Brain imaging in the differential diagnosis of young-onset dementias.

Young-onset dementia is a broad category of diseases that affect adults before the age of 65, with devastating effects on individuals and families. Neuroimaging plays a clear and ever-expanding role in the workup of these diseases. MRI demonstrates classic patterns of atrophy that help to confirm the clinical diagnosis and may predict the underlying disease. Functional nuclear imaging, such as PET, demonstrates areas of brain dysfunction even in the absence of visible atrophy. These techniques can inform important aspects of the care of young-onset dementia, such as the underlying pathologic condition, treatment, and prognosis.

Test-retest reliability of a new questionnaire for the retrospective assessment of long-term lithium use in bipolar disorder.

BACKGROUND: The identification of predictors of treatment response holds tremendous potential for the improvement of clinical outcomes in bipolar disorder (BP). The goal of this project is to evaluate the test-retest reliability of a new clinical tool, the Lithium Questionnaire (LQ), for the retrospective assessment of long-term lithium use in research participants with BP. METHODS: Twenty-nine individuals with BP-I (n=27), major depression (n=1), or schizoaffective disorder (n=1) were recruited for participation. The LQ was administered to all participants at two time-points, spaced 17 months apart on average, and used to determine each subject׳s score on the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder Scale, or the Alda Scale. Scores were confirmed through a best-estimate procedure, and test-retest reliability (intra-class correlation coefficient [ICC]) of the LQ was calculated. RESULTS: The correlation between the total Alda Scale scores at the two time-points was in the moderate range (ICC=0.60). Relevant clinical factors such as age or presence of Axis I psychiatric comorbidity did not influence the reliability. LIMITATIONS: The validity of the LQ was not examined. Inclusion of two participants with non-BP diagnoses may have affected the LQ׳s reliability, but re-analysis of our data after exclusion of these participants did not influence the reliability. The absence of measures of mood and cognition at time of LQ may be a limitation of this work. CONCLUSIONS: The LQ holds promise for the standardization of the retrospective assessment of long-term treatment in BP.

Pattern separation of emotional information in hippocampal dentate and CA3.

Emotional arousal, mediated by the amygdala, is known to modulate episodic memories stored by the hippocampus, a region involved in pattern separation (the process by which similar representations are independently stored). While emotional modulation and pattern separation have been examined independently, this study attempts to link the two areas of research to propose an alternative account for how emotion modulates episodic memory. We used an emotional discrimination task designed to tax pattern separation of emotional information by concurrently varying emotional valence and similarity of stimuli. To examine emotional modulation of memory at the level of hippocampal subfields, we used high-resolution fMRI (1.5 mm isotropic) of the medial temporal lobe. Consistent with prior reports, we observed engagement of the hippocampal dentate gyrus (DG) and CA3 during accurate discrimination of highly similar items (behavioral correlate of pattern separation). Furthermore, we observed an emotional modulation of this signal (negative > neutral) specific to trials on which participants accurately discriminated similar emotional items. The amygdala was also modulated by emotion, regardless of the accuracy of discrimination. Additionally, we found aberrant amygdala-hippocampal network activity in a sample of adults with depressive symptoms. In this sample, amygdala activation was enhanced and DG/CA3 activation was diminished during emotional discrimination compared to those without depressive symptoms. Depressive symptom severity was also negatively correlated with DG/CA3 activity. This study suggests a novel mechanistic account for how emotional information is processed by hippocampal subfields as well as how this network may be altered in mood disorders.

Asymmetric effects of emotion on mnemonic interference.

Emotional experiences can strengthen memories so that they can be used to guide future behavior. Emotional arousal, mediated by the amygdala, is thought to modulate storage by the hippocampus, which may encode unique episodic memories via pattern separation--the process by which similar memories are stored using non-overlapping representations. While prior work has examined mnemonic interference due to similarity and emotional modulation of memory independently, examining the mechanisms by which emotion influences mnemonic interference has not been previously accomplished in humans. To this end, we developed an emotional memory task where emotional content and stimulus similarity were varied to examine the effect of emotion on fine mnemonic discrimination (a putative behavioral correlate of hippocampal pattern separation). When tested immediately after encoding, discrimination was reduced for similar emotional items compared to similar neutral items, consistent with a reduced bias towards pattern separation. After 24h, recognition of emotional target items was preserved compared to neutral items, whereas similar emotional item discrimination was further diminished. This suggests a potential mechanism for the emotional modulation of memory with a selective remembering of gist, as well as a selective forgetting of detail, indicating an emotion-induced reduction in pattern separation. This can potentially increase the effective signal-to-noise ratio in any given situation to promote survival. Furthermore, we found that individuals with depressive symptoms hyper-discriminate negative items, which correlated with their symptom severity. This suggests that utilizing mnemonic discrimination paradigms allows us to tease apart the nuances of disorders with aberrant emotional mnemonic processing.

Diffusion tensor imaging of neuropsychiatric symptoms in mild cognitive impairment and Alzheimer's dementia.

Neuropsychiatric symptoms (NPS) occur frequently in mild cognitive impairment (MCI) and Alzheimer's dementia (AD). The authors examined the relationship between NPS and white-matter integrity in these conditions. Twenty-two individuals with MCI and 23 with mild AD underwent clinical assessments including the Neuropsychiatric Inventory Questionnaire and 3.0-tesla magnetic resonance scans. Fractional anisotropy (FA) was measured in the following manually-drawn regions of interest (ROI): fornix, cingulum bundle, splenium, and cerebral peduncles (control region). The probability of having NPS by tertile of ROI FA was assessed by logistic regression. Because associations were similar within MCI and AD groups, the two groups were combined. Compared with those in the highest tertile, participants within the lowest anterior cingulum (AC) FA tertile were more likely to exhibit irritability, agitation, dysphoria, apathy, and nighttime behavioral disturbances. After adjusting for Mini-Mental State Exam status, participants in the lowest versus highest tertile of AC FA were more likely to report irritability. Using DTI, low AC FA was associated with increased odds of irritability in mild AD and MCI participants. Further imaging studies are necessary to elucidate the role of the AC in the pathophysiology of neuropsychiatric symptoms in AD and MCI.

Total white matter hyperintensity volume in bipolar disorder patients and their healthy relatives.

OBJECTIVES: White matter hyperintensities (WMH) are more common in subjects with bipolar disorder (BP) than in healthy subjects (HS). Few studies have examined the effect of the diagnostic type of bipolar illness on WMH burden, and none have approached this question through a direct measurement of the volume of affected white matter in relationship to familiality. In this pilot study, we utilized a volumetric measurement of WMH to investigate the relationship between the total volume of WMH and the familiality and type of BP. METHODS: Forty-five individuals with bipolar I disorder (BP-I) with psychotic features, BP-I without psychotic features, or bipolar II disorder (BP-II), seven of their unaffected relatives, and 32 HS were recruited for participation. T-2 weighted magnetic resonance imaging scans were obtained on all subjects, and the total volume of all WMH for each subject was measured in cubic centimeters. The significance of difference between groups was tested using ANOVA with post-hoc adjustment for multiple comparisons. Further, we used logistic regression to test for trends between symptom load and total WMH volume. RESULTS: The mean total volume of WMH in BP-I patients with psychotic features was significantly higher (p < 0.05) than that of HS. Further, we observed a positive linear trend by familiality and type of affectedness when comparing mean total WMH volume of HS, unaffected family members, subjects with BP-II, and BP-I with and without a history of psychosis (p < 0.05). CONCLUSIONS: Based on a quantitative technique, WMH burden appears to be associated with familiality and type of BP. The significance of these findings remains to be fully elucidated.

Predictors of lithium response in bipolar disorder.

While lithium is generally regarded as the first-line agent for patients with bipolar disorder, it does not work for everyone, which raises the question: can we predict who will be most likely to respond? In this paper, we review the most compelling clinical, biologic, and genetic predictors of lithium response in bipolar disorder. Among clinical factors, the strongest predictors of good response are fewer hospitalizations preceding treatment, an episodic course characterized by an illness pattern of mania followed by depression, and a later age at onset of bipolar disorder. While several biologic predictors have been studied, the results are preliminary and require replication with studies of larger patient samples over longer observation periods. Neuroimaging is a particularly promising method given that it might concurrently illuminate pathophysiologic underpinnings of bipolar disorder, the mechanism of action of lithium, and potential predictors of lithium response. The first genome-wide association study of lithium response was recently completed. No definitive results emerged, perhaps because the study was underpowered. With major new initiatives in progress aiming to identify genes and genetic variations associated with lithium response, there is much reason to be hopeful that clinically useful information might be generated within the next several years. This could ultimately translate into tests that could guide the choice of mood-stabilizing medication for patients. In addition, it might facilitate pharmacologic research aimed at developing newer, more effective medications that might act more quickly and yield fewer side effects.

The association between activity participation and time to discharge in the assisted living setting.

OBJECTIVES: Given recent evidence that activity participation may reduce functional decline, the effect of activity on resident ability to remain in assisted living (AL) is of interest. This study examines the relationship between participation in activities and the length of time residents remain in AL. METHODS: The data reported here were gathered in the initial phase of the Maryland Assisted Living Study (MDAL), an epidemiologic study of psychiatric disorders in AL. A stratified, random sample of 198 residents of 22 AL facilities in central Maryland was evaluated using a number of cognitive, behavioral, general health, and functional assessments. The total amount of time each resident spent in group and solitary activity in the prior month was quantified. The dependent variable, time to discharge (TTD), was the number of days between the date of initial assessment by the study team and the date of death in AL, discharge, or administrative censoring. RESULTS: Greater levels of activity participation at baseline are associated with longer TTD in an univariate Cox proportional hazards model. After adjustment for global cognitive functioning, general medical health, and mobility, greater activity participation remained associated with longer TTD in AL (p=0.017). CONCLUSIONS: Higher levels of activity are associated with longer retention in the AL setting. This effect appeared to be independent of other potentially confounding factors such as general health, cognitive impairment, and mobility. This finding is consistent with the hypothesis that engagement in activities delays functional decline, but further longitudinal research is needed to understand this finding.