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.

Major depressive disorder (MDD) contributes to a significant worldwide disease burden, expected to be second only to heart disease by 2050. However, accurate diagnosis has been a historical weakness in clinical psychiatry. As a result, there is a demand for diagnostic modalities with greater objectivity that could improve on current psychiatric practice that relies mainly on self-reporting of symptoms and clinical interviews. Over the past two decades, literature on a growing number of putative biomarkers for MDD increasingly suggests that MDD patients have significantly different biological profiles compared to healthy controls. However, difficulty in elucidating their exact relationships within depression pathology renders individual markers inconsistent diagnostic tools. Consequently, further biomarker research could potentially improve our understanding of MDD pathophysiology as well as aid in interpreting response to treatment, narrow differential diagnoses, and help refine current MDD criteria. Representative of this, multiplex assays using multiple sources of biomarkers are reported to be more accurate options in comparison to individual markers that exhibit lower specificity and sensitivity, and are more prone to confounding factors. In the future, more sophisticated multiplex assays may hold promise for use in screening and diagnosing depression and determining clinical severity as an advance over relying solely on current subjective diagnostic criteria. A pervasive limitation in existing research is heterogeneity inherent in MDD studies, which impacts the validity of biomarker data. Additionally, small sample sizes of most studies limit statistical power. Yet, as the RDoC project evolves to decrease these limitations, and stronger studies with more generalizable data are developed, significant advances in the next decade are expected to yield important information in the development of MDD biomarkers for use in clinical settings.

Background: The "primacy effect," i.e., increased memory recall for the first items of a series compared to the following items, is reduced in amnestic mild cognitive impairment (aMCI). Memory task-fMRI studies demonstrated that primacy recall is associated with higher activation of the hippocampus and temporo-parietal and frontal cortical regions in healthy subjects. Functional magnetic resonance imaging (fMRI) at resting state revealed that hippocampus functional connectivity (FC) with neocortical brain areas, including regions of the default mode network (DMN), is altered in aMCI. The present study aimed to investigate whether resting state fMRI FC between the hippocampus and cortical brain regions, especially the DMN, is associated with primacy recall performance in aMCI. Methods: A number of 87 aMCI patients underwent resting state fMRI and verbal episodic memory assessment. FC between the left or right hippocampus, respectively, and all other voxels in gray matter was mapped voxel-wise and used in whole-brain regression analyses, testing whether FC values predicted delayed primacy recall score. The delayed primacy score was defined as the number of the first four words recalled on the California Verbal Learning Test. Additionally, a partial least squares (PLS) analysis was performed, using DMN regions as seeds to identify the association of their functional interactions with delayed primacy recall. Results: Voxel-based analyses indicated that delayed primacy recall was mainly (positively) associated with higher FC between the left and right hippocampus. Additionally, significant associations were found for higher FC between the left hippocampus and bilateral temporal cortex, frontal cortical regions, and for higher FC between the right hippocampus and right temporal cortex, right frontal cortical regions, left medial frontal cortex and right amygdala (p < 0.01, uncorr.). PLS analysis revealed positive associations of delayed primacy recall with FC between regions of the DMN, including the left and right hippocampus, as well as middle cingulate cortex and thalamus (p < 0.04). In conclusion, in the light of decreased hippocampus function in aMCI, inter-hemispheric hippocampus FC and hippocampal FC with brain regions predominantly included in the DMN may contribute to residual primacy recall in aMCI.

Background: Numerous studies have suggested that the APOE e4 allele, an established risk factor for AD, may act synergistically with depression to increase the risk for progressive cognitive decline and conversion to MCI/AD. However, these findings remain controversial and have been reported inconsistently. A possible reason for these conflicting results is differences in methodologies across studies, including differences in the definition of depression, failure to properly diagnose depression or AD, short duration of follow up, differences in age, and possible inclusion of individuals with preexisting cognitive decline or MCI. These considerations prompted us to conduct a 3-year longitudinal prospective study in cognitively intact elderly individuals, who either had a diagnosis of MDD or were healthy controls, to determine if e4 and depression interacted with respect to progressive cognitive decline. We focused primarily on neurobehavioral tests sensitive to early AD and also examined the CSF total tau/Ab42 ratio, which has been linked to incident MCI/AD-related decline. Methods: 91 participants were included in this study, 60 older and with an MMSE score of at least 28 at the beginning of the 3-year longitudinal investigation. 45 participants had a diagnosis of MDD. APOE status and CSF AD biomarkers were determined at baseline and participants underwent a comprehensive neuropsychological test battery that included the Buschke Selective Reminding Test and the Boston Naming Task. Regression models examining change scores from baseline to follow-up were employed to test our hypotheses. Results: Adjusting for age and MMSE score, elderly participants with depression and carrying APOE e4 showed greater decline on average in the Boston Naming Task (p < 0.01) and a trend with high imagery performance (p = 0.05). A higher CSF total tau/Ab42 ratio was associated with decline in memory performance among depressed subjects (r =-0.45, p = 0.03, n = 23), regardless of APOE status, but not in controls. Conclusions: Our results indicate that cognitively intact depressive e4 carriers have greater decline in selective cognitive tests especially in a confrontation naming task even during a relatively short three year longitudinal period compared to controls. Additionally, increased brain AD pathology as reflected by the CSF tau/Ab42 ratio appeared to be associated with greater decline in memory performance in all depressives, regardless of APOE e4 status

Background: The APOE e4 allele, an established risk factor for AD, may act synergistically with depression to increase the risk for progressive cognitive decline and conversion to MCI/AD. However, these findings have been reported inconsistently. Methodological differences across studies, including in the definition of depression, failure to properly diagnose depression or AD, short duration of follow up, and possible inclusion of individuals with preexisting cognitive decline or MCI. These considerations prompted us to conduct a 3-year longitudinal prospective study in cognitively intact elderly individuals, who either had a diagnosis of MDD or were healthy controls, to determine if e4 and depression interacted with respect to progressive cognitive decline. We focused primarily on neurobehavioral tests sensitive to early AD and also examined the CSF total tau/Abeta42 ratio, which has been linked to incident MCI/AD-related decline. Methods: 91 participants were included in this study, age 60 and older, with an MMSE 28 at the beginning of the 3- year longitudinal investigation. 45 participants had a diagnosis of MDD. Participants underwent a comprehensive neuropsychological test battery that included the Buschke Selective Reminding Test and Boston Naming Task at baseline and annually thereafter. APOE status on all and CSFAD biomarkers on a subset of subjects were determined at baseline. Regression analyses examining neuropsych change scores (baseline to follow-up) as functions of baseline characteristics. Results: Adjusting for age and MMSE score, participants with depression and carrying. Conclusions: Our results indicate that cognitively intact depressive e4 carriers have greater decline in selective cognitive tests especially in a confrontation naming task even during a relatively short three year longitudinal period compared to controls. Additionally, increased brain AD pathology as reflected by the CSF tau/Abeta42 ratio appeared to be associated with greater decline in memory performance in all depressives, regardless of APOE e4 status

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.