Table 1.
Details of all studies included in the current review.
| Scheme | Modality | Study Population | Design | Biomarker(s) Studied | Results |
|---|---|---|---|---|---|
| Brain imaging studies | |||||
| Chao et al., 2014 [51] | Structural MRI | Military veterans with PTSD as per DSM-IV criteria (n = 55) | Cross-sectional; association | Hippocampal volume as test region; caudate nucleus volume as a control region | Duration of PTSD significantly and negatively correlated with right hippocampal volume, even after adjusting for confounders. No association between PTSD duration and left hippocampal or caudate volumes. |
| Mueller et al., 2015 [52] | Structural MRI | Military veterans with (n = 40) and without (n = 45) significant PTSD symptoms as measured using CAPS | Cross-sectional; case-control | Cortical and hippocampal volumes; structural connectivity of the prefrontal-limbic network | PTSD significantly associated with reduced rostral cingulate and insular cortical thickness but no hippocampal volume loss. Evidence of reduced prefrontal-limbic structural connectivity in PTSD. |
| Main et al., 2017 [53] | DTI | Military veterans (n = 109); 71.6% PTSD as per DSM-IV criteria; 57.8% mild TBI; 9.2% moderate TBI | Cross-sectional; association | FA and diffusivity of white matter fiber tracts | Altered parameters in left cingulum and inferior frontal-occipital fasciculus and right anterior thalamic tract specifically associated with TBI. Altered white matter parameters in right cingulum and inferior longitudinal fasciculus and left anterior thalamic radiation associated with PTSD. |
| Basavaraju et al., 2021 [54] | Structural MRI | Older adults (age ≥ 50 years) with a history of trauma exposure with (n = 55) and without (n = 36) PTSD | Cross-sectional; case-control | Cortical volume | Significant reduction of right parahippocampal cortical volume, but not other cortical regions, in PTSD. |
| Olivé et al., 2021 [55] | Functional MRI | Patients with PTSD (n = 103; 38 with dissociative subtype of PTSD); healthy controls (n = 46) | Cross-sectional; case-control | Variability of BOLD signal in basal forebrain regions | Increased BOLD signal variability in extended amygdala and nucleus accumbens in dissociative PTSD compared to both PTSD and controls. |
| Brown et al., 2022 [56] | Structural MRI | Military veterans (n = 254); 59.8% PTSD as per DSM-IV-TR criteria; 34.4% severe PTSD; (CAPS ≥ 60); 45.7% mild TBI | Longitudinal (2-year follow-up) with group comparisons (severe vs. non-severe PTSD) | Changes in cortical thickness, area, and volume | Severe PTSD associated with reduced cortical thickness, area, and volume, especially in frontal regions. More marked reductions in severe PTSD with mild TBI. |
| Kritikos et al., 2022 [57] | DTI | World Trade Center responders (n = 99); 48.4% cognitive impairment not amounting to dementia; 47.5% PTSD as per DSM-IV criteria | Cross-sectional; association | Whole-brain FA of white matter tracts | Reduced FA in fornix, cingulum, forceps minor, and right uncinate fasciculus in subjects with PTSD and cognitive impairment. Reduced FA in superior thalamic radiation and cerebellum in PTSD regardless of cognitive impairment. |
| Genetic, epigenetic, and gene expression studies | |||||
| Kuan et al., 2019 [58] | Peripheral blood transcriptome | World Trade Center responders with (n = 20) and without (n = 19) PTSD as per DSM-IV criteria | Cross-sectional; case-control | Transcriptome-wide analysis of gene expression in four peripheral blood immune cell subtypes |
FKBP5 and PI4KAP1 upregulated across all cell types in PTSD. REST and SEPT4 upregulated in monocytes in PTSD. |
| Sragovich et al., 2021 [59] | Somatic mutation | Military veterans with (n = 27) and without (n = 55) PTSD as per DSM-IV criteria | Cross-sectional; case-control | Rates of somatic mutations based on peripheral blood samples | Increased number of mutations related to cytoskeletal genes and inflammation in PTSD. |
| Wolf et al., 2021 [60] | Post-mortem gene expression | Post-mortem cortical brain tissue from military veterans (n = 97); 43.3% PTSD as per DSM-5 criteria; 30.9% alcohol use disorder | Post-mortem; association | DNA methylation-based estimates of cellular age in relation to chronological age (DNAm age residuals); gene expression in cortical tissue. | Specific interaction effects with age residuals identified for four genes (SNORA73B, COL6A3, GCNT1, and GPRIN3) specific to PTSD. |
| Biochemical marker studies | |||||
| Clouston et al., 2019 [61] | Plasma assay | World Trade Center responders with (n = 17) and without (n = 17) probable PTSD as per PCL-17 | Cross-sectional; case-control | Plasma total amyloid-beta, amyloid-beta 42/40 ratio, total tau, and NfL | PTSD associated with lower plasma amyloid-beta and higher amyloid-beta 42/40 ratio. |
| Cimino et al., 2022 [62] | Serum assay | Adults, age ≥ 50, with a history of trauma exposure with (n = 44) and without (n = 26) subsequent PTSD as per DSM-5 criteria | Cross-sectional; case-control | Serum amyloid-beta 42 and 40 levels and ratio; serum total tau | No significant differences in amyloid-beta levels, ratios, or total tau levels between groups. |
| Immune-inflammatory marker studies | |||||
| Zhang et al., 2022 [63] | Serum assay | Residents living near the World Trade Center; 43.2% probable PTSD as per PCL; 50.3% dust cloud exposure | Cross-sectional; association | Serum CRP | Total CRP level and “high” CRP (>3 mg/L) both associated with PTSD. PCL score was a significant predictor of serum CRP. |
| Sleep-related marker studies | |||||
| Elliott et al., 2018 [64] | Polysomnography, self-report | Military veterans with a history of TBI (n = 130); 37.7% PTSD as per DSM-5 criteria | Cross-sectional; association | Sleep EEG/EMG; self-reported sleep disturbance; sensory (noise and light) sensitivity | Sleep disturbance and sensory sensitivity associated with PTSD in veterans with TBI. |
| Elliott et al., 2020 [65] | Polysomnography | Military veterans (n = 394); 28.6% probable PTSD as per PCL-5; 19.2% mild TBI | Cross-sectional; association | RSBD and other parasomnias | Increased rates of RSBD both in veterans with mild TBI and PTSD and in those with PTSD alone. |
| Feemster et al., 2022 [66] | Polysomnography | Patients with PTSD (n = 36), idiopathic RSBD (n = 18), and healthy controls (n = 51) | Cross-sectional; case-control | REM sleep with atonia | Higher REM sleep with atonia associated with PTSD independent of dream enactment behavior. |
| Liu et al., 2023 [67] | Self-report | Adults from fifteen countries (n = 21,870) during the COVID-19 pandemic; 3% COVID-19 positive; PTSD symptoms assessed using abbreviated PCL | Cross-sectional; association | Dream enactment behavior, weekly and lifetime | Screening positive for PTSD associated with a 1.2 to 1.4-fold increase in dream enactment behavior. |
| Multi-modality studies | |||||
| Baker et al., 2001 [68] | Plasma and CSF assays | Combat veterans (n = 11) with PTSD as per DSM-IV criteria; matched healthy controls (n = 8) | Cross-sectional; case-control | CSF levels of CRH, IL-6, norepinephrine; plasma levels of IL-6, ACTH, cortisol and norepinephrine | Increased CSF IL-6 in PTSD. Positive correlation between plasma IL-6 and norepinephrine in PTSD, but not in controls. |
| Mohlenhoff et al., 2014 [69] | Self-report (sleep); structural MRI (brain imaging) | Military veterans (n = 136); 7% PTSD as per DSM-IV criteria | Cross-sectional; association | Self-reported sleep disturbance; hippocampal volume | No association between PTSD and hippocampal volume. Possible association between sleep disturbance and left hippocampal volume. |
| Miller et al., 2015 [70] | Genetic association; structural MRI | Military veterans (n = 146); PTSD symptoms measured as a continuous variable using CAPS | Cross-sectional; interaction | Oxidative stress-related genes (ALOX12 and ALOX15); prefrontal cortex thickness | PTSD symptom severity negatively correlated with right, but not left, prefrontal volume. Two SNPs of ALOX12 moderated association between PTSD and right prefrontal volume. |
| O’Donovan et al., 2015 [71] | Serum assays; structural MRI | Military veterans with (n = 73) and without (n = 132) PTSD as per DSM-IV criteria | Cross-sectional; interaction | Serum IL-6 and sTNF-RII; hippocampal volume | sTNF-RII level negatively correlated with hippocampal volume regardless of PTSD diagnosis. PTSD severity associated with increased sTNF-RII and decreased IL-6. |
| Wolf et al., 2016 [72] | Plasma assays; structural MRI | Military veterans (n = 346); 77.2% PTSD as per DSM-IV criteria | Cross-sectional; interaction | Prevalence of metabolic syndrome as per NCEP-ATP III criteria; cortical thickness | Metabolic syndrome and its criteria more common in veterans with PTSD. Metabolic syndrome found to significantly mediate the association between PTSD and reduced cortical volume in precuneus, temporal cortex, rostral anterior cingulate cortex, and postcentral gyrus. |
| Hayes et al., 2017 [73] | Polygenic risk score; structural MRI | Military veterans (n = 160); 70% PTSD as per DSM-IV criteria; 65.6% mild TBI | Cross-sectional; interaction | Polygenic risk score for Alzheimer’s disease; cortical thickness | No significant association between cortical thickness and PTSD, either alone or in association with TBI or polygenic risk score. |
| Hayes et al., 2018 [74] | Genetic association; structural and functional MRI | Military veterans (n = 165); 66.7% mild TBI; 43% PTSD as per DSM-IV-TR criteria | Cross-sectional; interaction | BDNF genotype (9 SNPs); hippocampal volume; default mode network functional connectivity | No direct effect of PTSD on right or left hippocampal volume. TBI associated with reduced hippocampal volumes. Significant interaction between BDNF rs1157659 and TBI on hippocampal volume. No BDNF by PTSD interaction. |
| Kang et al., 2020 [75] | Peripheral blood and urine assays; structural MRI | Military veterans with (n = 102) and without (n = 113) PTSD as per DSM-IV criteria | Cross-sectional; interaction | Leukocyte telomere length; urinary catecholamines; amygdala volume | Shorter telomere length and increased amygdala volume associated with PTSD only in veterans exposed to high levels of trauma. Telomere shortening associated with increased urinary norepinephrine. |
| Terock et al., 2020 [76] | Genetic association; serum assay | 1653 adults with a history of trauma exposure; 3.8% PTSD as per DSM-IV criteria | Cross-sectional; interaction | Serum total vitamin D; two specific SNPs of the GC gene | Lower serum vitamin D associated with PTSD. Vitamin D deficiency more frequent in those with PTSD. CC genotype of rs4588 associated with lower risk of PTSD. T allele of rs7041 associated with increased risk of PTSD. |
| Guedes et al., 2021 [77] | Extracellular vesicle assay | Military veterans (n = 144); 31.3% PTSD as per PCL-5 screening; 80.6% mild TBI | Cross-sectional; association | Extracellular vesicle levels of 798 miRNAs; extracellular vesicle and plasma levels of NfL, amyloid-beta 42 and 40, tau, IL-10, IL-6, TNF-α, and VEGF | Elevated extracellular vesicle levels of NfL in patients with mTBI and PTSD. Significant association between miR-139-5p and PTSD symptom severity. |
| Weiner et al., 2022 [78] | CSF assay; structural MRI; PET | Military veterans (n = 289); 60.6% PTSD as per DSM-IV criteria; 47.8% moderate to severe TBI | Longitudinal (5-year follow-up) with group comparisons | CSF amyloid-beta 42, total tau, and p-tau181; PET measures of amyloid-beta and tau; cortical, hippocampal, and amygdala volume | No significant association of PTSD with biochemical or imaging markers, either cross-sectionally or at follow-up |
| Kritikos et al., 2023 [79] | Plasma assay; structural MRI | World Trade Center responders (n = 1173); 11.2% probable PTSD as per PCL-C; 16.4% mild cognitive impairment; 4.3% possible dementia | Cross-sectional; interaction | Plasma amyloid-beta 40/42 ratio, p-tau 181, NfL; hippocampal volume (only in 75 participants) | Significant intercorrelation between amyloid-beta 40/42, p-tau181, and NfL. PTSD associated with elevated amyloid-beta 40/42 ratio. Amyloid-beta 40/42 and p-tau 181 associated with reduced hippocampal volume. |
Note: Italics indicate gene names as per standard naming conventions. Abbreviations: ACTH, adrenocorticotrophic hormone; ALOX12, arachidonate 12-lipoxygenase gene; ALOX15, arachidonate 15-lipoxygenase gene; BDNF, brain-derived neurotrophic factor gene; BOLD, blood oxygen-level dependent; CAPS, Clinician-Administered PTSD Scale; COL6A3, collagen alpha-3 gene; CRH; corticotrophin-releasing hormone; CRP, C-reactive protein; CSF, cerebrospinal fluid; DSM, Diagnostic and Statistical Manual of Mental Disorders; DTI, diffusion tensor imaging; EEG, electroencephalogram; EMG; electromyogram; FA, fractional anisotropy; FKBP5, FK506 binding protein gene; GC, vitamin D-binding protein gene; GCNT1, glucosaminyl (N-acetyl) transferase 1 gene; GPRIN3, GPRIN family member 3 gene; IL, interleukin; miRNA, microRNA; MRI, magnetic resonance imaging; NCEP-ATP III, National Cholesterol Education Program—Adult Treatment Panel III; NfL, neurofilament light; PET, positron emission tomography; PCL, Post-traumatic Disorder Checklist; PI4KAP1, phosphatidylinositol 4-kinase alpha pseudogene 1; PTSD, post-traumatic stress disorder; REM, rapid-eye movement sleep; REST, RE1-silencing transcription factor gene; RSBD, REM sleep behaviour disorder; SEPT4, septin 4 gene; SNORA73B, small nucleolar RNA, H/ACA box 73B gene; SNP, single nucleotide polymorphism; TBI, traumatic brain injury; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.