Faculty Bibliography

The risk of Alzheimer's disease can be predicted by volumetric analyses of MRI data in the medial temporal lobe. The present study compared a volumetric measurement of the hippocampus with a novel measure of hippocampal integrity (HI) derived from the ratio of parenchyma volume over total volume. Participants were cognitively intact and aged 60 years or older at baseline, and were tested twice, roughly 3 years apart. Participants had been recruited for a study on late-life major depression (LLMD) and were evenly split between depressed patients and controls. Linear regression models were applied to the data with a cognitive composite score as the outcome, and HI and volume, together or separately, as predictors. Subsequent cognitive performance was predicted well by models that included an interaction between HI and LLMD status, such that lower HI scores predicted more cognitive decline in depressed patients. More research is needed, but tentative results from this study appear to suggest that the newly introduced measure HI is an effective tool for the purpose of predicting future changes in general cognitive ability, and especially so in individuals with LLMD.

Major depressive disorder (MDD), common in the elderly, is a risk factor for dementia. Abnormalities in glutamatergic neurotransmission via the N-methyl-d-aspartate receptor (NMDA-R) have a key role in the pathophysiology of depression. This study examined whether depression was associated with cerebrospinal fluid (CSF) levels of NMDA-R neurotransmission-associated amino acids in cognitively intact elderly individuals with MDD and age- and gender-matched healthy controls. CSF was obtained from 47 volunteers (MDD group, N=28; age- and gender-matched comparison group, N=19) at baseline and 3-year follow-up (MDD group, N=19; comparison group, N=17). CSF levels of glutamine, glutamate, glycine, l-serine and d-serine were measured by high-performance liquid chromatography. CSF levels of amino acids did not differ across MDD and comparison groups. However, the ratio of glutamine to glutamate was significantly higher at baseline in subjects with MDD than in controls. The ratio decreased in individuals with MDD over the 3-year follow-up, and this decrease correlated with a decrease in the severity of depression. No correlations between absolute amino-acid levels and clinical variables were observed, nor were correlations between amino acids and other biomarkers (for example, amyloid-beta42, amyloid-beta40, and total and phosphorylated tau protein) detected. These results suggest that abnormalities in the glutamine-glutamate cycle in the communication between glia and neurons may have a role in the pathophysiology of depression in the elderly. Furthermore, the glutamine/glutamate ratio in CSF may be a state biomarker for depression.

Adapted from the work of Kahana and colleagues (e.g., Kahana, 1996), we present two measures of order of recall in neuropsychological free recall tests. These are the position on the study list of the first recalled item, and the degree of variability in the order in which items are reported at test (i.e., the temporal distance across the first four recalled items). We tested two hypotheses in separate experiments: (1) whether these measures predicted generalized cognitive ability, and (2) whether they predicted gray matter hippocampal volume. To test hypothesis 1, we conducted ordinal regression analyses on data from a group of 452 participants, aged 60 or above. Memory performance was measured with Rey's AVLT and generalized cognitive ability was measured with the MMSE test. To test hypothesis 2, we conducted a linear regression analysis on data from a sample of 79 cognitively intact individuals aged 60 or over. Memory was measured with the BSRT and hippocampal volume was extracted from MRI images. Results of Experiment 1 showed that the position of the first item recalled and the degree of output order variability correlated with MMSE scores only in the delayed test, but not in the immediate test. In Experiment 2, the degree of variability in the recall sequence of the delayed trial correlated (negatively) with hippocampal size. These findings confirm the importance of delayed primacy as a marker of cognitive ability, and are consistent with the idea that the hippocampus is involved in coding the temporal context of learned episodes.

Background: Volumetric analyses of MRI data have been employed to predict conversion to Alzheimer's disease (AD), and individuals with preclinical AD tend to show atrophy in the right medial temporal lobe, which includes the hippocampus. In this study, we set out to compare a volumetric measurement of the hippocampus to a newly developed measure of hippocampal integrity in their respective potential for prediction of generalized cognitive performance (MMSE) over time. Methods: Ninety participants, who were cognitively intact at baseline and aged 60 or older, were recruited for a study on major depressive disorder (MDD) and tested twice, over three years. Linear regression models were applied to the data with the change in MMSE score as outcome, and hippocampal integrity (HI), hippocampal volume (HV), age and MDD status among the predictors. HI was measured for the left and right hippocampi as the ratio of the parenchymal voxels to the total number of voxels in an automatically determined hippocampus ROI. The ROI was determined by local affine registration of 65 previously delineated hippocampus atlases to the test subject. HVs were extracted from MRI images using an automated volumetric approach. Results: Change in MMSE performance was significantly predicted by both integrity and volume: greater HI and HV values were associated with less decline. However, when comparing predictors' contributions to the models, HI was slightly better than HV for the right side, and explained more of the variance in MMSE performance; HI and HV contributions were largely comparable for the left side. Conclusions: More research is needed to evaluate whether hippocampal integrity or hippocampal volume is a more accurate predictor of cognitive decline, but tentative results from this study appear to suggest that right side HI measures have the potential to be sensitive to future changes in general cognitive ability

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: An upregulation of monocyte chemoattractant protein-1 (MCP-1) and other chemokines (Interleukin-8 [IL-8] and Interferon gamma-induced protein 10 [IP-10]) has been reported in MCI and mild Alzheimer's disease (AD). MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. In AD, higher CSF MCP-1, and IP-10 have been associated with higher MMSE scores, suggesting potential beneficial effects of chemokine upregulation. This may include possible effects on AD biomarkers (Abeta and tau indices), which are known to be implicated in preclinical AD. This study examined the relationship between CSF chemokine levels and established AD biomarkers in older individuals with Major Depressive Disorder (MDD), which is a risk factor for AD, and in healthy controls. Methods: CSF was obtained from 47 older subjects with intact cognition and a Mini-Mental State Exam score of at least 28; 29 with MDD and 19 controls. MRI scans were performed to rule out structural brain abnormalities. No subject had gross MRI abnormalities other than white matter hyperintensities. CSF MCP-1, IP-10, IL-8, were determined using Luminex Corporation multiplexed beadbased immunoassays. Abeta40, Abeta42, total-tau, and ptau were determined using previously published methods. Results: MCP-1 was negatively correlated with CSF Abeta40 (r=-0.376, p=0.011), total tau (r=-0.361, p=0.014), and p-tau (r=-0.361, p=0.014); IL-8 was positively correlated with t-tau (r=0.357, p=0.015); IP-10 was positively correlated with t-tau (r=0.380, p=0.009) and p-tau (r=0.323, p=0.027). None of the chemokines showed a significant correlation with Abeta42 or significant group differences. Conclusions: Our findings suggest complex and differential associations between these chemokines and CSF AD Abeta and tau indices and highlight the need for further studies to determine their prognostic significance