Biomarkers of Neurodegeneration in Post-Traumatic Stress Disorder: An Integrative Review

Post-Traumatic Stress Disorder (PTSD) is a chronic psychiatric disorder that occurs following exposure to traumatic events. Recent evidence suggests that PTSD may be a risk factor for the development of subsequent neurodegenerative disorders, including Alzheimer’s dementia and Parkinson’s disease. Identification of biomarkers known to be associated with neurodegeneration in patients with PTSD would shed light on the pathophysiological mechanisms linking these disorders and would also help in the development of preventive strategies for neurodegenerative disorders in PTSD. With this background, the PubMed and Scopus databases were searched for studies designed to identify biomarkers that could be associated with an increased risk of neurodegenerative disorders in patients with PTSD. Out of a total of 342 citations retrieved, 29 studies were identified for inclusion in the review. The results of these studies suggest that biomarkers such as cerebral cortical thinning, disrupted white matter integrity, specific genetic polymorphisms, immune-inflammatory alterations, vitamin D deficiency, metabolic syndrome, and objectively documented parasomnias are significantly associated with PTSD and may predict an increased risk of subsequent neurodegenerative disorders. The biological mechanisms underlying these changes, and the interactions between them, are also explored. Though requiring replication, these findings highlight a number of biological pathways that plausibly link PTSD with neurodegenerative disorders and suggest potentially valuable avenues for prevention and early intervention.


Introduction
Post-Traumatic Stress Disorder (PTSD) is a chronic mental illness characterized by symptoms of increased vigilance and arousal, intrusive re-experiencing, avoidance behavior, and changes in effect and cognition lasting more than a month and following direct or indirect exposure to a traumatic stressor. Such stressors typically involve a risk of death, significant injury, or sexual violence [1,2]. It is estimated that PTSD affects around 5-10% of the world's population, with an approximate 2:1 female-to-male ratio [3]. In countries and regions characterized by high levels of traumatic stress or civil unrest, the prevalence of PTSD is estimated to be much higher, affecting over 25% of the population [4]. Though the course of PTSD is heterogeneous, it tends to be chronic and persistent in many individuals. Standard treatments for PTSD include both psychological approaches, such as cognitive and group therapy, and pharmacological agents, such as selective serotonin reuptake inhibitors. However, a substantial proportion of patients do not respond fully to these treatments: short-term response rates have been estimated to be around 35-40% for psychotherapies [5] and 50-60% for pharmacotherapies [6]. A meta-analysis of remission rates for PTSD over a period of three or more years found that only 44% of patients could be considered "noncases"; in other words, more than half remained symptomatic over this period [7]. PTSD is associated with significant levels of disability [8], impaired quality of life [9], high levels of (a) to summarize the existing research on biological markers associated with neurodegenerative disorders in individuals suffering from PTSD; (b) to critically examine the contributions of possible confounding factors; (c) to synthesize this information in a manner that would be useful to future researchers in this field.

Study Selection and Search Strategy
The current review was a scoping review of the existing research on biological markers associated with neurodegeneration in patients with a diagnosis of PTSD. For the purpose of this review, the definition of "biomarker" provided by the United States Food and Drug Administration-National Institutes of Health (FDA-NIH) Biomarker Working Group was used: "A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention". Biomarkers "can be derived from molecular, histologic, radiographic, or physiologic characteristics" and are objective in nature, as opposed to clinical outcomes obtained through interviews or external observations of patients [49]. Given the heterogeneity of the available literature and the integrative nature of this review, all potential biomarkers were considered for inclusion. As a result, a formal systematic review or meta-analysis was not undertaken. Instead, a scoping review methodology was adopted in accordance with the PRISMA-ScR guidelines [50].
The criteria used to select studies for inclusion in this review were as follows: • The study population should consist of patients with a diagnosis of PTSD, established using standard diagnostic criteria or rating scales, with or without a control or comparator group; • Study participants should not currently fulfill the criteria for dementia or other neurodegenerative disorders; • The study should measure one or more biomarkers that are actually or potentially linked to neurodegeneration, and this should be stated by the authors in the study methodology or protocol; • Only human studies were included to ensure the specificity of any identified biomarkers for human subjects with PTSD; • Only original research was included.
The PubMed and Scopus literature databases were searched using the key words "posttraumatic stress disorder" (OR its variants "post-traumatic stress disorder" and "PTSD") AND either "neurodegeneration" (OR its variant "neurodegenerative") OR "dementia" OR "Alzheimer's disease (OR its variant "Alzheimer's dementia") OR "Parkinson's disease", AND various terms used to identify studies of biological markers: the broad terms "biological marker" and "biomarker" (OR their plural forms), OR "genetic" (OR variants) OR "immune" (OR variants) OR "inflammation" (OR variants) OR "amyloid" OR "tau protein" OR "endocrine" (OR variants such as "neuroendocrine") OR "imaging" OR "MRI" OR "fMRI" OR "PET" OR "SPECT" OR "DTI" (OR their expansions, such as "magnetic resonance imaging" OR "positron emission tomography"). A complete list of the search strings used for the PubMed search, along with numerical results for the results retrieved, has been uploaded in Supplementary Table S1.
Through this process, a total of 342 citations were retrieved. After the removal of duplicate citations, the titles and abstracts of 252 citations were screened. Publication types other than original research in humans (n = 164) were excluded at this stage. In the next stage of the literature search, the full texts of the remaining 88 papers were checked to see if they fulfilled the review inclusion criteria. At this stage, 60 papers were excluded either because they did not measure biomarkers or because they did not include study participants with PTSD. Finally, the reference lists of the remaining 28 papers were searched for relevant research that might have been missed, and one further study was identified by this method. The current review thus covered a total of twenty-nine original studies of potential biomarkers of neurodegeneration in subjects diagnosed with PTSD .
The above process is depicted graphically in Figure 1.

Characteristics of the Included Studies
A complete list of the studies included in this review is provided in Table 1. From a preliminary review of each study's methodology, it was found that they fell into five broad categories: brain imaging studies (n = 16), genetic, epigenetic, and gene expression studies (n = 8), biochemical marker studies (n = 9), immune-inflammatory marker studies (n = 4) and sleep-related marker studies (n = 5). The sum of these numbers is greater than 29 because twelve studies used more than one modality or examined the interaction between two or more biomarkers. Of the 29 studies included, 18 were conducted on military veterans and 11 on civilians; 4 of the civilian studies involved World Trade Center responders. Of the 18 studies involving military personnel, 8 studies included subjects with a history of mild to moderate traumatic brain injury (TBI) but with no diagnosis of dementia or other marked cognitive impairment related to their injury. All the studies that fulfilled the inclusion criteria for this review were from high-income countries in North America or Europe. Except for one study published in 2001, all the papers included in this review were published between 2014 and 2023.

Characteristics of the Included Studies
A complete list of the studies included in this review is provided in Table 1. From a preliminary review of each study's methodology, it was found that they fell into five broad categories: brain imaging studies (n = 16), genetic, epigenetic, and gene expression studies (n = 8), biochemical marker studies (n = 9), immune-inflammatory marker studies (n = 4) and sleep-related marker studies (n = 5). The sum of these numbers is greater than 29 because twelve studies used more than one modality or examined the interaction between two or more biomarkers. Of the 29 studies included, 18 were conducted on military veterans and 11 on civilians; 4 of the civilian studies involved World Trade Center responders. Of the 18 studies involving military personnel, 8 studies included subjects with a history of mild to moderate traumatic brain injury (TBI) but with no diagnosis of dementia or other marked cognitive impairment related to their injury. All the studies that fulfilled the inclusion criteria for this review were from high-income countries in North America or Europe. Except for one study published in 2001, all the papers included in this review were published between 2014 and 2023. Total CRP level and "high" CRP (>3 mg/L) both associated with PTSD. PCL score was a significant predictor of serum CRP.

Brain Imaging Studies
Both structural and functional imaging have been used to identify potential markers of neurodegeneration in subjects with PTSD. Structurally, PTSD has been associated with reduced volumes of specific cortical brain regions, including the rostral anterior cingulate cortex, insula, and right parahippocampal cortex [52,54]. Severe PTSD has been associated with a general reduction in overall cortical thickness, particularly in frontal regions [56] and, more specifically, in the right frontal lobe [70]. A longer duration of PTSD has been associated with reduced right hippocampal volume [51]. However, negative findings regarding an association between PTSD and hippocampal volume have also been reported by several researchers [52,69,74]. An overall reduction in structural gray matter connectivity between the prefrontal cortex and amygdala has also been observed in PTSD [52]. In contrast to these findings of volume loss, a single study has reported an increased amygdalar volume in veterans with PTSD, but only in those with a history of exposure to severe trauma [75].
Two studies have examined changes in white matter tract integrity in relation to PTSD. The first, which was conducted in veterans, found evidence of altered fractional anisotropy (FA) and diffusivity in the right cingulum, right inferior longitudinal fasciculus, and left anterior thalamic radiation; these changes were distinct from those associated with traumatic brain injury in the study sample [53]. The second, which involved civilians with trauma exposure related to the World Trade Center (WTC) terrorist attack, found reduced FA in the superior thalamic radiations and cerebellum in those with PTSD; in the subgroup of subjects with PTSD and mild cognitive impairment, further reductions in FA were reported in several other regions, including the fornix and right uncinate fasciculus [57]. Overall, structural imaging studies suggest that PTSD is associated with structural brain changes affecting cortical and limbic regions and white matter tracts, with some evidence of a right-sided predominance.
There are relatively few studies of functional imaging changes putatively linked to neurodegeneration in PTSD. In a study of civilians, increased variability of the BOLD signal, a measure of regional brain activity, was observed in patients with the dissociative subtype of PTSD compared to both other patients with PTSD and healthy controls [55]. A study of veterans did not report any specific functional MRI changes in patients with PTSD; however, two-thirds of the subjects also had a history of TBI [74]. A single study used positron emission tomography (PET) to estimate levels of amyloid beta and tau protein in veterans over a period of five years but did not find any significant association between PTSD and changes in these imaging markers [78].

Genetic, Epigenetic, and Gene Expression-Related Markers
Three association studies examined the associations between functional polymorphisms of specific genes and possible neurodegeneration related to PTSD. The first study examined the effects of functional polymorphisms of the ALOX12 and ALOX15 genes, which are related to oxidative stress, on PTSD-related reductions in brain volume. In this study, two specific single nucleotide polymorphisms (SNPs) of ALOX12-rs1042357 and rs10852889-appeared to mediate the association between PTSD symptom severity and reductions in right prefrontal cortical thickness [70]. The second study evaluated nine SNPs of the BDNF gene, a key regulator of neural plasticity, in relation to hippocampal volume changes in veterans with mild TBI and/or PTSD. In this study, a single SNP (rs1157659) interacted with TBI to reduce hippocampal volume; however, there was neither a direct effect of PTSD nor a genotype x PTSD effect on this outcome [74]. The third study examined the effects of two SNPs of the vitamin D-binding protein (GC) gene. In this study, PTSD was associated with lower serum vitamin D levels; of the two SNPs studied, homozygotes for the C allele of rs4588 were at a lower risk of PTSD, while carriers of the T allele of rs7041 were at a higher risk of this disorder [76].
In a study involving a small number of WTC responders with or without PTSD, peripheral blood gene expression was examined in four white cell subtypes. It was found that the expression of FKBP5, involved in hypothalamic-pituitary-axis functioning and the stress response, as well as the pseudogene PI4KAP1, were increased in all cell types in PTSD. Two further genes, REST and SEPT4, were upregulated in the monocytes of individuals with PTSD [58]. In a study of military veterans, an increased number of somatic mutations were observed in veterans with a diagnosis of PTSD. These mutations appeared to be linked to cytoskeletal and inflammation-related genes [59]. Finally, a post-mortem study of gene expression in the brains of veterans found four genes (SNORA73B, COL6A3, GCNT1, and GPRIN3) whose expression was associated with a lifetime diagnosis of PTSD [60].
To test for the possibility of functional interactions between the proteins encoded by these genes, all the above genes of interest were entered into the STRING database [80]. Two genes (SNORA73B and PI4KAP1) were excluded by the database as they did not encode any known functional product. Of the remaining nine genes analyzed, possible functional interactions were identified between three: FKBP5, BDNF, and REST. This is illustrated in Figure 2 below. A single study examined the possible association between microRNAs (miRNAs) and PTSD. In this study, levels of 798 miRNAs were assessed. Of these, only miR-139-5p was significantly associated with PTSD symptom severity [77]. This particular miRNA is of significance as its expression has been found to differ significantly between patients with Alzheimer's disease and healthy controls [81].
In addition to these results, a single study examined the association between PTSD and telomere length, a putative marker of cellular aging, in military personnel. In this study, PTSD was associated with a shortened telomere length only in veterans with a history of exposure to severe trauma; this finding was also associated with an increased volume of the amygdala and increased urinary norepinephrine [75]. A single study examined the possible association between microRNAs (miRNAs) and PTSD. In this study, levels of 798 miRNAs were assessed. Of these, only miR-139-5p was significantly associated with PTSD symptom severity [77]. This particular miRNA is of significance as its expression has been found to differ significantly between patients with Alzheimer's disease and healthy controls [81].
In addition to these results, a single study examined the association between PTSD and telomere length, a putative marker of cellular aging, in military personnel. In this study, PTSD was associated with a shortened telomere length only in veterans with a history of exposure to severe trauma; this finding was also associated with an increased volume of the amygdala and increased urinary norepinephrine [75].

Biochemical Marker Studies
The biomarkers most frequently studied in this context are those putatively associated with dementia, such as levels of amyloid-beta (Aβ) or tau protein. In a study involving 34 WTC responders, PTSD was associated with both lower plasma Aβ and a lower Aβ 42/40 ratio [61], while a larger study (n = 1173) involving WTC responders also found a lower Aβ 42/40 ratio in those with PTSD, as well as an association between this parameter and hippocampal volume reduction. However, in a study of trauma-exposed adults with and without PTSD, no significant differences in Aβ or tau levels were observed between

Biochemical Marker Studies
The biomarkers most frequently studied in this context are those putatively associated with dementia, such as levels of amyloid-beta (Aβ) or tau protein. In a study involving 34 WTC responders, PTSD was associated with both lower plasma Aβ and a lower Aβ 42/40 ratio [61], while a larger study (n = 1173) involving WTC responders also found a lower Aβ 42/40 ratio in those with PTSD, as well as an association between this parameter and hippocampal volume reduction. However, in a study of trauma-exposed adults with and without PTSD, no significant differences in Aβ or tau levels were observed between groups [62]. An assay of extracellular vesicle levels of Aβ and tau in military veterans found no association between these markers and a diagnosis of PTSD [77]. A similar negative association between Aβ and tau levels and PTSD was observed in the cerebrospinal fluid of veterans, though 60% of these subjects also had a history of TBI [78]. Neurofilament light (NfL), a marker of neural axonal damage, was found to be elevated in patients with a history of PTSD and mild TBI in a single study [77]. However, two other studies did not observe a significant association between PTSD and NfL levels [61,79].
Among other biochemical markers possibly related to neurodegeneration, PTSD has been associated with reduced serum total vitamin D [76] and an increased risk of a metabolic syndrome characterized by elevated plasma glucose and dyslipidemia [75]. In the latter study, metabolic syndrome appeared to mediate the association between a diagnosis of PTSD and reduced volumes of specific regions of the frontal, temporal, and parietal cortices [75].

Immune and Inflammatory Marker Studies
Four studies have examined the relationship between PTSD and elevated levels of immune or inflammatory markers linked to neurodegeneration. In the earliest study in this population, CSF and plasma levels of interleukin-6 (IL-6) were examined in relation to levels of norepinephrine and adrenocortical hormones. CSF IL-6 was significantly higher in veterans with PTSD than in controls, and plasma IL-6 was positively correlated with norepinephrine only in PTSD cases [68]. In a study of individuals living near the WTC at the time of the 2001 attack, 43.2% fulfilled the criteria for PTSD. These individuals had significantly elevated levels of C-reactive protein (CRP), and CRP levels were positively correlated with PTSD symptom severity [63]. In contrast, two studies of military veterans yielded divergent results. In the first, PTSD severity was negatively correlated with IL-6 levels but positively associated with levels of soluble tumor necrosis factor-alpha receptor (sTNF-RII). sTNF-RII levels were negatively correlated with hippocampal volume, but this association was independent of PTSD diagnostic status [71]. In the second, no significant association was observed between PTSD and plasma levels of IL-10, IL-6, or TNF-α.

Sleep-Related Studies
Sleep-related behavioral and electrophysiological markers associated with neurodegeneration have been evaluated in relation to PTSD in five studies. Three of these involved military veterans; among these studies, two also included subjects with TBI. The first of these found an association between reduced sleep and reduced left hippocampal volume, but this was not related to a PTSD diagnosis [69]. The second, in which all participants had a history of mild TBI, found that PTSD was associated with self-reported sleep disturbances [64]. The third, which included only some subjects with TBI, found a significant association between PTSD and REM sleep behavior disorder (RSBD), considered a forerunner of neurodegeneration, both in subjects with and without TBI [65].
A polysomnographic study comparing patients with PTSD to those with idiopathic RSBD and healthy controls found a higher rate of REM sleep with atonia, as measured by electromyography, in those with PTSD [66]. A larger study based on self-report data, including over 20,000 adults in the context of the COVID-19 pandemic, found a significant positive association between self-reported PTSD symptoms and dream enactment behavior, which is a symptom of RSBD [67].

Integration of Existing Results on Biomarkers of Neurodegeneration in PTSD
A list of possible biomarkers associated with neurodegeneration in patients with PTSD, based on the existing literature, is provided in Table 2 below.
From the above results, it can be observed that even after discarding negative results, there are several potential biological markers of neurodegeneration in post-traumatic stress disorder. Neuroimaging studies have found that PTSD is associated with evidence of significant volume reductions in cortical regions-particularly in the right hemisphere-as well as reduced white matter integrity. In addition, there is some evidence to suggest that this disorder is associated with impaired grey matter structural connectivity between prefrontal and limbic regions. There is a significant overlap between these findings and those obtained in studies of patients with neurodegenerative disorders, particularly Alzheimer's disease (AD). For example, progressive reductions in cortical thickness, implicating many of the same regions identified in patients with PTSD, have been identified both in patients with early evidence of Alzheimer's pathology [82] and in patients with an established diagnosis of AD [83]. Similarly, disruptions of white matter integrity have also been documented across the spectrum of severity of AD [84,85]. Many of these alterations involve regions that have been identified in studies of individuals with PTSD, such as the fornix, uncinate fasciculus, and inferior longitudinal fasciculus [53,57]. Altered basal forebrain functioning has also been documented in both mild cognitive impairment and AD [86]; this is similar to findings reported in patients with the dissociative subtype of PTSD [55]. Though these associations are by themselves insufficient to establish a causal link, they suggest that PTSD may be associated with structural brain changes that differ from those of AD in degree rather than in kind. Table 2. Possible biomarkers linking post-traumatic stress disorder and neurodegeneration.

Biomarker Type Level of Evidence
Brain imaging Reduced cortical thickness ++ Reduced volume of specific right cortical regions ++ Reduced white matter tract integrity ++ Reduced structural grey matter connectivity + Reduced right hippocampal volume ± Increased amygdalar volume ? Increased BOLD variability in the basal forebrain ?
Biochemical Reduced serum total vitamin D + Increased rate of metabolic syndrome + Elevated peripheral NfL ± Reduced peripheral Aβ 42/40 ratio ± Immune-inflammatory Serum CRP + Serum sTNF-RII + CSF IL-6 + Sleep-related Increased rates of RSBD or dream enactment behavior ++ Increased REM sleep with atonia + Key: ++, positive evidence from more than one study; +, positive evidence from a single study; ±, conflicting results; ?, positive results only in sub-group analyses or results of uncertain significance.
Attempts to establish an association between biochemical markers of AD pathology, such as amyloid-beta and tau, have yielded inconsistent results in patients with PTSD. However, there is some evidence of indirect biochemical links between PTSD and neurodegenerative disorders. First, PTSD has been associated with an increased risk of metabolic syndrome, which is an established risk factor both for vascular dementia [87] and for disease onset and progression in AD [88,89]. Second, PTSD has been associated with low serum vitamin D, as well as with functional polymorphisms of the Gc protein that binds vitamin D and influences its levels. Vitamin D deficiency is associated with a modest but significant increase in the risk of dementia [90], as well as reductions in gray and white matter volumes [91], and there has been recent interest in vitamin D supplementation as a preventive measure against neurocognitive disorders [92]. Though both these findings require replication, they represent plausible pathways that could mediate the association between PTSD and neurodegeneration.
Immune and inflammatory mechanisms have been implicated in the progression of several neurodegenerative disorders, including AD [93], frontotemporal dementia [94], and Parkinson's disease [95]. PTSD has been consistently associated with increases in certain markers of systemic inflammation [24,96], though it is not known to what extent these correlate with central nervous system inflammatory activity. In the current review, these findings were replicated in the context of possible links with neurodegeneration, with results specifically implicating CRP, IL-6, and soluble TNF-α receptor II. Of these three inflammatory markers, CRP has been associated with progression to dementia even after adjustment for confounding factors [97], while IL-6 has been specifically associated with vascular dementia [98].
Among the genetic markers associated with features of neurodegeneration in PTSD in this review, four are of particular interest, and there is evidence linking them to neurodegenerative disorders in three cases. Methylation of ALOX12 has been associated with carotid artery intimal thickness, which is a risk factor for stroke and vascular dementia [99]. Septin-4, the protein encoded by the SEPT4 gene, has been identified in the alpha-synucleinpositive cytoplasmic inclusion bodies seen in Parkinson's and related diseases [100]. In a study comparing patients with AD and healthy controls, the expression of miR-139-5p was found to differ significantly between the two groups, suggesting a possible role for this specific microRNA in neurodegeneration [81,101]. Finally, on the basis of animal studies, it has been suggested that stress-induced changes in the methylation of FKBP5 might contribute to late-life AD [102]. Thus, there are plausible mechanisms linking genetic markers associated with PTSD to specific types of neurodegenerative disorders.
REM sleep behavior disorder (RSBD) has been associated with an increase in the subsequent risk of neurodegenerative disorders, and more specifically of synucleinopathies such as Parkinson's disease and dementia with Lewy bodies [103]. There is consistent evidence of an increase in RSBD, its symptoms, and its electrophysiological correlates in patients with PTSD [104]. Despite the consistency of this association, relatively little is known about the neurobiological mechanisms linking these two disorders and their implications for progression to a subsequent neurodegenerative disorder [105]. It has been suggested by some researchers that RSBD-like phenomena in PTSD have a distinctive pathophysiology characterized by hyperarousal and increased adrenergic activity rather than neurodegeneration [106]. If this hypothesis is correct, then symptoms of RSBD in PTSD may not necessarily increase the subsequent risk of dementia or Parkinson's disease; however, it requires verification through both neurobiological and longitudinal clinical research.
The figure below ( Figure 3) shows how these diverse findings can potentially be integrated. Innate genetic vulnerability, as well as epigenetic changes related to early life stressors and other environmental exposures, interact with exposure to one or more traumatic events, leading to the syndrome of PTSD. The biochemical, neurophysiological, and immune-inflammatory changes associated with PTSD can have an adverse impact on brain structure and function either directly or indirectly through atherogenesis and reduced cerebral blood flow. These changes may not be sufficient to lead to neurodegeneration in themselves, but they may interact with or amplify other risk factors, such as an innate genetic vulnerability towards neurodegenerative disorders, traumatic brain injury, or lifestyle factors. The outcomes of this process are likely to be heterogeneous, ranging from no or mild cognitive impairment to the clinical syndromes of AD, vascular dementia, or Parkinson's disease.
A key question that arises in this regard is whether the associations depicted in Figure 3 are of a correlational or a causal nature. In other words, does the syndrome of PTSD itself lead to pathophysiological processes that increase the risk of neurodegeneration, or are both disorders related to an inherent vulnerability or diathesis? This question is difficult to answer based on current evidence. Some authors believe that there is at least provisional evidence of a causal link between PTSD and subsequent neurodegenerative disorders [43,45], while others favor a simple correlation based on shared genetic or environmental risk factors [44,47]. There is some evidence to support the latter view. For example, it has been found that increased systemic inflammation may precede PTSD and predispose to it rather than represent a consequence of this disorder [107]. Longitudinal studies of both civilian and military populations involving measurements of specific biomarkers prior to as well as following exposure to traumatic stress are required to answer this question. However, such studies may be difficult to conduct in the former group.
Another issue that arises in this context is the specificity of the association, whether correlational or causal, between PTSD and neurodegeneration. Is it non-specific in nature, applying to a wide range or spectrum of neurodegenerative disorders, or is it specific to certain conditions, such as AD? Alternately, are there distinct pathways (for example, oxidative stress-induced atherogenesis in vascular dementia or RSBD-like sleep pathologies in Parkinson's disease) that mediate the association between PTSD and distinct types of neurodegenerative disorder? Research in this field is still in an early stage, and it is likely that more information on the specificity and consistency of these associations will be obtained in subsequent decades.
Biomedicines 2023, 11, x FOR PEER REVIEW 1 traumatic events, leading to the syndrome of PTSD. The biochemical, neurophysiol and immune-inflammatory changes associated with PTSD can have an adverse imp brain structure and function either directly or indirectly through atherogenesis a duced cerebral blood flow. These changes may not be sufficient to lead to neurode ation in themselves, but they may interact with or amplify other risk factors, such innate genetic vulnerability towards neurodegenerative disorders, traumatic brain or lifestyle factors. The outcomes of this process are likely to be heterogeneous, ra from no or mild cognitive impairment to the clinical syndromes of AD, vascular dem or Parkinson's disease. A key question that arises in this regard is whether the associations depicted ure 3 are of a correlational or a causal nature. In other words, does the syndrome of itself lead to pathophysiological processes that increase the risk of neurodegenerat are both disorders related to an inherent vulnerability or diathesis? This question i cult to answer based on current evidence. Some authors believe that there is at lea visional evidence of a causal link between PTSD and subsequent neurodegenerati orders [43,45], while others favor a simple correlation based on shared genetic or en mental risk factors [44,47]. There is some evidence to support the latter view. For ex it has been found that increased systemic inflammation may precede PTSD and p pose to it rather than represent a consequence of this disorder [107]. Longitudinal s of both civilian and military populations involving measurements of specific biom prior to as well as following exposure to traumatic stress are required to answer this tion. However, such studies may be difficult to conduct in the former group.
Another issue that arises in this context is the specificity of the association, w correlational or causal, between PTSD and neurodegeneration. Is it non-specific in n applying to a wide range or spectrum of neurodegenerative disorders, or is it spe certain conditions, such as AD? Alternately, are there distinct pathways (for examp idative stress-induced atherogenesis in vascular dementia or RSBD-like sleep patho

Limitations of the Existing Data
Despite the promising nature of the leads obtained through the current body of research, certain key limitations of existing studies deserve mention. First, the majority of studies have been conducted in Western countries, and it is not clear to what extent they can be generalized to other countries or cultures. Significant inter-ethnic and cross-national variations in the occurrence of PTSD following trauma exposure have been reported in large-scale studies. The reasons for these variations are not clear, but they may reflect innate differences in genetic vulnerability, as well as differences in environmental factors such as diet and social support [108,109]. Second, most of the published research on biomarkers has involved either military personnel or individuals affected by a single specific traumatic exposure, namely the WTC terrorist attacks. It is not clear if similar results would be obtained in individuals who develop PTSD in response to more commonly encountered forms of trauma, such as motor vehicle accidents or sexual assault [110]. Third, most positive findings reported in this review have not yet been replicated. Fourth, many studies of military veterans have included subjects with head trauma, which is an independent risk factor for dementia [111]. Fifth, the majority of studies have been cross-sectional in nature; therefore, it is not possible to draw clear inferences regarding a causal link between PTSD and neurodegenerative disorders based on their results. Finally, there is some evidence that the link between PTSD and certain neurodegenerative disorders may be non-specific and may extend to other stress-related disorders, such as acute stress disorder and adjustment disorder [40,112]. This facet requires further exploration in longitudinal studies.

Conclusions
Research on the links between PTSD and neurodegenerative disorders is a young and rapidly evolving field: 97% of the literature included in this review has been published in the last decade. There is significant evidence that several biological markers, including structural changes in cerebral gray and white matter, increased levels of pro-inflammatory markers, genetic polymorphisms related to oxidative stress and vitamin D levels, features of the metabolic syndrome, and RSBD-like parasomnias, may mediate the association between PTSD and neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. It is possible to integrate these diverse findings into a biologically plausible framework. Though questions of causality and temporal sequence remain unsettled and certain methodological limitations need to be considered, these results are of importance from clinical, research, and public health perspectives. The current review can be considered complementary to existing reviews that emphasize the clinical and epidemiological links between PTSD and neurodegenerative disorders [46,113] and draws attention to the biological mechanisms and pathways that might link these conditions. Future research, ideally involving ethnically diverse populations, with a greater focus on civilians and an effort to minimize potential confounders, will hopefully clarify the true nature of the association between PTSD and these biological markers, as well as their value in predicting subsequent neurodegeneration and cognitive impairment. This would facilitate the development of interventions that target one or more of the biological pathways that these markers are associated with, hopefully leading to better pharmacological approaches to the prevention or early treatment of neurodegenerative disorders in those exposed to traumatic stress.