Faculty Bibliography

Background: A common method of evaluating memory involves list learning in which the items to be remembered are presented in a temporal sequence. Studies of serial position have highlighted the importance of the order of presentation, but little attention has been paid so far to the order of recall. Following from the work of Kahana and colleagues (e.g., Kahana, 1996; Howard & Kahana, 1999), we have developed two memory indices for neuropsychological tests of memory to examine order of recall and use of temporal context. These are output order (i.e., the first item recalled) and output order variability (i.e., the temporal distance between the first four recalled items). We tested two hypotheses in separate cohorts: 1) whether these indices were correlated with generalized cognitive ability, and 2) whether they were associated with gray matter hippocampal volumes. Methods: To test hypothesis 1, we conducted ordinal and linear regression analyses on data from the Memory Evaluation Research Initiative (MERI), which comprised 680 participants, aged 60 or above. Memory performance was measured with the Rey's AVLT and we included only participants who recalled at least one item; generalized cognitive ability was measured with the MMSE. To test hypothesis 2, we analysed data from a sample of 81 cognitively intact individuals aged 60 or over. Memory was measured with the BSRT and hippocampal volume was extracted from MRI images using an automated volumetric approach. Results: Output order and variability correlated with MMSE scores only in the delayed trial, but not in the immediate trial: higher MMSE scores were associated with starting recall nearer the primacy position, and with less variability. Similarly, variability in the delayed trial correlated (negatively) with hippocampal size. Conclusions: These findings suggest that the hippocampus may be involved in coding the temporal context of the learning episode, and that measuring the ability to employ temporal information can be useful to predict future cognitive performance

INTRODUCTION/BACKGROUND:Volumes of hippocampus and cholinergic basal forebrain are associated with delayed recall performance and may modulate the effect of a muscarinic receptor antagonist on delayed recall in healthy volunteers. METHODS:We studied 15 older adults before and after the oral administration of a single dose of 1 or 2 mg of the preferential M1 muscarinic receptor antagonist trihexyphenidyl (Artane™) or placebo in a double-blind randomized cross-over design. Hippocampus and basal forebrain volumes were measured using magnetic resonance imaging. RESULTS:We found a significant interaction between treatment and hippocampus volume and a trend level effect between treatment and anterior basal forebrain volume on task performance, with an attenuation of the association between volume size and performance with trihexyphenidyl. DISCUSSION/CONCLUSIONS:These findings suggest a reduction of delayed recall performance with increasing doses of the muscarinic antagonist that is related to an uncoupling of the association of task performance with cholinergic basal forebrain and hippocampus volumes.

BACKGROUND: Primacy performance in recall has been shown to predict cognitive decline in cognitively intact elderly, and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Delayed primacy performance, but not delayed non-primacy performance, has been shown to be associated with hippocampal volume in cognitively intact older individuals. Since presence of neurofibrillary tangles is an early sign of AD-related pathology, we set out to test whether cerebrospinal fluid (CSF) levels of tau had an effect on delayed primacy performance, while controlling for hippocampal volume and CSF Abeta 1-42 levels. METHODS: Forty-seven individuals, 60 or older and cognitively intact, underwent a multi-session study including lumbar puncture, an MRI scan of the head and memory testing. RESULTS: Our regression analyses show that CSF levels of hyperphosphorylated (P) tau are only associated with reduced delayed primacy performance when hippocampal volumes are smaller. CONCLUSION: Our findings suggest that hippocampal size may play a protective role against the negative effects of P tau on memory.

Delayed recall at the primacy position (first few items on a list) has been shown to predict cognitive decline in cognitively intact elderly participants, with poorer delayed primacy performance associated with more pronounced generalized cognitive decline during follow-up. We have previously suggested that this association is due to delayed primacy performance indexing memory consolidation, which in turn is thought to depend upon hippocampal function. Here, we test the hypothesis that hippocampal size is associated with delayed primacy performance in cognitively intact elderly individuals. Data were analyzed from a group (N=81) of cognitively intact participants, aged 60 or above. Serial position performance was measured with the Buschke selective reminding test (BSRT). Hippocampal size was automatically measured via MRI, and unbiased voxel-based analyses were also conducted to explore further regional specificity of memory performance. We conducted regression analyses of hippocampus volumes on serial position performance; other predictors included age, family history of Alzheimer's disease (AD), APOE epsilon4 status, education, and total intracranial volume. Our results collectively suggest that there is a preferential association between hippocampal volume and delayed primacy performance. These findings are consistent with the hypothesis that delayed primacy consolidation is associated with hippocampal size, and shed light on the relationship between delayed primacy performance and generalized cognitive decline in cognitively intact individuals, suggesting that delayed primacy consolidation may serve as a sensitive marker of hippocampal health in these individuals.

BACKGROUND: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. METHODS: Cognitively intact elderly individuals (n=37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25 - 3.00mg) or placebo on different days, approximately 1week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. RESULTS: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. CONCLUSIONS: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population.

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-alpha, 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.

INTRODUCTION: Vilazodone is a potent serotonin (5-HT) reuptake inhibitor and 5-HT(1)A receptor partial agonist approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD) in adults. This study evaluated the efficacy and tolerability of vilazodone in the treatment of MDD. METHOD: This 8-week, randomized (1:1), double-blind, placebo-controlled, parallel-group, fixed-dose study conducted from January 2012 to February 2013 compared vilazodone 40 mg/d with placebo in outpatients with DSM-IV-TR-diagnosed MDD. The primary efficacy measure was Montgomery-Asberg Depression Rating Scale (MADRS) total score change from baseline to week 8 analyzed by a mixed-effects model for repeated measures on the intent-to-treat population (placebo = 252, vilazodone = 253). Secondary efficacy outcomes were Clinical Global Impressions-Severity of Illness (CGI-S) Scale score change from baseline and MADRS sustained response rate (total score