Late Life Depression is Not Associated With Alzheimer-Type Tau: Preliminary Evidence From a Next-Generation Tau Ligand PET-MR Study.

OBJECTIVE: To investigate whether tau accumulation is higher in late life depression (LLD) compared to non-depressed cognitively unimpaired (CU) older adults. To situate these findings in the neurodegeneration model of LLD by assessing group differences in tau and grey matter volume (GMV) between LLD, non-depressed CU and mild cognitive impairment due to Alzheimer's Disease (MCI). DESIGN: Monocentric, cross-sectional study. SETTING: University Psychiatric hospital, memory clinic and outpatient neurology practice. PARTICIPANTS: A total of 102 adults over age 60, of whom 19 currently depressed participants with LLD, 19 with MCI and 36 non-depressed CU participants completed neuropsychological testing and tau PET-MR imaging. MEASUREMENTS: PET-MRI: 18F-MK-6240 tracer SUVR for tau assessment; 3D T1-weighted structural MRI derived GMV in seven brain regions (temporal, cingulate, prefrontal and parietal regions); amyloid PET to assess amyloid positivity; Neuropsychological test scores: MMSE, RAVLT, GDS, MADRS. ANCOVA and Spearman's rank correlations to investigate group differences in tau and GMV, and correlations with neuropsychological test scores respectively. RESULTS: Compared to non-depressed CU participants, LLD patients showed lower GMV in temporal and anterior cingulate regions but similar tau accumulation and amyloid positivity rate. In contrast, MCI patients had significantly higher tau accumulation in all regions. Tau did not correlate with any neuropsychological test scores in LLD. CONCLUSION: Our findings suggest AD-type tau is not higher in LLD compared to non-depressed, cognitively unimpaired older adults and appears unlikely to contribute to lower gray matter volume in LLD, further underscoring the need to distinguish major depressive disorder from depressive symptoms occurring in early AD.

Mild Motor Signs in Healthy Aging Are Associated with Lower Synaptic Density in the Brain.

OBJECTIVE: To investigate whether mild motor signs (MMS) in old age correlate with synaptic density in the brain. BACKGROUND: Normal aging is associated with a decline in movement quality and quantity, commonly termed "mild parkinsonian signs" or more recently MMS. Whether MMS stem from global brain aging or pathology within motor circuits remains unresolved. The synaptic vesicle glycoprotein 2A positron emission tomography (PET) ligand 11 C-UCB-J allows the investigation of brain-motor associations at the synaptic level in vivo. METHOD: Fifty-eight healthy older adults (≥50 years) were included from two monocentric control cohorts. Brain magnetic resonance imaging and 11 C-UCB-J PET data were available in 54 participants. 11 C-UCB-J PET binding was quantified by standardized uptake value ratio (SUVR) values in grey matter (GM) volumes of interest (VOIs): caudate, putamen, globus pallidus, substantia nigra, thalamus, cerebellum, and the frontal, parietal, temporal, and occipital cortex. Multiple linear regression analyses were performed with Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score measuring MMS as the dependent variable and mean SUVR values in each VOI as the independent variable with age, Fazekas score (white matter lesion [WML] load), VOI and cohort as covariates. RESULTS: Participants (68 ± 7.5 years; 52% female) had an average MDS-UPDRS part III score of 3.3 ± 2.8. The MDS-UPDRS part III score was inversely associated with synaptic density, independently of WML load or GM volume, in the caudate, substantia nigra, thalamus, cerebellum, and parietal, occipital, temporal cortex. Cohen's f2 showed moderate effect sizes for subcortical (range, 0.30-0.35), cortical (0.28-0.35) and cerebellar VOIs (0.31). CONCLUSION: MMS in healthy aging are associated with lower synaptic density throughout the brain. © 2023 International Parkinson and Movement Disorder Society.

The Cortisol Awakening Response as a Biomarker for Cognitive Side-Effects of Electroconvulsive Therapy.

OBJECTIVE: To test whether the cortisol awakening response (CAR) could be a biomarker for cognitive decline during electroconvulsive therapy (ECT). METHODS: We studied 50 older patients with depression who were treated with ECT from the MODECT cohort. We used linear regression analyses to examine the association between CAR and cognitive change, assessed by the change in Mini Mental State Examination scores between baseline and 1 week after ECT course. CAR was assessed by the area under the curve of cortisol levels, according to Pruessner's-formula. Associations were adjusted for putative confounders, based on previous literature and availability. RESULTS: We found no significant associations between the CAR and cognitive change during the ECT course in (un)adjusted models. CONCLUSION: Our results indicate that the CAR is not usable as a biomarker for ECT-induced cognitive decline during ECT course. Further research in cohorts with larger samples is needed.

The Leuven late life depression (L3D) study: PET-MRI biomarkers of pathological brain ageing in late-life depression: study protocol.

BACKGROUND: Major depressive disorders rank in the top ten causes of ill health in all but four countries worldwide and are the leading cause of years lived with disability in Europe (WHO). Recent research suggests that neurodegenerative pathology may contribute to the development of late-life depression (LLD) in a sub-group of patients and represent a target for prevention and early diagnosis. In parallel, electroconvulsive therapy (ECT), which is the most effective treatment for severe LLD, has been associated with significant brain structural changes. In both LLD and ECT hippocampal volume change plays a central role; however, the neurobiological mechanism underlying it and its relevance for clinical outcomes remain unresolved. METHODS: This is a monocentric, clinical cohort study with a cross-sectional arm evaluating PET-MR imaging and behavioural measures in 64 patients with LLD compared to 64 healthy controls, and a longitudinal arm evaluating the same imaging and behavioural measures after 10 ECT sessions in 20 patients receiving ECT as part of their normal clinical management. Triple tracer PET-MRI data will be used to measure: hippocampal volume (high resolution MRI), synaptic density using [11C]UCB-J, which targets the Synaptic Vesicle Glycoprotein 2A receptor, tau pathology using [18F]MK-6240, and cerebral amyloid using [18F]-Flutemetamol, which targets beta-amyloid neuritic plaques in the brain. Additional MRI measures and ultrasound will assess cerebral vascular structure and brain connectivity. Formal clinical and neuropsychological assessments will be conducted alongside experience sampling and physiological monitoring to assess mood, stress, cognition and psychomotor function. DISCUSSION: The main aim of the study is to identify the origin and consequences of hippocampal volume differences in LLD by investigating how biomarkers of pathological ageing contribute to medial temporal lobe pathology. Studying how synaptic density, tau, amyloid and vascular pathology relate to neuropsychological, psychomotor function, stress and ECT, will increase our pathophysiological understanding of the in vivo molecular, structural and functional alterations occurring in depression and what effect this has on clinical outcome. It may also lead to improvements in the differential diagnosis of depression and dementia yielding earlier, more optimal, cost-effective clinical management. Finally, it will improve our understanding of the neurobiological mechanism of ECT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03849417 , 21/2/2019.

Preliminary evidence for preserved synaptic density in late-life depression.

Late-life depression has been consistently associated with lower gray matter volume, the origin of which remains largely unexplained. Recent in-vivo PET findings in early-onset depression and Alzheimer's Disease suggest that synaptic deficits contribute to the pathophysiology of these disorders and may therefore contribute to lower gray matter volume in late-life depression. Here, we investigate synaptic density in vivo for the first time in late-life depression using the synaptic vesicle glycoprotein 2A receptor radioligand 11C-UCB-J. We included 24 currently depressed adults with late-life depression (73.0 ± 6.2 years, 16 female, geriatric depression scale = 19.5 ± 6.8) and 36 age- and gender-matched healthy controls (70.4 ± 6.2 years, 21 female, geriatric depression scale = 2.7 ± 2.9) that underwent simultaneous 11C-UCB-J positron emission tomography (PET) and 3D T1- and T2-FLAIR weighted magnetic resonance (MR) imaging on a 3-tesla PET-MR scanner. We used analyses of variance to test for 11C-UCB-J binding and gray matter volumes differences in regions implicated in depression. The late-life depression group showed a trend in lower gray matter volumes in the hippocampus (p = 0.04), mesial temporal (p = 0.02) and prefrontal cortex (p = 0.02) compared to healthy control group without surviving correction for multiple comparison. However, no group differences in 11C-UCB-J binding were found in these regions nor were any associations between 11C-UCB-J and depressive symptoms. Our data suggests that, in contrast to Alzheimer's Disease, lower gray matter volume in late-life depression is not associated with synaptic density changes. From a therapeutic standpoint, preserved synaptic density in late-life depression may be an encouraging finding.

Characterization of gray matter volume changes from one week to 6 months after termination of electroconvulsive therapy in depressed patients.

BACKGROUND: Increased gray matter volume (GMV) following electroconvulsive therapy (ECT) has been well-documented, with limited studies reporting a subsequent decrease in GMV afterwards. OBJECTIVE: This study characterized the reversion pattern of GMV after ECT and its association with clinical depression outcome, using multi-site triple time-point data from the Global ECT-MRI Research Collaboration (GEMRIC). METHODS: 86 subjects from the GEMRIC database were included, and GMV in 84 regions-of-interest (ROI) was obtained from automatic segmentation of T1 MRI images at three timepoints: pre-ECT (T0), within one-week post-ECT (T1), and one to six months post-ECT (T2). RM-ANOVAs were used to assess longitudinal changes and LMM analyses explored associations between GMV changes and demographical and clinical characteristics. RESULTS: 63 of the 84 ROIs showed a significant increase-and-decrease pattern (RM-ANOVA, Bonferroni corrected p < 0.00059). Post hoc tests indicated a consistent pattern in each of these 63 ROIs: significant increase from T0 to T1inGMV, followed by significant decrease from T1 to T2 and no difference between T0 and T2, except for both amygdalae, right hippocampus and pars triangularis, which showed the same increase and decrease but GMV at T2 remained higher compared to T0. No consistent relationship was found between GMV change pattern and clinical status. CONCLUSION: The GEMRIC cohort confirmed a rapid increase of GMV after ECT followed by reversion of GMV one to six months thereafter. The lack of association between the GMV change pattern and depression outcome scores implies a transient neurobiological effect of ECT unrelated to clinical improvement.

Biophysical mechanisms of electroconvulsive therapy-induced volume expansion in the medial temporal lobe: A longitudinal in vivo human imaging study.

BACKGROUND: Electroconvulsive therapy (ECT) applies electric currents to the brain to induce seizures for therapeutic purposes. ECT increases gray matter (GM) volume, predominantly in the medial temporal lobe (MTL). The contribution of induced seizures to this volume change remains unclear. METHODS: T1-weighted structural MRI was acquired from thirty patients with late-life depression (mean age 72.5 ± 7.9 years, 19 female), before and one week after one course of right unilateral ECT. Whole brain voxel-/deformation-/surface-based morphometry analyses were conducted to identify tissue-specific (GM, white matter: WM), and cerebrospinal fluid (CSF) and cerebral morphometry changes following ECT. Whole-brain voxel-wise electric field (EF) strength was estimated to investigate the association of EF distribution and regional brain volume change. The association between percentage volume change in the right MTL and ECT-related parameters (seizure duration, EF, and number of ECT sessions) was investigated using multiple regression. RESULTS: ECT induced widespread GM volume expansion with corresponding contraction in adjacent CSF compartments, and limited WM change. The regional EF was strongly correlated with the distance from the electrodes, but not with regional volume change. The largest volume expansion was identified in the right MTL, and this was correlated with the total seizure duration. CONCLUSIONS: Right unilateral ECT induces widespread, bilateral regional volume expansion and contraction, with the largest change in the right MTL. This dynamic volume change cannot be explained by the effect of electrical stimulation alone and is related to the cumulative effect of ECT-induced seizures.

Cortisol is not associated with pre-treatment medial temporal lobe volume or volume changes after electroconvulsive therapy in patients with late-life depression.

Accumulating evidence suggests that late-life depression is associated with reduced hippocampal volume and that cortisol might be related to this volumetric reduction. We explored whether cortisol awaking response (CAR), which is the increase in cortisol after awakening, was associated with volumetric changes in the medial temporal lobe (MTL) after electroconvulsive therapy (ECT) in 41 patients (age ≥ 55) treated for major depressive disorder (MDD) with ECT. Cortisol was measured before the start of the ECT treatment and was related to MTL volumes derived from structural T1-weighted images. The study assessed associations between CAR and pre-treatment MTL volumes, and CAR and ECT-induced MTL volumetric changes. There were no significant correlations found between CAR, operationalized as Area Under the Curve with respect to ground (AUCg) and Area Under the Curve with respect to increase (AUCi), and pre-treatment MTL volumes. Neither was there an association between AUCg or AUCi and the ECT-induced changes in MTL volumes after correction for multiple comparisons. Finally, neither AUCg or AUCi were able to predict ECT-induced volumetric changes in the MTL. Hence, we conclude that CAR is unrelated to pre-treatment hippocampus and amygdala volumes, and to the volumetric changes in the aforementioned areas following ECT.