Alzheimer Disease: Krishnan KR

Krishnan KR. · Department of Psychiatry and Behavioral, Duke University Medical Center, Durham, NC 27710, USA. · Am J Geriatr Psychiatry. · Pubmed #17095750 No free full text.

Abstract: The concept of disease in geriatric psychiatry has to keep up with the rapid expansion in knowledge about the putative etiology of various diseases of interest. This article reviews the new knowledge that has been acquired about dementia. The proposed classification system has two axes: one for clinical manifestations and the other for etiology. Implementing this nomenclature will allow rapid adaptation of new knowledge for causation while at the same time communicating information on the clinical state. This should improve our ability to incorporate and communicate new knowledge in a dynamic format. In turn, this strategy should improve our ability to discern particular features of a disease and refine our notion of its clinical presentation and lead toward novel and improved treatments for our patients.

Mori E, Hashimoto M, Krishnan KR, Doraiswamy PM. · Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan. · Alzheimer Dis Assoc Disord. · Pubmed #16772752 No free full text.

Abstract: The progression of Alzheimer disease (AD) corresponds to a prolonged course of neuronal loss in the cerebral cortex. Strategies aimed at reducing the rates of neuronal loss are therefore particularly important. The clinical measures to evaluate the disease-modifying effect of an intervention are readily confounded by any symptomatic benefit of the intervention. Thus, when testing putative neuroprotective agents that are known to have symptomatic effects, it can be difficult to separate the 2 effects. The hypothesis that cholinesterase inhibitors (ChEIs) only treat symptoms caused by cholinergic imbalances in AD is overly simplistic. Evidence has now accumulated that ChEIs have a neuroprotective, disease-modifying property. In this paper, to answer the question of what constitutes clinical evidence for neuroprotection in AD, we have reviewed clinical studies with specific designs, including "delaying end point," "withdrawal," and "randomized start" designs. We have also reviewed data on surrogate biomarkers of disease progression that may indicate a disease-modifying action. In addition, we have reviewed evidence indicating that ChEIs may protect cells in the brain of patients with AD. Among the clinical data suggesting a possible neuroprotective effect of ChEIs, the most rigorous published evidence comes from magnetic resonance imaging (MRI) hippocampal volumetric studies with donepezil.

Krishnan KR. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · Mol Psychiatry. · Pubmed #16077681 No free full text.

Abstract: Although the introduction of explicit diagnostic criteria and rule-based classifications, such as Research Diagnostic Criteria, Diagnostic and Statistical Manual Ed 3 and Ed 4, has dramatically influenced teaching and research psychiatric practice, it has significant limitations. As new knowledge is developed with genetic, imaging and metabolomic technologies, a method to incorporate this research in a systematic manner with current classification systems is needed. The current approach, which is essentially nominalist in character, has to be developed where new data and new concepts of disease can be integrated and tested. Examples of how this could happen is shown in the context of Alzheimer's disease and subcortical ischemic disease. It is likely that a standardized approach that can develop and modify classification systems in a timely manner, based on science and free of societal and political influence, can enhance research, teaching and clinical practice.

Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T. · Department of Psychiatry, University of Chicago Medical School, and the Leonard Schanfield Research Institute at Council for Jewish Elderly, Chicago, IL 60091, USA. · Int J Geriatr Psychiatry. · Pubmed #14716694 No free full text.

Abstract: OBJECTIVE: To examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. METHODS AND MATERIALS: Patients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score > or =2 in at least one domain), were treated with donepezil (5-10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50-200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. RESULTS: 24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as > or = 50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. CONCLUSION: Sertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia.

Krishnan KR, Charles HC, Doraiswamy PM, Mintzer J, Weisler R, Yu X, Perdomo C, Ieni JR, Rogers S. · Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA. · Am J Psychiatry. · Pubmed #14594748 links to  free full text

Abstract: OBJECTIVE: The authors examined the effect of the acetylcholinesterase inhibitor donepezil on magnetic resonance markers of neurodegeneration in Alzheimer's disease. METHOD: In this randomized, double-blind, placebo-controlled pilot study, 67 patients with mild to moderate Alzheimer's disease received 24 weeks of treatment with donepezil (5 mg/day for the first 28 days and 10 mg/day thereafter) or placebo. Patients were reevaluated at 6-week intervals to measure change from baseline in several outcome measures, including right, left, and total hippocampal volumes, measured with magnetic resonance imaging; brain concentrations of N-acetylaspartate, measured with proton magnetic resonance spectroscopy; and cognition, assessed with the Alzheimer's Disease Assessment Scale cognitive subscale. RESULTS: At some interim assessments, mean normalized measures of N-acetylaspartate concentration tended to be higher in the donepezil-treated patients than in the patients who received placebo, but these differences were not significant at endpoint. At endpoint, the donepezil-treated patients had significantly smaller mean decreases in total and right hippocampal volumes and a smaller, nearly significant mean decrease in left hippocampal volume, compared with the placebo-treated patients. Mean Alzheimer's Disease Assessment Scale cognitive subscale scores were improved after treatment with donepezil, relative to placebo, at weeks 6, 12, 18, and 24. CONCLUSIONS: These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.

Krishnan KR, Levy RM, Wagner HR, Chen G, Gersing K, Doraiswamy PM. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3950 DUMC, Durham, NC 27710, USA. · Psychopharmacol Bull. · Pubmed #12397880 links to  free full text

Abstract: An informant-rated cognitive screen may have the potential to reliably help detect early dementia. A valuable scale should have good interitem associations and strong reliability when tested in groups with and without cognitive impairment. Our scale, the Brief Cognitive Scale (BCS), consists of 18 questions designed to assess cognitive function that affects everyday activities. Each question is coded with one of four levels, ranging from no impairment to severe impairment. We administered this screen to 120 subjects: 26 controls, 28 with a diagnosis of mild cognitive impairment (MCI), and 66 with a diagnosis of dementia. In addition, we administered a Folstein Mini-Mental Status Examination (MMSE) to each subject. Our results showed that the BCS scores were lowest in the control group and highest in the dementia group. In our sample, this scale was effective at discriminating between subjects with no cognitive impairment, MCI, and dementia. However, the scale needs further refinement before it can be employed in a clinical setting.

Doraiswamy PM, Krishnan KR, Anand R, Sohn H, Danyluk J, Hartman RD, Veach J. · Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #12188103 No free full text.

Abstract: Goals of the study included evaluating the long-term efficacy of rivastigmine in Alzheimer's disease (AD) patient categories stratified by baseline dementia severity, and post hoc investigation of particular benefits of early initiation of rivastigmine treatment in moderately severe AD. Both rivastigmine-treated groups (originally randomized to 1-4 or 6-12 mg/day) experienced significantly smaller declines in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores from baseline than the projected placebo group after 52 weeks. Patients receiving rivastigmine from Day 1 experienced significantly less decline compared with patients originally receiving placebo and then initiating rivastigmine treatment after a 6-month delay. Furthermore, cognitive benefits were more robust in patients with moderately severe disease compared with previous reports in mild to moderately severe AD. Findings suggest that early treatment with rivastigmine 6-12 mg/day is associated with sustained long-term cognitive benefits in patients with moderately severe AD. The results support the value of early treatment of AD patients, particularly those with moderately severe AD.

Kim DK, Kim BL, Sohn SE, Lim SW, Na DG, Paik CH, Krishnan KR, Carroll BJ. · Department of Neuropsychiatry, Samsung Medical Center, College of Medicine, Sungkyunkwan University, Seoul, Korea. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #10509375 No free full text.

Abstract: 1. The authors investigated the candidate neuroanatomic substrates underlying delusional thought disorder in old-aged depressed patients by using magnetic resonance imaging (MRI), and examined the relationship between volumes for individual brain structures and clinical correlates of particular relevance to depression: executive cognitive impairment and global severity of depression. 2. MR morphometry was performed on nineteen deluded depressed patients and 26 non-deluded depressed patients, all older than 55 years of age. Subjects were administered a neuropsychological test battery and measures of depression. 3. The absolute volume of prefrontal cortex (PFC) was smaller in the deluded depressed group than in non-deluded depressed group (131.79 +/- 37.26 ml vs. 152.65 +/- 26.13 ml, p = 0.03); a difference that was statistically significant even after adjusting for the effect of whole brain volume (p = 0.01). No group differences were observed in the volumes of the basal ganglia, the temporal lobes, the superior temporal gyri, the amygdala-hippocampal complex, the lateral ventricles, or whole brain. The relative volume of PFC correlated inversely and significantly with the index of Wisconsin Card Sorting Test (WCST) performance (r = -0.76, p < 0.01) in depressed patients. 4. PFC may be one of the candidate neuroanatomic substrates underlying delusional thought disorder in old-aged depression.

Gillen TE, Gregg KM, Yuan H, Kurth MC, Krishnan KR. · Pharsight Corp., 11230 Sorrento Valley Road, San Diego, CA 92121, USA. · Psychopharmacol Bull. · Pubmed #12397889 links to  free full text

Abstract: The database of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is a seminal work in the field of cognitive dysfunction and Alzheimer's disease. This 24-center study of 1,094 patients with Alzheimer's disease who received no treatment for their cognitive dysfunction and 463 normal control subjects is rich in neurobehavioral data and contains extensive imaging and neuropathologic findings. However, the Alzheimer's Disease Assessment Scale (ADAS) was not administered as part of the CERAD study, which limits the study's applicability to modern drug trials, in which the ADAS-cognitive subsection (ADAS-cog) is a popular end point. The purpose of this investigation was to develop a derived ADAS-cog score from the neurobehavioral data obtained from subjects during their evaluation in the CERAD study. Two calculated ADAS-cog scores were developed. The first was based on clinically mapping the items on the ADAS-cog to assessments that were performed in the CERAD study. The second was based on rescaling the Mini-Mental Status Exam (MMSE), using published results correlating the ADAS-cog to the MMSE. Standard characteristics of both calculated ADAS-cog scores were calculated and compared with each other and with the literature. Both calculated ADAS-cog scores performed comparably to published characteristics of the ADAS-cog. The clinically based calculated ADAS-cog outperformed the rescaled MMSE. Using the CERAD database, it is now possible to model the progression of an untreated (placebo) population of patients with Alzheimer's disease and correlate it to a study using ADAS-cog.

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.

Kishnani PS, Spiridigliozzi GA, Heller JH, Sullivan JA, Doraiswamy PM, Krishnan KR. · No affiliation provided · Am J Psychiatry. · Pubmed #11136652 links to  free full text

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