People who have experienced post-traumatic stress disorder (PTSD) are up to twice as likely to develop dementia later in life, according to a new study by UCL researchers.
The research, published in the British Journal of Psychiatry, is the first meta-analysis of global evidence on PTSD and dementia risk.
For the study, the researchers analysed findings from 13 studies conducted on four continents, including data from a total of 1,693,678 people, investigating whether a PTSD diagnosis was associated with increased risk of dementia up to 17 years later.
By pooling data from eight of the studies, the researchers found that people with PTSD faced a 61% higher risk of dementia.
Analysing data from two studies that used different methods, they found that PTSD was associated with double the odds of developing dementia.
Dementia risk among people who have had PTSD was higher in the general population compared to veterans, as in the general population people with a PTSD diagnosis were more than twice as likely to develop dementia.
The researchers say this may point to an effect of treating PTSD: veterans are typically more likely to receive treatment for PTSD (at least in the countries the studies were conducted), so the findings suggest that treating PTSD may reduce subsequent dementia risk.
Senior author Dr. Vasiliki Orgeta (UCL Psychiatry) said: “Our study provides important new evidence of how traumatic experiences can impact brain health, and how the long-term effects of trauma may impact the brain in many ways increasing vulnerability to cognitive decline and dementia.
“A lot of people with PTSD don’t access treatment, sometimes due to a lack of mental health care capacity but also because of stigma which often keeps people away from seeking help.
We now have more evidence of how traumatic experiences and accessing treatment could have a long-lasting impact for individuals and influence future risk of developing dementia.”
The researchers say the risk could be higher than the studies suggest, as PTSD also increases the likelihood of developing other known dementia risk factors, such as depression, social isolation, or elevated alcohol intake. Most of the studies adjusted for some of these factors, so the overall findings might underestimate the true cost of PTSD.
It remains unclear how PTSD raises dementia risk, but the researchers say it may be related to hypervigilance and recurrent re-experiencing of trauma, contributing to threat and stress-related activity in the brain, while withdrawal from social life may reduce cognitive reserve and resilience.
The study’s first author, Mia Maria Günak, led the research as part of her MSc dissertation in Dr. Orgeta’s lab at UCL. She commented: “Our findings add to a growing body of evidence that dementia can sometimes be prevented by addressing risk factors throughout an individual’s life course.
“Here we have identified an additional group of people who face an elevated risk of dementia, who may benefit from further mental health support.”
Dr. Orgeta added: “PTSD, which appears to be common among people who have been hospitalised with COVID-19, remains an underdiagnosed, undertreated, and under researched mental health condition, yet it can have serious long-term consequences. As our study has shown, PTSD impacts our brain health by increasing vulnerability to dementia.
An important question is how, and whether we could learn from these findings to develop preventative treatments for those with elevated risk.”
This research is the latest in a series of UCL-led studies investigating how modifiable factors across the lifespan can affect dementia risk, including a major review and meta-analysis of 12 risk factors such as lack of education, hearing loss, and smoking, as well as other recent studies on how repetitive negative thinking and living alone can increase dementia risk.
Neuropsychiatric symptoms (NPS) are now rec- ognized as a major component of neurocognitive disorders, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD).
NPS in dementia, also referred to as behavioral and psychological symptoms of dementia, can take various forms, including psychotic symptoms, mood disturbances (e.g., depressive symptoms, and anxiety), and socially inappropriate behaviors.1,2
NPS are highly prevalent in the course of these disorders, with a large cross- sectional study reporting up to 80% of individuals exhibiting a clinically signiﬁcant neuropsychiatric manifestation after onset of cognitive and functional impairment.3
Additionally, NPS may be present in prodromal stages of dementia, even before meaningful cognitive impairment can be objectiﬁed on neuro-psychological testing.
For instance, late-life onset of depression and irritability in cognitively intact individuals has been demonstrated to be strong predictors of an underlying neurodegenerative disorders with subsequent conversion to dementia.4
Post-traumatic stress disorder (PTSD), a stressor-related disorder with numerous clinical manifestations precipitated after the experience of a traumatic event, has also been linked to cognitive impairment and dementia.
The epidemiology of PTSD varies greatly according to the population and trauma stud- ied, with lifetime prevalence in the general popula- tion estimated to be between 7.8% and 12.3%.5,6
Acutely and subacutely, individuals diagnosed with PTSD have been demonstrated to present meaningful cognitive deﬁcits in sustained attention, working memory, and learning memory when compared to healthy controls.7,8
Furthermore, PTSD has been pos- tulated to be a possible risk factor for the develop- ment of dementia. Studies conducted in male war veterans have reported a signiﬁcantly higher inci- dence of dementia in those diagnosed with the condition.9,10 Recent studies have also described an increased risk of dementia in females and civilians suffering from PTSD.11,12
The reverse temporal association has also been described in the literature, with onset of cognitive deﬁcits precipitating the development of PTSD symptoms in older adults, such as recurrent and intrusive distressing memories from the past and nightmares related to previously experi- enced traumas.
Cases have been reported of delayed onset, worsening, or recurrence of PTSD symptoms in individuals with a progressing neurocognitive disor- der such as AD,13,14 suggesting a complex interplay between PTSD and dementia.
While previous observational studies have explored speciﬁc unidirectional relationships between PTSD and dementia, the reciprocal interactions and temporal associations between these two conditions have not been extensively examined before.
The purpose of the present study is to assess the evidence for a bidirectional relationship between PTSD and dementia.
We present a comprehensive systematic review of observational studies pertaining to both conditions wherein we
1) describe the populations studied;
2) report the different stressors and underly- ing neuropathologies involved; and
3) examine the temporal relationships between the traumatic events and the onset of these conditions.
Data Extraction and Statistical Analyses
Two trained reviewers (PD and DW) independently extracted the data using a standardized data abstraction form that was previously pilot-tested.
Disagreements in coding were resolved by consensus. Data pertaining to study setting and design, popula- tion and participant demographics and baseline characteristics, age at trauma, at onset of PTSD, and at onset of dementia, stressors involved, etiologies of dementia, and study main outcomes were collected.
Studies were classiﬁed based on whether the expo- sure of interest was PTSD or dementia, with the corresponding outcome of interest being onset of dementia or onset of PTSD manifestations, respectively.
Temporal relationships between trauma, dementia, and PTSD were described based on available data regard- ing age at onset of these events, which were catego- rized as follows: early-life: <40 years; mid-life: 40−60 years; and late-life: >60 years. We performed descrip- tive and analytic statistics using IBM SPSS Statistics
24.0 (IBM corp. Armonk, NY).16
Search Process and Study Characteristics
A total of 1,283 records were identiﬁed and screened, 65 of which were assessed at the full-text stage. Twenty-ﬁve articles9−14,18−36 met eligibility criteria and were included (see Fig. 1).
Fourteen articles 9−12,18,21,23−26,28−30,33 reported the long-term outcomes of developing dementia in subjects with a history of PTSD, while 11 articles13,14,19,20,22,27,31,32,34−36 reported the new onset or worsening of PTSD manifestations in subjects with a diagnosis of dementia. Overall, the risk of bias was low (see Supplementary Data).
Characteristics of the included studies are reported in Table 1. Studies investigating PTSD as a risk factor for dementia had different designs (cross-sectional and longitudinal) and were mainly retrospective, while all studies reporting late onset of PTSD manifestations in dementia subjects were case reports/ series.
The latter studies had small sample size, rang- ing from 1 to 11 cases reported per article (median of three cases per article). The majority of PTSD and dementia studies focused on war veterans speciﬁcally (60% and 64%, respectively) and enrolled male sub- jects (70.1% and 75.3%, respectively).
The average age at baseline of subjects in PTSD studies was 67.4 +- 7.1 years compared to 80.3 +- 11.1 years for subjects with dementia presenting with late-onset PTSD.
|TABLE 1. Characteristics of the Included Studies (N = 25)|
|PTSD è Dementia (n = 15)a||Dementia è PTSD (n = 11)|
|Cross-sectional study||4 (27%)||0 (0%)|
|Longitudinal study||10 (67%)||0 (0%)|
|Case report/series||1 (7%)||11 (100%)|
|Veterans||9 (60%)||7 (64%)|
|Civilians||6 (40%)||1 (9%)|
|Both||0 (0%)||3 (27%)|
|War combat||10 (67%)||10 (91%)|
|Holocaust survivor||1 (7%)||2 (18%)|
|Accident survivor (e.g., Titanic, car crash)||2 (13%)||1 (9%)|
|Physical and/or sexual assault||2 (13%)||2 (18%)|
|Not specified||2 (13%)||0 (0%)|
|Size of sample (n) <10||1 (7%)||9 (82%)|
|10−99||4 (27%)||2 (18%)|
|100−999||2 (13%)||0 (0%)|
|1,000−9,999||2 (13%)||0 (0%)|
|≥10,000||6 (40%)||0 (0%)|
|Median size||849 (48 − 10,481)||3 (1 − 3)|
|Proportion of female subjects (%)|
|<25||4 (27%)||7 (64%)|
|25−49.9||1 (7%)||1 (9%)|
|50−74.9||2 (13%)||2 (18%)|
|≥75||2 (13%)||1 (9%)|
|Not specified||4 (27%)||0 (0%)|
|Unweighted mean percentage of females||29.9 (32.6)||24.7 (37.4)|
|Average age of subjects (years)|
|50−59 years||3 (20%)||0 (0%)|
|60−69 years||4 (27%)||2 (18%)|
|70−79 years||6 (40%)||3 (27%)|
|80−89 years||0 (0%)||4 (36%)|
|90 years+||0 (0%)||2 (18%)|
|Not specified||2 (13%)||0 (0%)|
|Unweighted mean average age (SD)||67.4 (7.1)||80.3 (11.1)|
This systematic review provides the most compre- hensive overview to date on the complex interplay between PTSD and dementia, suggesting the presence of a bidirectional relationship between these two con- ditions. Current evidence indicates a strong and clini- cally meaningful association between PTSD occurring in mid to late-life and subsequent development of late-life dementia.
The short intervals of time between the emergence of PTSD and the later onset of dementia reported in some of the studies11,21,25 sug- gest that PTSD manifestations in older adults may represent a prodromal stage of dementia, similar to other NPS.4 Signiﬁcant associations have been described with most neurocognitive disorders, including AD, PD/LBD, and FTD.
Interestingly, com- pared to the natural epidemiology in the general pop- ulation, FTD cases were disproportionally overrepresented in some of these studies.9,11 Further- more, several studies have reported the emergence and worsening of PTSD manifestations with late-life onset of dementia in individuals with a history of early-life trauma. In particular, numerous case series reported the new and delayed-onset of PTSD in AD and VaD.
Collectively, these studies suggest the exis- tence of various possible trajectories following a trau- matic event (Fig. 2) and an intricate bidirectional relationship between dementia and PTSD (Fig. 3).
The possible causal pathological mechanisms underlying the relationship between PTSD and the subsequent development of dementia are currently unknown.
The different distribution of etiologies in regard to PTSD predating and postdating onset of dementia is noteworthy. It could be hypothesized that PTSD in mid-life may initiate and catalyze the pathological cascade of speciﬁc neurodegenerative disorders, such as FTLD and PD/LBD, while all neu- rocognitive disorders in late-life (where AD and VaD are the most prevalent etiologies in the general population) predispose individuals to the emergence or worsening of PTSD manifestations if they were previ- ously exposed to a signiﬁcant traumatic experience.
The long-term consequences of repeated acute stress episodes and chronic stress conditions likely play a pivotal role in the pathophysiology. Previous studies have demonstrated the presence of a hypothalamic- pituitaryadrenal axis dysfunction in war veterans with and without PTSD37,38 as well as abnormal plas- matic cortisol levels.39
Elevated glucocorticoid plasmatic levels, whether secondary to endogenous or exogenous causes, have been associated with impaired cognitive performance,40−43 to correlate with hippocampal atrophy,42 and have been shown to predict incident cognitive impairment.43 Several structural magnetic resonance imaging studies have reported smaller hippocampal volumetrics (i.e., atro- phy) in PTSD subjects compared to normal con- trols.44,45
However, it remains uncertain whether PTSD causes hippocampal atrophy or hippocampal atrophy predisposes to PTSD.44 Furthermore, individ- uals with PTSD appear to share similarities with indi- viduals with a diagnosis of AD with regards to the presence of hypometabolism in the medial temporal lobe, hippocampus, and cingulate cortex.46
Chronic stress has also been demonstrated to affect the dopaminergic system in animal models by triggering neurodegeneration in the substantia nigra pars compacta through oxidative stress and microglial activation,47 which could explain the higher risk of PD reported in subjects with PTSD.21
Likewise, the causal pathological mechanisms underlying the relationship between late-life demen- tia and the subsequent emergence or worsening of PTSD manifestations are not well characterized. Similar to individuals with PTSD, hypothalamic- pituitary-adrenal axis dysfunction has been reported in individuals with mild cognitive impairment and AD.48 Neurodegeneration of the limbic structures associated with emotional regula- tion, such as the amygdala and the hippocampus, secondary to proteinopathies such as amyloid beta and alpha-synucleinopathy, or from vascular insults could promote the emergence of PTSD manifesta- tions.13,32,34
Lastly, impairment in executive func- tions, which are prefrontal lobe processes, has also been hypothesized to contribute to the delayed onset of PTSD through decrease in inhibition on the amygdala.13,19,34
Many questions remain unanswered regarding the association between PTSD and dementia, due in part to limitations of the included studies. First, it is not known whether there are developmental trends between these conditions, such as a higher risk for dementia with a younger age at trauma or at onset of PTSD.
Several elements were inconsistently mea- sured or reported in the retrieved studies; the initial traumas were infrequently described in detail and rarely situated in time comparatively to the onset of dementia and PTSD. Moreover, many studies9,10,12,21,23−26 included a minimum age eligibility criterion for enrollment, excluding subjects with a history of PTSD that began at an early age.
The risk of developing dementia in PTSD may therefore be overestimated in these studies. Second, the evidence for a dose-dependent association (i.e., a more severe trauma more likely to cause PTSD and dementia or a more severe PTSD more likely to cause dementia) is limited, as only a few studies25,26 used a severity measure of PTSD. Third, the prognostic factors for the risk of developing dementia in the context of PTSD remain unknown.
The semiology and phe- nomenology of PTSD were rarely reported and ana- lyzed in the studies, such as duration, severity, recurrence/chronicity, all of which could potentially be predictors for the risk of dementia.
The natural evolution of dementia in individuals with a history of PTSD remains to be better characterized as well. Lastly, none of the studies reported the neuropathological conﬁrmation of the neurocognitive diagnoses and neuroimaging investigations were not system- atically performed nor their ﬁndings methodically reported in the articles.
These latter limitations are substantial as, for instance, the described association between PTSD and FTD could be due to clinical misdiagnosis of FTD (e.g., misidentiﬁcation of the hyperarousal state found in PTSD for the aggressive disinhibition found in FTD.)
The main strength of this study is the focus on the temporal relationship between the onset of trauma, PTSD, and dementia, in addition to emphasis on the precise stressors and the possible underlying neuro-pathologies.
Our approach has allowed us to synthesize the important ﬁndings as well as the current gaps in the literature. Moreover, by using a systematic approach and wide eligibility criteria for inclusion, we included all relevant studies pertaining to both PTSD and dementia, allowing the detailed description of many possible trajectories following the onset of a signiﬁcant trauma.
Limitations of this review must be acknowledged as well. First, as our focus was speciﬁcally on neurodegenerative disorders, we excluded studies involving subjects with diagnoses of alcohol-related dementia and pseudo-dementia, which could have provided further insights.
Second, there was a high level of heterogeneity amongst the included studies, which may be due to the different populations enrolled, stressors included, and age eligibility criteria used in the studies. With signiﬁcant variation within studies, pooled estimates may be unreliable and bias.
At last, while we were able to retrieve studies describing the emergence and recurrence of PTSD manifestations in subjects with dementia, these studies were mainly case series with small sample sizes. Hence, although the relationship between PTSD and dementia may be bidirectional, the importance and prevalence of late-onset PTSD in dementia remains to be determined.
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More information: British Journal of Psychiatry (2020). DOI: 10.1192/bjp.2020.150