of California, San Diego, San Diego, CA, and Veterans Affairs San Diego Health Care System, San Diego, CA 92161, USA. · Am J Geriatr Psychiatry. · Pubmed #16473983 No free full text.

Abstract: OBJECTIVE: This analysis examined whether patients with Alzheimer disease (AD) tolerate continuous positive airway pressure (CPAP). METHOD: Thirty patients with AD were randomized to CPAP or sham CPAP and completed sleep, depression, and quality-of-life questionnaires. Participants could choose to continue treatment after the trial. RESULTS: Patients wore CPAP for 4.8 hours per night. More depressive symptoms were associated with worse adherence (rS=-0.37; N=30, p<0.04). Patients who continued using CPAP had fewer depressive symptoms (t [19]=2.45, p=0.02) and better adherence (t [19]=2.32, p=0.03) during the trial. CONCLUSION: Patients with AD with obstructive sleep apnea can tolerate CPAP. Adherence and long-term use may be more difficult among those patients with more depressive symptoms.

Tiraboschi P, Salmon DP, Hansen LA, Hofstetter RC, Thal LJ, Corey-Bloom J. · Dipartimento di Scienze Neurologiche, Ospedale Niguarda Ca' Granda, Milano, Italy. · Brain. · Pubmed #16401618 links to  free full text

Abstract: To determine which clinical feature(s) [among visual hallucinations (VH), extrapyramidal signs (EPS) and visuospatial impairment] in the earliest stages of disease best predicted a diagnosis of dementia with Lewy bodies (DLB) at autopsy, first-visit data of 23 pathologically proven DLB and 94 Alzheimer's disease cases were compared. There were no group differences with regard to age, gender, education or global severity of dementia at presentation (mean Mini-Mental State Examination: 24.0 versus 25.0, mean Dementia Rating Scale: 123.6 versus 125.7). DLB patients at initial presentation displayed an increased frequency of VH (P = 0.001), but not EPS (P = 0.3), compared to Alzheimer's disease patients. However, only a minority of DLB cases had either VH (22%), EPS (26%) or both (13%). In contrast, although not a core feature, visuospatial/constructional impairment was observed in most of the DLB cases (74%). Among clinical variables, presence/recent history of VH was the most specific to DLB (99%), and visuospatial impairment was the most sensitive (74%). As a result, VH at presentation were the best positive predictor of DLB at autopsy (positive predictive value: 83% versus 32% or less for all other variables), while lack of visuospatial impairment was the best negative predictor (negative predictive value: 90%). We conclude that the best model for differentiating DLB from Alzheimer's disease in the earliest stages of disease includes VH and visuospatial/constructional dysfunction, but not spontaneous EPS, as predictors. This suggests that clinical history plus a brief assessment of visuospatial function may be of the greatest value in correctly identifying DLB early during the course of disease.

Gehrman P, Marler M, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. · SDSU/UCSD Joint Doctoral Program in Clinical Psychology, Department of Psychiatry, University of California, San Diego, USA. · J Gerontol A Biol Sci Med Sci. · Pubmed #15528777 No free full text.

Abstract: BACKGROUND: Older adults with dementia often have disruptions in circadian rhythms, including disruptions of the rest-activity rhythm. These disruptions are a product of internal neuronal activity and external environmental influences, both of which are deficient in dementia. However, the consequences of disturbed rhythms are unknown. This study examined the relationship between rest-activity rhythms and death in patients with dementia. METHODS: The authors recruited 149 older adults with dementia (104 women; mean age, 84.1 years) from nursing homes. Activity was recorded with wrist actigraphs from each participant for 3 days. Survival was determined by examining public death records. Cox proportional hazards models were used to determine which aspects of rest-activity rhythms were related to survival. RESULTS: The timing of each participant's rest-activity rhythm compared with a sample of persons without dementia was related to survival, such that those who more closely resembled the persons without dementia lived longer. CONCLUSIONS: Although rest-activity rhythms as a whole were not related to survival, the timing of the rhythm was. Patients with dementia appear to develop an abnormal timing of their rhythms, which is predictive of shorter survival. It may be possible to intervene with these patients to correct the timing of their rhythms and possibly prolong their lives.

Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. · Dipartimento di Scienze Neurologiche, Ospedale Niguarda Ca' Granda, Milan, Italy. · Neurology. · Pubmed #15184601 No free full text.

Abstract: OBJECTIVE: To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Tiraboschi P, Hansen LA, Masliah E, Alford M, Thal LJ, Corey-Bloom J. · Dipartimento di Scienze Neurologiche, Ospedale Niguarda Ca' Granda, Milano, Italy. · Neurology. · Pubmed #15184600 No free full text.

Abstract: BACKGROUND: 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. OBJECTIVE: To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Tiraboschi P, Sabbagh MN, Hansen LA, Salmon DP, Merdes A, Gamst A, Masliah E, Alford M, Thal LJ, Corey-Bloom J. · Dipartimento di Scienze Neurologiche, Ospedale Niguarda Ca' Granda, Milan, Italy. · Neurology. · Pubmed #15079014 No free full text.

Abstract: OBJECTIVE: To compare the clinical and pathologic features of plaque only Alzheimer disease (POAD) with plaque and tangle Alzheimer disease (PTAD). METHODS: An autopsy series of 16 patients with POAD and 32 subjects with PTAD on whom extensive antemortem neuropsychological testing was available. Plaques, tangles, and cerebral amyloid angiopathy were examined in the neocortex and hippocampus using thioflavin S staining. In addition, immunocytochemical analysis with AT8 for phosphorylated tau was performed. Midfrontal (MF) synaptic density, MF choline acetyltransferase (ChAT) activity, and apolipoprotein E genotyping were also assessed. RESULTS: Initial neuropsychological test scores and rates of cognitive decline on the Mini-Mental State Examination and Blessed Information-Memory-Concentration were similar between the two groups. However, compared to PTAD, POAD patients tended to deteriorate more slowly on the Mattis Dementia Rating Scale. Furthermore, they were somewhat less impaired on all these measures at last examination. There was an older age at onset and death, and a trend toward a shorter disease duration, in POAD compared to PTAD patients. POAD subjects, by definition, had no neocortical neurofibrillary tangles (NFT) (Braak stages IV or less). In addition, they also had fewer hippocampal NFT, fewer neuritic plaques, and higher mean MF ChAT activity than PTAD subjects. On the other hand, the two groups did not differ significantly in brain weight or MF synaptic density. Although lacking overt tangle formation, the POAD group displayed abnormal phosphorylated tau immunoreactivity in neocortical pyramidal neurons. CONCLUSIONS: Dementing syndromes virtually indistinguishable from each other can, and do, develop in the presence or absence of neocortical NFT. Patients without neocortical NFT are, on average, older at disease onset and death, and show a trend toward a shorter disease duration with somewhat slower deterioration. Although neocortical NFT per se are not obligatory for the development of clinical dementia, more subtle neocortical cytoskeletal tau pathology may contribute to cognitive decline in these subjects.

Gehrman PR, Martin JL, Shochat T, Nolan S, Corey-Bloom J, Ancoli-Israel S. · San Diego State Unviersity of California, San Diego Joint Doctoral Program in Clinical Psychology, Brown University of Psychiatry and Human Behavior, San Diego, California 92161, USA. · Am J Geriatr Psychiatry. · Pubmed #12837671 No free full text.

Abstract: OBJECTIVE: The authors examined the relationship between sleep-disordered breathing (SDB) and agitation in patients with Alzheimer disease (AD). METHODS: Thirty-eight AD patients (29 women, 9 men) in nursing homes in San Diego, CA participated. The mean age was 82.3 years, with a range of 61 to 95 years. Mean Mini-Mental State Exam score was 6.5 (range: 0-16). Sleep was recorded for one night, and agitation was measured with behavioral observations and ratings by nursing staff. RESULTS: SDB was very prevalent in this sample and was related to some types of agitation during the day but not in the evening or night. Aggressive Agitation on the Cohen-Mansfield Agitation Inventory and Manual Manipulation on the Agitated Behavior Rating Scale were greater with more severe SDB. Searching and wandering agitation decreased with more severe SDB. CONCLUSION: This study supports the hypothesis that SDB is related to agitation in AD, although the results are specific to certain types of agitation. Treatment of SDB may decrease agitation, easing the burden of caregiving and prolonging the time that patients are able to remain at home.

Merdes AR, Hansen LA, Jeste DV, Galasko D, Hofstetter CR, Ho GJ, Thal LJ, Corey-Bloom J. · Department of Neurosciences, University of California, San Diego 92161, USA. · Neurology. · Pubmed #12771246 No free full text.

Abstract: OBJECTIVE: To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB). BACKGROUND: 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. Design/Methods: 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. RESULTS: 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). CONCLUSIONS: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

Tiraboschi P, Hansen LA, Alford M, Merdes A, Masliah E, Thal LJ, Corey-Bloom J. · Neurologia, Ospedale San Paolo, Milano, Italy. · Arch Gen Psychiatry. · Pubmed #12365882 links to  free full text

Abstract: BACKGROUND: Reductions in cholinergic function occur in Alzheimer disease (AD) and dementia with Lewy bodies and correlate with cognitive decline. However, whether such alterations appear in early-stage disease is unclear. OBJECTIVE: To examine the timing of cholinergic deficits in AD and dementia with Lewy bodies. METHODS: Autopsy series of 89 patients with AD and 50 patients with the Lewy body variant of AD (LBV). Stage of disease was stratified according to results of the last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. We analyzed choline acetyltransferase (ChAT) activity in the midfrontal, superior temporal, and inferior parietal cortices. RESULTS: Although compared with a normal control group ChAT activity was decreased in the AD and LBV cohorts, ChAT activity reduction for the LBV cohort was much greater. Moreover, although the decline in ChAT activity in the AD cohort compared with the normal control group was significant only for patients in later stages of the illness, the decline in the LBV cohort was significant for those who died with mild-stage disease. When less impaired patients in each cohort (MMSE, > or = 10) underwent separate analysis, the relationship of ChAT activity with the MMSE score was strong and significant for the LBV cohort alone. CONCLUSIONS: Although cholinergic deficits are seen in both AD and LBV, loss of ChAT activity is less severe and occurs later in the clinical course of AD. Conversely, in LBV, loss of ChAT activity is already prominent in the earliest stages of the illness, suggesting that cholinergic replacement therapy may be more effective in LBV than in AD, especially in mild-stage disease.