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.

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 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.

Can perfusion CT unmask postictal stroke mimics? A case-control study of 133 patients.

OBJECTIVE: To study the diagnostic value of volume perfusion CT (VPCT) in patients with transient focal neurologic deficits following and during epileptic seizures, that mimic symptoms of stroke. METHODS: A retrospective case-control study was performed on 159 patients who presented with a seizure and received an emergency VPCT within the first 3.5 hours of admission, after being misjudged to have an acute stroke. The reference test was a clinical-based, EEG-supported diagnostic algorithm for seizure. RESULTS: We included 133 patients: 94 stroke-mimicking cases with postictal focal neurologic deficits ("Todd phenomenon," n = 67) or ongoing seizure on hospital admission ("ictal patients," n = 27), and 39 postictal controls without focal neurologic deficits. Patients with Todd phenomenon showed normal perfusion (64%), hypoperfusion (21%), and hyperperfusion (14%) on early VPCT. Ictal patients displayed more hyperperfusion compared to postictal patients (p = 0.015). Test sensitivity of hyperperfusion for ictal patients is 38% (95% confidence interval [CI] 20.7%-57.7%), specificity 86% (95% CI 77.3%-91.7%), positive predictive value is 42% (95% CI 27.5%-58.7%), and the negative predictive value 83% (95% CI 78.6%-86.9%). A cortical distribution was seen in all hyperperfusion scans, compared to a cortico-subcortical pattern in hypoperfusion (p < 0.001). A history of complex focal seizure and age were associated with hyperperfusion (p = 0.046 and 0.038, respectively). CONCLUSION: VPCT can differentiate ictal stroke mimics with hyperperfusion from acute ischemic stroke, but not postictal patients who display perfusion patterns overlapping with ischemic stroke. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that VPCT accurately differentiates ictal stroke mimics from acute ischemic stroke.