Alzheimer Disease: Steffens DC

Potter GG, Steffens DC. · From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. · Neurologist. · Pubmed #17495754 No free full text.

Abstract: BACKGROUND: The objective of this review is to provide information for clinicians regarding current research and opinions on the association of depression to conditions of cognitive impairment and dementia. We also intend to integrate this current research and thinking into strategies for the assessment and treatment of depression in the context of cognitive impairment. REVIEW SUMMARY: Depression is highly prevalent in mild cognitive impairment and most dementias. It may be a risk factor for the subsequent development of dementia and in some conditions may be a prodromal symptom. It is important to detect and effectively treat depression because the comorbidity of depression and cognitive impairment is associated with greater cognitive and functional decline and higher rates of institutionalization. Depression often can be differentiated from Alzheimer disease and other dementias based on characteristics of clinical history and presentation. Screening of depression and cognitive impairment will help characterize the presence and severity of these conditions, but limitations in screening approaches may necessitate comprehensive assessment in complex cases where differential diagnosis is important to treatment planning. CONCLUSION: Although depression and cognitive impairment are important issues in the treatment of older adults, there are particular risks when they occur together. Appropriate assessment and screening can help guide the clinician to appropriate and timely interventions. Pharmacologic and nonpharmacologic treatment approaches are both efficacious in reducing depression in cognitive impairment and dementia.

Young AJ, Johnson S, Steffens DC, Doraiswamy PM. · Duke University Medical Center, Durham, NC 27703, USA. · CNS Spectr. · Pubmed #17192765 links to  free full text

Abstract: Coenzyme Q10 (CoQ10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals produced during oxidative phosphorylation in the inner mitochondrial membrane. Oxidative stress, resulting in glutathione loss and oxidative DNA and protein damage, has been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Experimental studies in animal models suggest that CoQ10 may protect against neuronal damage that is produced by ischemia, atherosclerosis and toxic injury. Though most have tended to be pilot studies, there are published preliminary clinical trials showing that CoQ10 may offer promise in many brain disorders. For example, a 16-month randomized, placebo-controlled pilot trial in 80 subjects with mild Parkinson's disease found significant benefits for oral CoQ10 1,200 mg/day to slow functional deterioration. However, to date, there are no published clinical trials of CoQ10 in Alzheimer's disease. Available data suggests that oral CoQ10 seems to be relatively safe and tolerated across the range of 300-2,400 mg/day. Randomized controlled trials are warranted to confirm CoQ10's safety and promise as a clinically effective neuroprotectant.

Siegler IC, Bastian LA, Steffens DC, Bosworth HB, Costa PT. · Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina 27710, USA. · J Consult Clin Psychol. · Pubmed #12090387 No free full text.

Abstract: A brief history of behavioral medicine and aging is followed by a series of perspectives that help to understand how age is used as a variable in this research, the relative importance of age to declines in cognitive functioning, and the impact of behavioral risk indicators on healthy survival. The authors discuss Alzheimer's disease and the role of age in clinical practice. Also discussed are potential problems in age-related research, ways to improve the knowledge base in behavioral medicine and aging, and thoughts about future challenges to enhance work in behavioral medicine and aging.

Wang CS, Burke JR, Steffens DC, Hulette CM, Breitner JC, Plassman BL. · Department of Psychiatry, Tainan Hospital, Department of Health, Taiwan. · J Neurol Neurosurg Psychiatry. · Pubmed #19372291 No free full text.

Abstract: AIM: Little is known about the concordance rate in twins for dementia with Lewy bodies (DLB). The rate of agreement between clinical and pathological diagnoses for DLB is typically low, necessitating confirmation of the diagnosis neuropathologically. METHODS: Participants were 17 twin pairs enrolled in the Duke Twins Study of Memory in Aging in which at least one member of the pair had an autopsy confirmed diagnosis of DLB, Alzheimer's disease (AD) with Lewy bodies or frontotemporal dementia with Lewy bodies. The characteristics of those with dementia were assessed and rates of concordance for pathological confirmed dementia were examined. RESULTS: Four monozygotic twin pairs had a proband with neuropathologically confirmed pure DLB; all remained discordant for dementia for periods up to 16 years or more. Five of 13 pairs in which the proband had AD plus DLB were concordant for dementia but only one pair was concordant for AD plus DLB, while the co-twins in the other four pairs had other types of dementia. CONCLUSIONS: The present study indicates that even among twins, a diagnosis of DLB in one twin does not predict the same diagnosis in the other twin. Neuropathological discordance in type of dementia among monozygotic pairs hints at environmental or epigenetic factors playing a role in Lewy body pathology.

Naylor JC, Hulette CM, Steffens DC, Shampine LJ, Ervin JF, Payne VM, Massing MW, Kilts JD, Strauss JL, Calhoun PS, Calnaido RP, Blazer DG, Lieberman JA, Madison RD, Marx CE. · Durham Veterans Affairs Medical Center, 508 Fulton Street, MHSL 116A, Durham, North Carolina 27705, USA. · J Clin Endocrinol Metab. · Pubmed #18477662 links to  free full text

Abstract: OBJECTIVE: It is currently unknown whether cerebrospinal fluid (CSF) neurosteroid levels are related to brain neurosteroid levels in humans. CSF and brain dehydroepiandrosterone (DHEA) levels are elevated in patients with Alzheimer's disease (AD), but it is unclear whether CSF DHEA levels are correlated with brain DHEA levels within the same subject cohort. We therefore determined DHEA and pregnenolone levels in AD patients (n = 25) and cognitively intact control subjects (n = 16) in both CSF and temporal cortex. DESIGN: DHEA and pregnenolone levels were determined by gas chromatography/mass spectrometry preceded by HPLC. Frozen CSF and temporal cortex specimens were provided by the Alzheimer's Disease Research Center at Duke University Medical Center. Data were analyzed by Mann-Whitney U test statistic and Spearman correlational analyses. RESULTS: CSF DHEA levels are positively correlated with temporal cortex DHEA levels (r = 0.59, P < 0.0001) and neuropathological disease stage (Braak and Braak) (r = 0.42, P = 0.007). CSF pregnenolone levels are also positively correlated with temporal cortex pregnenolone levels (r = 0.57, P < 0.0001) and tend to be correlated with neuropathological disease stage (Braak) (r = 0.30, P = 0.06). CSF DHEA levels are elevated (P = 0.032), and pregnenolone levels tend to be elevated (P = 0.10) in patients with AD, compared with cognitively intact control subjects. CONCLUSIONS: These findings indicate that CSF DHEA and pregnenolone levels are correlated with temporal cortex brain levels of these neurosteroids and that CSF DHEA is elevated in AD and related to neuropathological disease stage. Neurosteroids may thus be relevant to the pathophysiology of AD.

Sun X, Steffens DC, Au R, Folstein M, Summergrad P, Yee J, Rosenberg I, Mwamburi DM, Qiu WQ. · Department of Psychiatry, Tufts-New England Medical Center, Campus Box 1007, 750 Washington St, Boston, MA 02111, USA. · Arch Gen Psychiatry. · Pubmed #18458206 links to  free full text

Abstract: CONTEXT: A high ratio of plasma amyloid-beta peptide 40 (Abeta(40)) to Abeta(42), determined by both high Abeta(40) and low Abeta(42) levels, increases the risk of Alzheimer disease. In a previous study, we reported that depression is also associated with low plasma Abeta(42) levels in the elderly population. OBJECTIVE: To characterize plasma Abeta(40):Abeta(42) ratio and cognitive function in elderly individuals with and without depression. DESIGN: Cross-sectional study. SETTING: Homecare agencies. PARTICIPANTS: A total of 995 homebound elderly individuals of whom 348 were defined as depressed by a Center for Epidemiological Studies Depression score of 16 or greater. MAIN OUTCOME MEASURES: Cognitive domains of memory, language, executive, and visuospatial functions according to levels of plasma Abeta(40) and Abeta(42) peptides. RESULTS: Subjects with depression had lower plasma Abeta(42) levels (median, 14.1 vs 19.2 pg/mL; P = .006) and a higher plasma Abeta(40):Abeta(42) ratio (median, 8.9 vs 6.4; P < .001) than did those without depression in the absence of cardiovascular disease and antidepressant use. The interaction between depression and plasma Abeta(40):Abeta(42) ratio was associated with lower memory score (beta = -1.9, SE = 0.7, P = .006) after adjusting for potentially confounders. Relative to those without depression, "amyloid-associated depression," defined by presence of depression and a high plasma Abeta(40):Abeta(42) ratio, was associated with greater impairment in memory, visuospatial ability, and executive function; in contrast, nonamyloid depression was not associated with memory impairment but with other cognitive disabilities. CONCLUSION: Amyloid-associated depression may define a subtype of depression representing a prodromal manifestation of Alzheimer disease.

Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, McArdle JJ, Willis RJ, Wallace RB. · Duke University Medical Center, Durham, North Carolina 27701, USA. · Ann Intern Med. · Pubmed #18347351 links to  free full text

Abstract: BACKGROUND: Cognitive impairment without dementia is associated with increased risk for disability, increased health care costs, and progression to dementia. There are no population-based prevalence estimates of this condition in the United States. OBJECTIVE: To estimate the prevalence of cognitive impairment without dementia in the United States and determine longitudinal cognitive and mortality outcomes. DESIGN: Longitudinal study from July 2001 to March 2005. SETTING: In-home assessment for cognitive impairment. PARTICIPANTS: Participants in ADAMS (Aging, Demographics, and Memory Study) who were age 71 years or older drawn from the nationally representative HRS (Health and Retirement Study). Of 1770 selected individuals, 856 completed initial assessment, and of 241 selected individuals, 180 completed 16- to 18-month follow-up assessment. MEASUREMENTS: Assessments, including neuropsychological testing, neurologic examination, and clinical and medical history, were used to assign a diagnosis of normal cognition, cognitive impairment without dementia, or dementia. National prevalence rates were estimated by using a population-weighted sample. RESULTS: In 2002, an estimated 5.4 million people (22.2%) in the United States age 71 years or older had cognitive impairment without dementia. Prominent subtypes included prodromal Alzheimer disease (8.2%) and cerebrovascular disease (5.7%). Among participants who completed follow-up assessments, 11.7% with cognitive impairment without dementia progressed to dementia annually, whereas those with subtypes of prodromal Alzheimer disease and stroke progressed at annual rates of 17% to 20%. The annual death rate was 8% among those with cognitive impairment without dementia and almost 15% among those with cognitive impairment due to medical conditions. LIMITATIONS: Only 56% of the nondeceased target sample completed the initial assessment. Population sampling weights were derived to adjust for at least some of the potential bias due to nonresponse and attrition. CONCLUSION: Cognitive impairment without dementia is more prevalent in the United States than dementia, and its subtypes vary in prevalence and outcomes.

Steffens DC, Potter GG, McQuoid DR, MacFall JR, Payne ME, Burke JR, Plassman BL, Welsh-Bohmer KA. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · Am J Geriatr Psychiatry. · Pubmed #17623814 No free full text.

Abstract: OBJECTIVE: Several studies suggest that depression is a risk factor for development of dementia in the elderly. In a study of older depressed individuals, the authors examined both neuroimaging and genetic factors in development of dementia. The authors hypothesized that change in subcortical gray matter and white matter hyperintensity volumes would be associated with development of dementia, as would presence of an apolipoprotein E (APOE) epsilon 4 allele. METHODS: The sample consisted of 161 older depressed subjects without dementia who had magnetic resonance imaging scans at baseline and at two years. Blood samples were also taken to determine APOE genotype. All participants were treated with antidepressants using a guideline-based treatment algorithm. Their cognitive status was evaluated annually. A consensus panel of experts evaluated each case to determine cognitive status and assign a diagnosis. RESULTS: Twenty subjects became demented over the follow-up period (5.4 years on average). Change in white matter hyperintensity volume was significantly associated with development of dementia, especially among non-Alzheimer dementias. There was a trend for change in subcortical gray matter hyperintensity volume to be associated with incident dementia. APOE genotype was not associated with onset of dementia. CONCLUSION: Worsening cerebrovascular disease in older depressed adults is associated with cognitive decline and dementia, particularly of the non-Alzheimer disease type. The association of change in white matter lesion volume and incident dementia among depressed elders extends the vascular depression hypothesis of geriatric depression to include cognitive outcomes of depression in the elderly.

Marx CE, Trost WT, Shampine LJ, Stevens RD, Hulette CM, Steffens DC, Ervin JF, Butterfield MI, Blazer DG, Massing MW, Lieberman JA. · Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Durham, North Carolina 27705, USA. · Biol Psychiatry. · Pubmed #16997284 No free full text.

Abstract: BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.

Steinberg M, Corcoran C, Tschanz JT, Huber C, Welsh-Bohmer K, Norton MC, Zandi P, Breitner JC, Steffens DC, Lyketsos CG. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Int J Geriatr Psychiatry. · Pubmed #16955439 No free full text.

Abstract: OBJECTIVE: To investigate the probability of individual neuropsychiatric symptoms in dementia patients as a function of eight risk factors. METHODS: In the Cache County Study, we administered the Neuropsychiatric Inventory (NPI) to 328 dementia patients at baseline. Approximately 18 months later, we re-administered the NPI to 184 participants available for follow-up. Generalized estimating equation methods were used to model the probability of individual neuropsychiatric symptoms as a function of: gender, age, education, dementia type and severity, APOE status, time of observation, and general medical health. RESULTS: Women showed increased tendency toward anxiety, [odds ratio (OR) 2.22, 95% confidence interval (CI) 1.31-3.76] and delusions (OR 2.15, CI 1.22-3.78), but older persons of both sexes showed less tendency toward anxiety. Dementia severity increased the tendency toward hallucinations and agitation (OR 2.42, CI 1.81-3.23) and decreased risk of depression. Positive APOE epsilon4 status increased the tendency toward aberrant motor behavior (OR 1.84, CI 1.05-3.22). Among dementia diagnoses, those with Alzheimer's disease showed decreased tendency toward agitation (OR 0.58, CI 0.35-0.95), depression (OR 0.56, CI 0.33-0.96) and disinhibition (OR 0.46, CI 0.24-0.88). Later time of observation increased risk of aberrant motor behavior and delusions, and more serious medical comorbidity increased risk of, agitation, irritability, disinhibition, and aberrant motor behavior. CONCLUSIONS: Gender, age, dementia severity, APOE epsilon4, dementia diagnosis, time of observation, and general medical health appear to influence the occurrence of individual neuropsychiatric symptoms.

Sair HI, Welsh-Bohmer KA, Wagner HR, Steffens DC. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center Box 3903 Durham, NC 27710, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #16525080 links to  free full text

Abstract: The authors hypothesized that older depressed patients would perform more poorly on the Ascending Digits Task (ADT) when matched against a nondepressed elderly comparison group. In a novel measure, the ADT, 129 older depressives scored more poorly than 129 comparison subjects in bivariate analyses and models controlling for demographic variables. The ADT may be a good measure of executive function in older adults.

Lyketsos CG, Toone L, Tschanz J, Rabins PV, Steinberg M, Onyike CU, Corcoran C, Norton M, Zandi P, Breitner JC, Welsh-Bohmer K, Anthony J, Østbye T, Bigler E, Pieper C, Burke J, Plassman B, Green RC, Steffens DC, Klein L, Leslie C, Townsend JJ, Wyse BW, Munger R, Williams M, Anonymous00077. · Division of Geriatric Psychiatry and Neuropsychiatry, Dept. of Psychiatry and Behavioral Sciences, School of Medicine, The Johns Hopkins University, Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Am J Geriatr Psychiatry. · Pubmed #16085781 No free full text.

Abstract: OBJECTIVE: Authors investigated medical comorbidity in persons with dementia and "Cognitive Impairment, No Dementia" (CIND). METHODS: The Cache County Study is an ongoing population-based study of the epidemiology of dementia, the risk factors for conversion from CIND to dementia, and the progression of dementia. As part of the study's first incidence wave, persons with dementia (N=149), CIND (N=225), or without cognitive impairment (N=321) were identified and studied. Participants received comprehensive clinical evaluations and were rated on the General Medical Health Rating (GMHR), a global measure of seriousness of medical comorbidity. Participants and informants also completed the Mini-Mental State Exam and provided self-report information about comorbid medical conditions and functioning in activities of daily living. RESULTS: There were few differences in number or type of comorbid medical conditions between persons with CIND and dementia, but persons with dementia were prescribed more medications. Stroke was more common in dementia participants, but other illnesses common in old age were not significantly different across cognitive groups. Medical comorbidity was more serious in both dementia and CIND, such that both groups were less likely to have "little to no" comorbidity. Seriousness of medical comorbidity was significantly associated with worse day-to-day functioning and cognition. CONCLUSIONS: Persons with CIND and dementia have more serious medical comorbidity than comparable persons without cognitive impairment. This comorbidity may play a role in the progression of CIND and dementia. Future studies should investigate the role of medical comorbidity and its treatment on dementia onset or progression, as well as the mechanisms mediating its neuropathologic effects.

Doraiswamy PM, Steffens DC, McQuoid DR. · Department of Psychiatry and Medicine (Geriatrics), Duke University Medical Center, Durham, North Carolina, USA. · Am J Alzheimers Dis Other Demen. · Pubmed #15553983 No free full text.

Abstract: Statins are investigational therapies for preventing or treating Alzheimer's disease (AD) and mild cognitive impairment (MCI). Hippocampal atrophy is a characteristic feature of MCI and AD. This study analyzed cross-sectional data from 246 nondemented elderly subjects to test the effect of lipid lowering agent (LLA) therapy on cognition and brain magnetic resonance imaging (MRI) measures of white matter lesions and hippocampal volume. The study also compared rates of hippocampal volume change over two and four years in a smaller subset. At baseline, LLA users were younger, better educated, more likely to be male, and had higher cognitive scores. Cognitive performance also varied by age and gender, and MRI measures varied by age. After adjusting for these differences, the effect of LLA use on baseline cognition, baseline hippocampal volume, and baseline white matter lesion scores was not significant. The effect of LLA use on hippocampal volume loss at two-year and four-year follow-ups was also not significant. This study is the first to examine statin effects on brain atrophy measured by MRI. In this cohort, statin use was not associated with rate of change of hippocampal volume. While the study was limited by a relatively small number of statin users, the findings seem consistent with three prior randomized trials that found no cognitive benefits for statins in nondemented subjects. Prospective studies in both nondemented and AD subjects may provide more conclusive answers.

Steffens DC, Norton MC, Hart AD, Skoog I, Corcoran C, Breitner JC, Anonymous00043. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · Psychol Med. · Pubmed #12701674 No free full text.

Abstract: BACKGROUND: The role of allelic variation in APOE, the genetic locus for apolipoprotein E, in geriatric depression is poorly understood. There are conflicting reports as to an association between the epsilon4 allele and depression in late life. METHOD: Using a community based study of non-demented elders in Cache County, Utah, that included many very old individuals, we examined the relationship between APOE and late-onset (age > 60) depression, with particular attention to possible age effects. RESULTS: There was no overall association between APOE and depression. However, there was a significant interaction effect of APOE and age such that the relationship of late-onset depression with respect to presence of the epsilon4 allele was larger among those 80 and older compared with those below age 80. Consistent with previous studies, women were more likely to experience late-onset depression than men. CONCLUSIONS: Because we excluded prevalent cases of dementia, this pattern of relative risk with age may reflect the appearance of depressive symptoms as a prodrome of Alzheimer's disease or vascular dementia. Longitudinal studies should help to confirm or refute this explanation of the data.

Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC, Anonymous00334. · Department of Mental Hygiene, School of Hygiene and Public Health, the Johns Hopkins University, Baltimore, Md, USA. · JAMA. · Pubmed #12413371 links to  free full text

Abstract: CONTEXT: Previous studies have shown a sex-specific increased risk of Alzheimer disease (AD) in women older than 80 years. Basic neuroscience findings suggest that hormone replacement therapy (HRT) could reduce a woman's risk of AD. Epidemiologic findings on AD and HRT are mixed. OBJECTIVE: To examine the relationship between use of HRT and risk of AD among elderly women. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of incident dementia among 1357 men (mean age, 73.2 years) and 1889 women (mean age, 74.5 years) residing in a single county in Utah. Participants were first assessed in 1995-1997, with follow-up conducted in 1998-2000. History of women's current and former use of HRT, as well as of calcium and multivitamin supplements, was ascertained at the initial contact. MAIN OUTCOME MEASURE: Diagnosis of incident AD. RESULTS: Thirty-five men (2.6%) and 88 women (4.7%) developed AD between the initial interview and time of the follow-up (3 years). Incidence among women increased after age 80 years and exceeded the risk among men of similar age (adjusted hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.22-3.86). Women who used HRT had a reduced risk of AD (26 cases among 1066 women) compared with non-HRT users (58 cases among 800 women) (adjusted HR, 0.59; 95% CI, 0.36-0.96). Risk varied with duration of HRT use, so that a woman's sex-specific increase in risk disappeared entirely with more than 10 years of treatment (7 cases among 427 women). Adjusted HRs were 0.41 (95% CI, 0.17-0.86) for HRT users compared with nonusers and 0.77 (95% CI, 0.31-1.67) compared with men. No similar effect was seen with calcium or multivitamin use. Almost all of the HRT-related reduction in incidence reflected former use of HRT (9 cases among 490 women; adjusted HR, 0.33 [95% CI, 0.15-0.65]). There was no effect with current HRT use (17 cases among 576 women; adjusted HR, 1.08 [95% CI, 0.59-1.91]) unless duration of treatment exceeded 10 years (6 cases among 344 women; adjusted HR, 0.55 [95% CI, 0.21-1.23]). CONCLUSIONS: Prior HRT use is associated with reduced risk of AD, but there is no apparent benefit with current HRT use unless such use has exceeded 10 years.

Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD. · Adult and Geriatric Treatment and Preventive Interventions Research Branch, National Institute of Mental Health, Bethesda, MD 20892-9635, USA. · Am J Geriatr Psychiatry. · Pubmed #11925273 No free full text.

Abstract: The authors, a group of investigators with extensive research and clinical experience related to both late-life depression and Alzheimer disease (AD), propose provisional affective and behavioral inclusion and exclusion diagnostic criteria for Depression of AD.

Kim DH, Payne ME, Levy RM, MacFall JR, Steffens DC. · Psychiatry and Behavioral Sciences, Durham, North Carolina 27710, USA. · Biol Psychiatry. · Pubmed #11904138 No free full text.

Abstract: BACKGROUND: Apolipoprotein E has been associated with hippocampal volume loss in Alzheimer's disease and in elderly controls. In this study, we examined the role of apolipoprotein E and hippocampal volume change in 45 older nondemented depressed subjects. All had baseline and 2-year magnetic resonance imaging scans. METHODS: Hippocampal volumes were determined using a semiautomated method. RESULTS: Compared with 36 depressed subjects without an apolipoprotein E epsilon4 allele, 9 subjects with at least one APOE epsilon4 allele showed significant decline in hippocampal volume, particularly in the right hippocampus. In a logistic model, percent change in right hippocampal volume remained associated with presence of an APOE epsilon4 allele after controlling for age, gender, Mini-Mental State Examination score, and baseline total cerebral volume. CONCLUSIONS: Future studies are needed to explain this association and to determine whether the finding for the right hippocampus has a biological basis, or if it is merely a function of small sample size.

Steffens DC, Payne ME, Greenberg DL, Byrum CE, Welsh-Bohmer KA, Wagner HR, MacFall JR. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · Am J Geriatr Psychiatry. · Pubmed #11790636 No free full text.

Abstract: The authors investigated the role of baseline hippocampal volume on later clinical emergence of dementia in a group of older, non-demented depressed individuals. Subjects were 115 depressed, non-demented participants in a mental health clinical research center. All subjects were screened for dementia and agreed to have a magnetic resonance imaging (MRI) brain scan at baseline. Subjects were clinically evaluated by geriatric psychiatrists quarterly for up to 5 years and received annual neuropsychological testing. Bivariate analyses examined age, gender, race, educational level, baseline depression severity, age at depression onset, baseline Mini-Mental State Exam (MMSE), left and right hippocampal volume, and total cerebral volume. Age, baseline MMSE, total cerebral volume, and having a small left hippocampal volume were associated with later dementia and were included in subsequent survival analysis. Small left hippocampal volume was significantly associated with later dementia (hazard ratio=2.762). Small left hippocampal size on neuroimaging may be a marker for dementia in depressed patients who have not yet met criteria for a clinical diagnosis of a dementing disorder.

Lyketsos CG, Sheppard JM, Steinberg M, Tschanz JA, Norton MC, Steffens DC, Breitner JC. · Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, USA. · Int J Geriatr Psychiatry. · Pubmed #11746650 No free full text.

Abstract: OBJECTIVE: We investigated the frequency and inter-relationship of neuropsychiatric disturbances in a population sample of persons suffering from Alzheimer's disease (AD). METHOD: Screening 5,092 elderly residents (90% of the population aged 65 and older) of Cache County, Utah, for dementia, we identified 198 persons with AD using a comprehensive neuropsychiatric examination protocol. This examination included the Neuropsychiatric Inventory (NPI), a widely used measure of dementia-associated neuropsychiatric disturbances. RESULTS: Overall, 60% of individuals with AD reported one or more neuropsychiatric symptoms. A latent class analysis revealed that these participants could be classified into three groups (classes) based on their neuropsychiatric symptom profile. The largest class included cases with no neuropsychiatric symptoms (40%) or with a mono-symptomatic disturbance (19%). A second class (28%) exhibited a predominantly affective syndrome, while a third class (13%) had a psychotic syndrome. CONCLUSION: Data from this first US population-based study of AD-associated neuropsychiatric disturbances suggest that a significant majority of persons with AD suffer from one or more neuropsychiatric disturbance. Based on phenomenological study, the spectrum of neuropsychiatric symptoms in AD can be empirically classified into three groups: an affective syndrome, a psychotic syndrome and other neuropsychiatric disturbance. The biologic and predictive validity of this classification merits further investigation.

Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer KA, Burke JR, Guralnik JM, Breitner JC. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA. · Neurology. · Pubmed #11071494 No free full text.

Abstract: BACKGROUND: The association between antecedent head injury and AD is inconsistent. OBJECTIVE: To examine the association between early adult head injury, as documented by military hospital records, and dementia in late life; and to evaluate the interaction between head injury and APOE epsilon4 as risk factors for dementia. METHODS: The study had a population-based prospective historical cohort design. It included men who were World War II Navy and Marine veterans, and were hospitalized during their military service with a diagnosis of either a nonpenetrating head injury or another unrelated condition. In 1996 to 1997, military medical records were abstracted to document the occurrence and details of closed head injury. The entire sample was then evaluated for dementia and AD using a multistage procedure. There were 548 veterans with head injury and 1228 without head injury who completed all assigned stages of the study. The authors estimated risk of dementia, specifically AD, using proportional hazards models. RESULTS: Both moderate head injury (hazard ratio [HR] = 2.32; CI = 1.04 to 5.17) and severe head injury (HR = 4.51; CI = 1.77 to 11.47) were associated with increased risk of AD. Results were similar for dementia in general. The results for mild head injury were inconclusive. When the authors stratified by the number of APOE epsilon4 alleles, they observed a nonsignificant trend toward a stronger association between AD and head injury in men with more epsilon4 alleles. CONCLUSIONS: Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life. However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.

Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. · Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Am J Psychiatry. · Pubmed #10784462 links to  free full text

Abstract: OBJECTIVE: The authors report findings from a study of 5,092 community residents who constituted 90% of the elderly resident population of Cache County, Utah. METHOD: The 5,092 participants, who were 65 years old or older, were screened for dementia. Based on the results of this screen, 1,002 participants (329 with dementia and 673 without dementia) underwent comprehensive neuropsychiatric examinations and were rated on the Neuropsychiatric Inventory, a widely used method for ascertainment and classification of dementia-associated mental and behavioral disturbances. RESULTS: Of the 329 participants with dementia, 214 (65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/aggression (24%) were the most common in participants with dementia. These disturbances were almost four times more common in participants with dementia than in those without. Only modest differences were observed in the prevalence of mental or behavioral disturbances in different types of dementia or at different stages of illness: participants with Alzheimer's disease were more likely to have delusions and less likely to have depression. Agitation/aggression and aberrant motor behavior were more common in participants with advanced dementia. CONCLUSIONS: On the basis of their findings in this large community population of elderly people, the authors conclude that a wide range of dementia-associated mental and behavioral disturbances afflict the majority of individuals with dementia. Because of their frequency and their adverse effects on patients and their caregivers, these disturbances should be ascertained and treated in all cases of dementia.

Steffens DC, Plassman BL, Helms MJ, Welsh-Bohmer KA, Newman TT, Breitner JC. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · Neurology. · Pubmed #10680788 No free full text.

Abstract: OBJECTIVE: To examine the independent effects of the APOE genotype (APOE) and concordance for AD in twin pairs on the occurrence of AD in first-degree relatives. BACKGROUND: Studies of twins have been undertaken to investigate the influence of genes in a variety of conditions, including AD. A previous study, performed before reports linking APOE to AD, demonstrated an increase in AD among first-degree relatives of twins concordant for AD compared with relatives of discordant twins. METHODS: In a sample of 94 twin pairs the authors examined the association between concordance for AD within the twin pair and family history of AD among first-degree relatives of twins. They then examined the extent to which the presence of the APOE epsilon4 allele in the twin pair explains the association between concordance for AD within the twin pair and family history of AD. RESULTS: Concordance among twins was associated with increased risk of AD among relatives (logrank test, chi2 = 12.558; p = 0.0004), and the presence of at least one APOE epsilon4 allele in each member of the twin pair is also associated with increased risk of AD among family members (logrank test, chi2 = 7.712; p = 0.0055). CONCLUSIONS: APOE genotype explains much but not all of the association between concordance among twins and increased familial risk of AD.

Breitner JC, Wyse BW, Anthony JC, Welsh-Bohmer KA, Steffens DC, Norton MC, Tschanz JT, Plassman BL, Meyer MR, Skoog I, Khachaturian A. · Department of Mental Hygiene, The Johns Hopkins University, Baltimore, MD 21205, USA. · Neurology. · Pubmed #10430421 No free full text.

Abstract: OBJECTIVE: To examine the prevalence of Alzheimer's disease (AD) and other dementias in relation to age, education, sex, and genotype at APOE. Recent studies suggest age heterogeneity in the risk of AD associated with the APOE genotype and a possible interaction between APOE-epsilon4 and female sex as risk factors. We studied these topics in the 5,677 elderly residents of Cache County, Utah, a population known for long life expectancy and high participation rates. METHODS: We screened for dementia with a brief cognitive test and structured telephone Dementia Questionnaire, then examined all individuals with apparent cognitive symptoms and a sample of others. We estimated age-specific prevalence of AD and other dementias and used multiple logistic regression models to describe relation of AD prevalence to age, sex, education, and APOE genotype. RESULTS: We found 335 demented individuals, 230 (69%) with definite, probable, or possible AD (positive predictive value versus autopsy confirmation 85%). The adjusted prevalence estimate for AD was 6.5% and for all dementias 9.6%. After age 90, the adjusted prevalence estimate for AD was 28% and for all dementias 38%. Regression models showed strong variation in AD prevalence with age, sex, education, and number of epsilon4 alleles (effect of epsilon2 not significant). Models were improved by a term for age-squared (negative coefficient) and by separate terms for interaction of age with presence of one or two epsilon4 alleles. An association of AD with female sex was ascribable entirely to individuals with epsilon4. CONCLUSIONS: In participants with no epsilon4 alleles, the age-specific prevalence of AD reached a maximum and then declined after age 95. In epsilon4 heterozygotes a similar maximum was noted earlier at age 87, in homozygotes at age 73. Female sex was a risk factor for AD only in those with epsilon4. The epsilon4 allele accounted for 70% of the population attributable risk for AD.