Abstract Background Post-mortem studies have demonstrated considerable dendritic pathologies among persons with schizophrenia and to some extent among those with bipolar-I disorder(BD-I). Modeling ...gray matter(GM) microstructural properties is now possible with a recently proposed diffusion-weighted MRI modeling technique: Neurite-Orientation Dispersion and Density Imaging(NODDI). This technique may bridge the gap between neuroimaging and histopathological findings. Methods We performed an extended series of multi-shell diffusion-weighted imaging and other structural imaging series using a 3T MRI. Participants scanned included individuals with schizophrenia(n=36), BD-I(n=29), and healthy controls(HC;n=35). GM-based spatial statistics was used to compare NODDI-driven microstructural measures(orientation-dispersion-index and neurite-density-indexNDI) among groups, and assess their relationship with neurocognitive performance. We also investigated the accuracy of these measures in the prediction of group membership, and whether combining them with cortical thickness and white matter fractional anisotropy further improved accuracy. Results The GM-NDI was significantly lower in temporal pole, anterior parahippocampal gyrus, and hippocampus of the schizophrenia patients than the HC. The GM-NDI of BD-I patients did not differ significantly from either schizophrenia patients or HC, and was intermediate between the two groups in the post-hoc analysis. Irrespective of diagnosis, higher performance in spatial working memory was significantly associated with higher GM-NDI mainly in the fronto-temporal areas. Addition of GM-NDI to cortical thickness resulted in higher accuracy to predict group membership. Conclusions GM-NDI captures brain differences in the major psychoses not accessible with other structural-MRI methods. Given the strong association of GM-NDI with disease state and neurocognitive performance, its potential utility for biological subtyping should be further explored.
The broadening use of antidepressants among older Americans has not been associated with a notable decrease in the burden of geriatric depression. This article, based on a selective review of the ...literature, explores several explanations for this paradox. The authors propose that the effectiveness of antidepressants depends in large part on the way they are used. Evidence supports that antidepressant pharmacotherapy leads to better outcomes when guided by a treatment algorithm as opposed to attempting to individualize treatment. Several published guidelines and pharmacotherapy algorithms developed for the treatment of geriatric depression are reviewed, and an updated algorithm proposed.
Summary Background Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation ...pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. Methods We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale MADRS score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150–300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg maximum 15 mg daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00892047. Findings From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 44% vs 26 29% participants; odds ratio OR 2·0 95% CI 1·1–3·7, p=0·03; number needed to treat NNT 6·6 95% CI 3·5–81·8). Akathisia was the most common adverse effect of aripiprazole (reported in 24 26% of 91 participants on aripiprazole vs 11 12% of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 17% of 86 vs two 2% of 81 participants), but not with treatment-emergent suicidal ideation (13 21% of 61 vs 19 29% of 65 participants) or other measured safety variables. Interpretation In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. Funding National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.
Alzheimer's dementia (AD) is associated with electroencephalography (EEG) abnormalities including in the power ratio of beta to theta frequencies. EEG studies in mild cognitive impairment (MCI) have ...been less consistent in identifying such abnormalities. One potential reason is not excluding the EEG aperiodic components, which are less associated with cognition than the periodic components. Here, we investigate whether aperiodic and periodic EEG components are disrupted differently in AD or MCI vs. healthy control (HC) individuals and whether a periodic based beta/theta ratio differentiates better MCI from AD and HC groups than a ratio based on the full spectrum.
Data were collected from 44 HC (mean age (SD) = 69.1 (5.3)), 114 MCI (mean age (SD) = 72.2 (7.5)), and 41 AD (mean age (SD) = 75.7 (6.5)) participants. Aperiodic and periodic components and full spectrum EEG were compared among the three groups. Receiver operating characteristic curves obtained via logistic regression classifications were used to distinguish the groups. Last, we explored the relationships between cognitive performance and the beta/theta ratios based on the full or periodic spectrum.
Aperiodic EEG components did not differ among the three groups. In contrast, AD participants showed an increase in full spectrum and periodic relative powers for delta, theta, and gamma and a decrease for beta when compared to HC or MCI participants. As predicted, MCI group differed from HC participants on the periodic based beta/theta ratio (Bonferroni corrected p-value = 0.036) measured over the occipital region. Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI participants, and outperformed classifiers based on beta/theta power ratio in full spectrum EEG. Beta/theta ratios were comparable in their association with cognition.
In contrast to a full spectrum EEG analysis, a periodic-based analysis shows that MCI individuals are different on beta/theta ratio when compared to healthy individuals. Focusing on periodic components in EEG studies with or without other biological markers of neurodegenerative diseases could result in more reliable findings to separate MCI from healthy aging, which would be valuable for designing preventative interventions.
Working memory deficits are common among individuals with Alzheimer's dementia (AD) or mild cognitive impairment (MCI). Yet, little is known about the mechanisms underlying these deficits. ...Theta-gamma coupling-the modulation of high-frequency gamma oscillations by low-frequency theta oscillations-is a neurophysiologic process underlying working memory. We assessed the relationship between theta-gamma coupling and working memory deficits in AD and MCI. We hypothesized that: (1) individuals with AD would display the most significant working memory impairments followed by MCI and finally healthy control (HC) participants; and (2) there would be a significant association between working memory performance and theta-gamma coupling across all participants. Ninety-eight participants completed the N-back working memory task during an electroencephalography (EEG) recording: 33 with AD (mean ± SD age: 76.5 ± 6.2), 34 with MCI (mean ± SD age: 74.8 ± 5.9) and 31 HCs (mean ± SD age: 73.5 ± 5.2). AD participants performed significantly worse than control and MCI participants on the 1- and 2-back conditions. Regarding theta-gamma coupling, AD participants demonstrated the lowest level of coupling followed by the MCI and finally control participants on the 2-back condition. Finally, a linear regression analysis demonstrated that theta-gamma coupling (
= 0.69,
< 0.001) was the most significant predictor of 2-back performance. Our results provide evidence for a relationship between altered theta-gamma coupling and working memory deficits in individuals with AD and MCI. They also provide insight into a potential mechanism underlying working memory impairments in these individuals.
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