PTSD has been linked to an increased risk of cognitive impairment and dementia, with neuroinflammation, metabolic dysfunction, and neuropathological markers such as beta-amyloid and tau implicated as potential mechanisms. However, the roles of altered functional connectivity and amyloid deposition as biomarkers in the progression of cognitive impairment among PTSD patients remain unclear, with limited and often conflicting evidence from existing neuroimaging studies. This study examines these neuroimaging markers in PTSD patients with and without cognitive impairment to better understand the neurobiological pathways contributing to cognitive decline in PTSD.
MATERIALS AND METHODS:
Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Department of Defense (DOD) ADNI databases. A cohort of 178 age-matched male subjects was divided into four groups: PTSD with cognitive impairment (CI) (PTSD-CI); PTSD and cognitively normal (CN) (PTSD-CN); non-PTSD (NPTSD with CI (NPTSD-CI); and NPTSD and CN (NPTSD-CN). All subjects underwent resting-state functional MRI and amyloid PET imaging, with PTSD diagnosis and CI confirmed through clinical assessments. Functional connectivity was analyzed using the CONN Toolbox, and amyloid burden was quantified via standardized uptake value ratios. Analyses controlled for demographic and genetic factors, including age, education, APOE4 status, and depression.
RESULTS:
Compared to the NPTSD-CN group, the PTSD-CI group showed significantly increased amyloid uptake in the temporal and parietal lobes, with corresponding functional connectivity increase between the bilateral temporal lobes and parietal operculum. In contrast, PTSD-CN patients exhibited no significant amyloid increase but showed increased connectivity between the salience network, postcentral gyri and sensorimotor areas, and decreased connectivity between the sensorimotor network and anterior cingulate cortex. These distinct patterns suggest differing neurobiological profiles between PTSD-CI and PTSD-CN patients.
CONCLUSIONS:
The findings suggest that elevated amyloid and altered connectivity patterns are associated with CI in PTSD, particularly in the temporal and parietal regions. In contrast, PTSD without cognitive decline was associated with functional connectivity changes in salience and sensorimotor networks but no increased amyloid deposition. This study underscores the importance of neuroimaging biomarkers in understanding PTSD-related cognitive decline and suggests avenues for further investigation into the mechanistic pathways involved. ABBREVIATIONS: ACC = anterior division of the cingulate gyrus; ADAS-Cog = Alzheimer's Disease Assessment Scale-Cognitive; CAPS = Clinician-Administered PTSD Scale; PTSD = post-traumatic stress disorder; CI = cognitively impaired; CN = cognitively normal; ECog = Everyday Cognition; GDS = Geriatric Depression Scale; MoCA = Montreal Cognitive Assessment; NPTSD = non-PTSD.
Psychosis is among the most disabling complications of Parkinson's disease (PD). The chronicity of PD psychosis remains understudied and the relative importance of dopaminergic therapy versus the disease process itself in engendering psychosis remains unclear.To examine pharmacologic and motoric correlates of PD psychosis onset and remission in a longitudinally monitored PD cohort.We analyzed data from 165 participants enrolled in a longitudinal PD study through the Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins University. Evaluations included formal psychiatric assessment and were conducted at two-year intervals. Regression with generalized estimated equations (GEE) was used to produce unadjusted and adjusted estimates for time-varying longitudinal associations between psychosis and putative risk factors.Sixty-two participants (37.6%) were diagnosed with psychosis during at least one evaluation. Of forty-nine participants with psychosis followed over multiple evaluations, 13 (26.5%) demonstrated remission despite significant Hoehn & Yahr stage increase (p=0.009); two of these cases later relapsed. Multivariable regression with GEE identified dementia diagnosis, akinesia-rigidity, anticholinergic usage, and levodopa-carbidopa dose to be significantly associated with psychosis, while disease duration was not. A sub-analysis of 30 incident psychosis cases suggested that dopamine agonist dose was lowered after psychosis onset with a compensatory increase in levodopa-carbidopa dosage.Our findings suggest that in the context of standard therapy, PD-related psychotic disorder can remit at a frequency of approximately 27%. Additionally, akinetic-rigid motor impairment was more strongly associated with psychosis than disease duration, independent of cognitive impairment and medications.
Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.
Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson's disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1α expression and dopaminergic neuronal survival.
Neuroimaging is widely utilized in studying traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). The risk for PTSD is greater after TBI than after non-TBI trauma, and PTSD is associated with worse outcomes after TBI. Studying the neuroimaging correlates of TBI-related PTSD may provide insights into the etiology of both conditions and help identify those TBI patients most at risk of developing persistent symptoms. The objectives of this systematic review were to examine the current literature on neuroimaging in TBI-related PTSD, summarize key findings, and highlight strengths and limitations to guide future research. A Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) compliant literature search was conducted in PubMed (MEDLINE®), PsycINFO, Embase, and Scopus databases prior to January 2022. The database query yielded 4486 articles, which were narrowed based on specified inclusion criteria to a final cohort of 16 studies, composed of 854 participants with TBI. There was no consensus regarding neuroimaging correlates of TBI-related PTSD among the included articles. A small number of studies suggest that TBI-related PTSD is associated with white matter tract changes, particularly in frontotemporal regions, as well as changes in whole-brain networks of resting-state connectivity. Future studies hoping to identify reliable neuroimaging correlates of TBI-related PTSD would benefit from ensuring consistent case definition, preferably with clinician-diagnosed TBI and PTSD, selection of comparable control groups, and attention to imaging timing post-injury. Prospective studies are needed and should aim to further differentiate predisposing factors from sequelae of TBI-related PTSD.
Background Genetics of Recurrent Early-Onset Depression study (GenRED II) data were used to examine the relationship between posttraumatic stress disorder (PTSD) and attempted suicide in a population of 1,433 individuals with recurrent early-onset major depressive disorder (MDD). We tested the hypothesis that PTSD resulting from assaultive trauma increases risk for attempted suicide among individuals with recurrent MDD. Methods Data on lifetime trauma exposures and clinical symptoms were collected using the Diagnostic Interview for Genetic Studies version 3.0 and best estimate diagnoses of MDD, PTSD, and other DSM-IV Axis I disorders were reported with best estimated age of onset. Results The lifetime prevalence of suicide attempt in this sample was 28%. Lifetime PTSD was diagnosed in 205 (14.3%) participants. We used discrete time-survival analyses to take into account timing in the PTSD-suicide attempt relationship while adjusting for demographic variables (gender, race, age, and education level) and comorbid diagnoses prior to trauma exposure. PTSD was an independent predictor of subsequent suicide attempt (HR = 2.5, 95% CI: 1.6, 3.8; P < .0001). Neither assaultive nor nonassaultive trauma without PTSD significantly predicted subsequent suicide attempt after Bonferroni correction. The association between PTSD and subsequent suicide attempt was driven by traumatic events involving assaultive violence (HR = 1.7, 95% CI: 1.3, 2.2; P< .0001). Conclusions Among those with recurrent MDD, PTSD appears to be a vulnerability marker of maladaptive responses to traumatic events and an independent risk factor for attempted suicide. Additional studies examining differences between those with and without PTSD on biological measures might shed light on this potential vulnerability.
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