George S. Zubenko

Bio: George S. Zubenko is an academic researcher from Carnegie Mellon University. The author has contributed to research in topics: Dementia & Membrane fluidity. The author has an hindex of 56, co-authored 171 publications receiving 8940 citations. Previous affiliations of George S. Zubenko include University of Pittsburgh & Harvard University.

Complicated grief and bereavement-related depression as distinct disorders : preliminary empirical validation in elderly bereaved spouses

Abstract: Objective: This study sought to determine whether a set of symptoms interpreted as cornplicated grief could be identified and distinguished from bereavement-related depression and whether the presence of complicated grief would predict enduring functional impairments. Method: Data were derived from a study group of 82 recently widowed elderly individuals recruited for an investigation ofphysiological changes in bereaved persons. Baseline data were collected 3-6 months after the deaths of the subjects’ spouses, and follow-up data were collected from 56 of the subjects I 8 months after the baseline assessments. Candidate items for assessing complicated griefcame from a variety ofscales used to evaluate emotional functioning (e.g., the Hamilton Depression Rating Scale, the BriefSymptom Inventory). The outcome variables measured were global functioning, medical illness burden, sleep, mood, self-esteem, and anxiety. Results: A principal-components analysis conducted on intake data (N=82) revealed a complicated grieffactor and a bereavement-depression factor. Seven symptoms constituted complicated grief: searching, yearning, preoccupation with thoughts of the deceased, crying, disbelief regarding the death, feeling stunned by the death, and lack of acceptance of the death. Baseline complicated griefscores were significantly associated with impairments in global functioning, mood, sleep, and self-esteem in the 56 subjects available for follow-up. Conclusions: The symptoms of complicated grief may be distinct from depressive symptoms and appear to be associated with enduring functional impairments. The symptoms of complicated grief, therefore, appear to define a unique disorder deserving of specialized treatment. (Am J Psychiatry 1995; 152:22-30)

A Collaborative Study of the Emergence and Clinical Features of the Major Depressive Syndrome of Alzheimer’s Disease

Abstract: OBJECTIVE: This report provides a description of the prevalence and clinical features of the major depressive syndrome of Alzheimer’s disease using data derived from structured diagnostic assessments of 243 patients with probable Alzheimer’s disease and 151 nondemented elderly comparison subjects. METHOD: Subjects were characterized by a consortium of four Alzheimer’s disease research centers and the Geriatric Psychiatry Branch of the National Institute of Mental Health. All sites administered the Clinical Assessment of Depression in Dementia, a structured, anchored diagnostic interview that was developed to reliably diagnose and characterize major depressive episodes in this population. RESULTS: Despite the use of a common, reliable methodology for the assessment and diagnosis of major depressive episodes, the prevalence of major depression in Alzheimer’s disease ranged widely from 22.5% to 54.4% across the recruitment sites. The prevalence of major depressive episodes among Alzheimer’s disease patients ...

Neuropathologic and neurochemical correlates of psychosis in primary dementia.

Abstract: • Neuropathologic and neurochemical correlates of psychosis were determined using brain tissue from 27 autopsy-confirmed cases of Alzheimer's disease. The densities of senile plaques and neurofibrillary tangles were determined in the middle frontal and superior temporal cortex, the prosubiculum, and the entorhinal cortex of the hippocampus. The concentrations of norepinephrine, dopamine, and serotonin, the metabolites of these biogenic amines, and the specific activity of choline acetyltransferase were also determined in these four cortical regions as well as in the substantia nigra, thalamus, amygdala, and caudate nucleus. Psychosis was associated with significantly increased densities of senile plaques and neurofibrillary tangles in the prosubiculum and middle frontal cortex, respectively, with trends toward increased densities of these lesions in the other areas examined. This finding is consistent with the increased rate of cognitive decline that accompanies this behavioral disorder. Psychosis was also associated with the relative preservation of norepinephrine in the substantia nigra, with trends in this direction for five of the remaining seven brain regions examined, and a significant reduction of serotonin in the prosubiculum that was accompanied by trends toward reduced levels of serotonin and 5 hydroxyindoleacetic acid in the remaining regions. The profile of neuropathologic and neurochemical changes associated with psychosis is distinct from that previously reported for major depression in the context of primary dementia.

Major Depression in Primary Dementia: Clinical and Neuropathologic Correlates

Abstract: • Cytopathologic features were quantified in seven brain regions in the brains of 37 demented patients, with or without major depression, and in those of seven controls with no history of dementia or depression. The middle frontal and superior temporal cortex, prosubiculum and entorhinal cortex of the hippocampus, nucleus basalis of Meynert, locus ceruleus, and substantia nigra were the areas evaluated. Patients with major depression had significantly more degenerative findings in the locus ceruleus and substantia nigra than demented patients who were not depressed. In contrast, these groups were similar with respect to other clinical features and indexes of global severity of dementia. A logistic regression model that included the degenerative features of both the locus ceruleus and the substantia nigra was significantly better at predicting the presence of major depression than those employing the characteristics of either pigmented nucleus alone. Our results indicate that the development of major depression in patients with primary dementia is associated with the degeneration of the locus ceruleus and substantia nigra.

Neurochemical Correlates of Major Depression in Primary Dementia

Abstract: • Biogenic amine neurotransmitters and metabolites as well as choline acetyltransferase activity were quantified in eight brain regions from 37 demented patients, with or without major depression, and 10 controls with no history of dementia or depression. The middle frontal and temporal cortex, prosubiculum and entorhinal cortex of the hippocampus, substantia nigra, thalamus, amygdala, and caudate were examined. Demented patients with major depression exhibited a 10-fold to 20-fold reduction in the level of norepinephrine in the cortex, along with relative preservation of choline acetyltransferase activity in subcortical regions, compared with demented patients who were not depressed. Serotonin levels were reduced in all eight brain regions, but the reduction did not reach statistical significance in any region examined. A para-doxical increase in dopamine levels was observed in the entorhinal cortex of depressed, demented patients, although no consistent pattern of change in the level of this neurotransmitter emerged across brain regions. Our results indicate that the development of major depression in primary dementia is associated with a profile of concurrent neurochemical changes that is largely consistent with existing neurochemical hypotheses of idiopathic affective disorders, and qualitatively distinct from that associated with primary dementia.

The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia

Abstract: We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patient's behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.

The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions

Abstract: Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.

Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.

Abstract: We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.

Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis

Abstract: Objective. —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. Data Sources. —Forty research teams contributed data onAPOEgenotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. Main Outcome Measures. —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed forAPOEgenotypes ∈2/∈2,∈2/∈3,∈2/∈4,∈3/∈4 and ∈4/∈4 relative to the ∈3/∈3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. Results. —Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes ∈2/∈4 (OR=2.6, 95% Cl=1.6-4.0), ∈3/∈4 (OR=3.2, 95% Cl=2.8-3.8), and ∈4/∈4 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs were decreased for people with genotypes ∈2/∈2 (OR=0.6, 95% Cl=0.2-2.0) and ∈2/∈3 (OR=0.6, 95% Cl=0.5-0.8). TheAPOE∈4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P Conclusions. —TheAPOE∈4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association betweenAPOE∈4 and AD in African Americans requires clarification, and the attenuated effect ofAPOE∈4 in Hispanics should be investigated further.