Nunzio Pomara

Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial.

OBJECTIVE The objective of this study was to compare the efficacy and safety of the moderate-affinity, uncompetitive N-methyl-d-aspartate receptor antagonist, memantine, versus placebo in patients with mild to moderate Alzheimer disease (AD). METHOD This was a randomized, double-blind, placebo-controlled clinical trial conducted at 42 U.S. sites. Participants were 403 outpatients with mild to moderate AD and Mini-Mental State Examination scores of 10-22 randomized to memantine (20 mg/day; N=201) or placebo (N=202) for 24 weeks. Primary outcomes were change from baseline at 24 weeks on the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-cog), a measure of cognition, and on the Clinicians Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), a global measure. Secondary outcomes included change on the Neuropsychiatric Inventory (NPI) and the Alzheimers Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL(23)), measures of behavior and function, respectively. RESULTS Most (82.4%) participants completed the trial. Memantine resulted in significantly better outcomes than placebo on measures of cognition, global status, and behavior when based on the protocol-specified primary last observation carried forward imputation as well as a mixed-models repeated-measures approach applied to the continuous outcomes. Treatment discontinuations because of adverse events for memantine versus placebo were 19 (9.5%) and 10 (5.0%), respectively. CONCLUSIONS These results support the safety and efficacy of memantine for the treatment of mild to moderate AD.

The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry

The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6–85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.

White matter abnormalities in HIV-1 infection: A diffusion tensor imaging study

Diffuse white matter pallor is the most frequent neuropathological feature of HIV-1 infection and has been found to be particularly prominent in the advanced stages of the disease. The purpose of this study was to determine whether subtle white matter abnormalities can be detected in medically stable, ambulatory HIV-1 patients, in vivo, using diffusion tensor imaging (DTI). DTI is a magnetic resonance imaging (MRI) technique that is uniquely suited for the study of subtle white matter abnormalities. DTI was performed in six HIV-1 patients and nine controls. The two groups were similar in age. Abnormal fractional anisotropy was found in the white matter of the frontal lobes and internal capsules of the HIV-1 patients, in the absence of group differences in mean diffusivity, computed proton density, and computed T2. DTI may be more sensitive than conventional MRI methods for detecting subtle white matter disruptions in HIV-1 disease.

Reduced frontal white matter integrity in cocaine dependence: a controlled diffusion tensor imaging study

BACKGROUND In vivo magnetic resonance studies have found that cocaine dependence is associated with T2 signal hyperintensities and metabolite abnormalities in cerebral white matter (WM). Functional neuroimaging studies have suggested that chronic cocaine use is primarily associated with frontal lobe deficits in regional cerebral blood flow and brain glucose metabolism levels; however, the effects of cocaine dependence, if any, on frontal WM microstructure are unknown. Thus, we sought to examine the effects of cocaine dependence on frontal WM integrity. METHODS Diffusion tensor imaging was employed to examine the WM integrity of frontal regions at four levels: 10 mm above, 5 mm above, 0 mm above, and 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. The fractional anisotropy (FA) of 12 cocaine-dependent patients and 13 age-similar control subjects was compared. RESULTS The cocaine-dependent patients had significantly reduced FA in the frontal WM at the AC-PC plane and a trend toward reduced FA at 5 mm below the AC-PC plane, suggestive of reduced WM integrity in these regions. CONCLUSIONS These findings were consistent with the hypothesis that cocaine dependence involves alterations in orbitofrontal connectivity, which may be involved in the decision-making deficits seen in this disorder.

A review of the relationship between proinflammatory cytokines and major depressive disorder

BACKGROUND Determining etiological factors and reviewing advances in diagnostic modalities sensitive and specific to Major Depressive Disorder (MDD) is of importance in its evaluation and treatment. The inflammatory hypothesis is one of the most prevalent topics concerning MDD and may provide insight into the pathogenesis of depression, development of biomarkers, and ultimately production of more effective depression therapies. METHOD We reviewed several studies to evaluate contemporary concepts concerning proinflammatory cytokines and their relationship to various depressive disorders, the use of anti-inflammatory therapies in MDD treatment, and the application of neuroimaging in conjunction with cytokine profiles from both plasma and CSF as possible diagnostic tools. RESULTS Proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of depressive disorders in different populations. Studies have shown elevated serum levels of IL-1, IL-6, TNF-α, CRP, and MCP-1 in depressed patients, but have presented mixed results with IL-8 serum levels, and with IL-6 and MCP-1 CSF levels. Anti-inflammatory treatment of MDD may have adjuvant properties with current depression medications. MRI and NIRS neuroimaging confirm neurological abnormalities in the presence of elevated proinflammatory cytokines in depressed or stressed patients. LIMITATIONS Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis. CONCLUSION There is significant evidence that inflammatory processes influence the development and progression of MDD. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific modes of diagnostics in determining MDD etiology and provide guidance in individual therapies.

Aging and cortisol resistance to suppression by dexamethasone: a positive correlation

Cortisol resistance to suppression by 0.5 mg of dexamethasone given at 11 p.m. was studied in 30 normal subjects, 17 to 78 years of age. Serum cortisol concentrations were determined by radioimmunoassay. A strong positive correlation was found between age and cortisol concentrations 9 hours after dexamethasone administration. The data suggest that aging, per se, might contribute to the increased cortisol resistance to suppression by dexamethasone reported in depression and dementia.

Selective Reductions in Plasma Aβ 1-42 in Healthy Elderly Subjects During Longitudinal Follow-Up: A Preliminary Report

OBJECTIVE Longitudinal changes in plasma beta amyloid protein 1-42 and 1-40 (Abeta42 and Abeta40) levels and possible relationships with cognitive decline and apolipoprotein (APOE) genotype were studied in healthy elderly individuals. METHODS Authors determined cognitive level and plasma Abeta40 and Abeta42 levels twice, approximately 4 years apart, in 34 elderly subjects. RESULTS Analyses revealed a selective reduction in Abeta42 levels at follow-up, which were not modulated by the epsilon4 allele. Greater reductions and higher baseline plasma Abeta42 levels were associated with reductions in cognitive scores. CONCLUSIONS Alterations in plasma Abeta42 levels may be associated with subtle cognitive decline in elderly subjects without dementia.

CSF corticotropin-releasing factor (CRF) in Alzheimer's disease: its relationship to severity of dementia and monoamine metabolites

The concentration of corticotropin-releasing factor-like immunoreactivity (CRF-LI) in the cerebrospinal fluid (CSF) of 15 probable Alzheimers disease (AD) patients with mild to moderate dementia and 10 neurologically normal age-matched controls was examined. There were no significant alterations in the mean CSF CRF-LI concentration in AD compared to controls. However, in the AD group, CSF CRF-LI correlated significantly with the global neuropsychological impairment ratings, suggesting that greater cognitive impairment was associated with lower CSF CRF-LI concentrations. There was a significant reduction in the CSF concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the AD patients, and there was a positive correlation between the concentration of CRF-LI and 5-HIAA in CSF. This latter finding suggests that serotoninergic neuronal systems may interact with CRF-containing neurons.

Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown.

TO THE EDITOR In humans, apolipoprotein E (apoE) has three isoforms: apoE2, apoE3, and apoE4. APOE4 is a major genetic risk factor for Alzheimer’s disease (AD).1 ApoE4 has direct effects on the cerebrovascular system resulting in microvascular lesions and blood-brain barrier (BBB) damage, as recently reviewed.2 Neurovascular dysfunction is also present in cognitively normal APOE4 carriers and individuals with APOE4-associated disorders including AD.1 - 3 Moreover, post-mortem brain tissue analysis has indicated that BBB breakdown in AD patients is more pronounced in APOE4 carriers compared to APOE3 or APOE2.4 - 6 Our recent studies in transgenic mice have demonstrated that apoE4 leads to BBB breakdown by activating the proinflammatory cyclophilin A (CypA)-matrix metalloproteinase-9 (MMP-9) pathway in brain pericytes which in turn results in degradation of the BBB tight junctions and basement membrane proteins.7 It has also been shown that apoE4-mediated BBB breakdown leads to secondary neuronal injury and cognitive decline in transgenic mice.7 ApoE2 and apoE3 maintained normal BBB integrity in transgenic mice by suppressing the CypA-MMP9 pathway.7 Here, we studied the cerebrospinal fluid (CSF)/plasma albumin quotient (QAlb), an established marker of BBB breakdown8, and CypA and active MMP-9 levels in CSF of cognitively normal individuals with different APOE genotypes to determine whether apoE4-dependent changes in BBB permeability and CypA-MMP9 pathway as shown in APOE4, but not APOE3 and APOE2 transgenic mice, also occur in humans.

Elevation in Plasma Abeta42 in Geriatric Depression: A Pilot Study

Elevated plasma amyloid beta 1–42 (Aβ42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Aβ levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer’s disease, have not been studied. We compared plasma Aβ in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Aβ42 levels and the Aβ42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Aβ42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Aβ levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Aβ42 and Aβ42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.