Abstract
We aimed to prospectively assess the change in neuropsychiatric symptoms among people who develop cognitive impairment and have a history of post-traumatic stress disorder (PTSD). We analyzed longitudinal data from the National Alzheimer’s Coordinating Center Unified Data Set (UDS; March 2015-December 2021). Analyses included individuals who were cognitively normal and who had non-missing assessment of PTSD at initial visit and had at least one follow-up visit with cognitive impairment. We compared the difference in the mean neuropsychiatric symptom score at the first UDS visit vs first visit with a Clinical Dementia Rating of 0.5 between those with and without a history of PTSD. Mean neuropsychiatric symptom score change did not differ between those with and without a history of PTSD (1.06 vs 0.77, respectively; p=0.79). The null results found in this study warrant future research. Several methodological limitations might explain these results.
Keywords: Post-traumatic stress disorder, cognitive impairment, neuropsychiatric symptoms, dementia
Objective
The link between post-traumatic stress disorder (PTSD) and cognitive impairment has gained attention in recent years.1 Most research studying the link between PTSD and cognitive impairment focuses on PTSD as a risk factor for developing Alzheimer’s disease.1 However, few studies focus on the impact cognitive impairment has on neuropsychiatric symptoms among people with a history of PTSD. Progressive retrograde amnesia, disorientation, mood changes and other cognitive decline related to Alzheimer’s disease and other dementias may increase or cause the relapse of recurrent intrusive memories, dreams, or flashbacks of traumatic events among individuals with a history of PTSD or trauma. Executive dysfunction and short-term memory impairment may also reduce individuals’ ability to cope with those intrusions. In fact, case reports and series suggest that cognitive impairment might lead to a delayed onset, worsening, or recurrence of PTSD-related neuropsychiatric symptoms among people with a history of trauma or PTSD.1 Biological mechanisms for this phenomena have been suggested, including the atrophy of cortical structures and relative preservation of the amygdala.2,3
The aim of this study is to prospectively assess the change in neuropsychiatric symptoms among people who develop cognitive impairment and have a history of PTSD (PTSD+). We hypothesize that people who develop cognitive impairment and are PTSD+ will have more neuropsychiatric symptom worsening than those without a history of PTSD (PTSD-). To our knowledge, there are only three previous studies that have assessed similar associations.4–6 Results have been mixed, but all studies were conducted in Veteran Affairs clinics with small sample sizes, and most were retrospective and included one or few neuropsychiatric symptoms as outcomes. The current study overcomes some of these limitations by including a well-characterized sample that is larger and has civilians, using a prospective design, and using a summary score of a wide range of neuropsychiatric symptoms as the outcome.
Methods
Data source
We used data from the National Alzheimer’s Coordinating Center (NACC).7 NACC maintains the Unified Data Set (UDS), which includes standardized clinical data reported by past and present NIA-funded Alzheimer’s Disease Research Centers (ADRCs) throughout the United States. Each ADRC recruits participants according to its own protocols; participants may come from clinician referral, self-referral by patients or family members, active recruitment through community organizations, and volunteers who wish to contribute to dementia research. Data were collected by clinicians or trained interviewers at each ADRC. Assessments were conducted approximately annually. Informed consent was obtained from all participants at the individual ADRCs. Centers received approval to gather data from their institutional IRB.
Study sample
The analytic sample included individuals with NACC UDS Version 3 data collected between March 2015 and December 2021. Inclusion criteria for this analysis were the following: 1) non-missing data on health history or a diagnosis of PTSD at initial visit, 2) Clinical Dementia Rating (CDR®) global score (CDR-GS) of 0 (normal cognition) at initial visit and at least one follow-up visit with a CDR-GS >0.8
Measures
Independent variable
PTSD: Clinicians in the NACC UDS Version 3 collect data about whether a participant has ever been diagnosed or treated for PTSD at the initial visit, as part of the Subject Health History form. Response options include: 1) Absent, 2) Recent/active, 3) Remote/inactive or 4) Unknown. Additionally, on the Clinician diagnosis form, clinicians can indicate whether a participant’s cognitive impairment is due to PTSD. If a participant had recent/active PTSD, remote/inactive PTSD, or a diagnosis of PTSD at their initial visit, then they were classified as PTSD+ in this analysis. If a participant did not have PTSD (absent or no diagnosis), they were classified as PTSD-.
Outcome
The outcomes were the difference between the mean total and individual symptom NPI-Q severity scores at the first visit with a CDR-GS of 0.5 and the same scores at the first UDS visit (CDR-GS=0). The NPI-Q asks informants about the presence or absence of 12 neuropsychiatric symptoms (e.g., delusions, depression).9 For each present symptom, informants rate their severity on a three-point scale (mild-severe). The total severity summary score was calculated by adding the severity scores of all items.
Statistical Analyses
To compare the demographic characteristics and clinical measures between PTSD+ and PTSD- groups, Pearson’s chi-square or Fisher’s exact tests for the categorical variables, and two-sample Welch’s t-tests for the continuous variables were applied. We compared differences in mean NPI-Q severity difference scores between the groups using t-tests. Linear regression models were run to explore the annual rate of change in NPI-Q scores. We used p<0.05 as the level of statistical significance. Statistical analyses were performed using SAS 9.4 Software.10
Results
The final analytic sample included 18 PTSD+ participants and 585 PTSD- participants. Table 1 summarizes the participant characteristics at the baseline visit, by PTSD history. PTSD+ participants were younger than PTSD- participants (mean=66.6 vs 71.6; p=0.01). There was a higher representation of individuals who identified as ethnically or racially minoritized in the PTSD+ group compared to the PTSD- group (66.7% vs 34.8%; p=0.02). Regarding the clinical characteristics, PTSD+ participants had higher BMIs than PTSD- participants (mean=31.3 vs 27.6; p=0.04), higher Geriatric Depression Scale (GDS) scores (indicating more severe depression; mean=3.7 vs 1.7; p=0.05), exhibited a higher frequency of alcohol abuse (22.2% vs 4.1%; p=0.02) and other substance abuse (11.1% vs 1.2%; p=0.05), and diagnoses of depression (72.2% vs 26.3%; p<0.01) and other psychiatric disorders (55.6% vs 22.6%; p=0.01). Other sociodemographic (e.g., follow-up years, sex, years of education) and clinical characteristics (APOE-e4 status, smoking status, hypertension) did not vary by PTSD history.
Table 1.
Participant baseline characteristics
| Characteristic | PTSD n=18 | no PTSD n=585 | p-value |
|---|---|---|---|
| Age, yrs, mean (sd) | 66.6 (6.8) | 71.6 (8.5) | 0.01 |
| Follow-up time, yrs, mean (sd) | 3.1 (1.8) | 3 (1.4) | 0.77 |
| Female, n (%) | 11 (61.1) | 341 (58.3) | 0.81 |
| Race/ethnicity, n (%) | 0.02 | ||
| Non-Latino White | 6 (33.3) | 379 (64.8) | |
| Non-Latino Black | 3 (16.7) | 92 (15.7) | |
| Latino | 6 (33.3) | 63 (10.8) | |
| Other non-Latino | 3 (16.7) | 46 (7.9) | |
| Education, yrs, mean (sd) | 15.7 (2.8) | 15.9 (3.1) | 0.73 |
| APOE e4 carrier, n (%) | 7 (38.9) | 146 (25.0) | 0.41 |
| Smoking status, n (%) | 0.06 | ||
| Never | 8 (44.4) | 349 (59.7) | |
| Former | 6 (33.3) | 200 (34.2) | |
| Current | 4 (22.2) | 33 (5.6) | |
| BMI, mean (sd) | 31.3 (6.6) | 27.6 (5.4) | 0.04 |
| Hypercholesterolemia, n (%) | 9 (50.0) | 311 (53.2) | 0.85 |
| Hypertension, n (%) | 10 (55.6) | 280 (47.9) | 0.65 |
| Diabetes, n (%) | 5 (27.8) | 91 (15.6) | 0.21 |
| Cerebrovascular disease, n (%) | 2 (11.1) | 32 (5.5) | 0.27 |
| Cardiovascular disease, n (%) | 4 (22.2) | 149 (25.5) | 1.00 |
| Alcohol abuse, n (%) | 4 (22.2) | 24 (4.1) | 0.02 |
| Other substance abuse, n (%) | 2 (11.1) | 7 (1.2) | 0.05 |
| Total GDS score, mean (sd) | 3.7 (4.0) | 1.7 (2.3) | 0.05 |
| Depression, n (%) | 13 (72.2) | 154 (26.3) | <0.01 |
| Apathy, n (%) | 2 (11.1) | 45 (7.7) | 0.64 |
| Other psychiatric disorders1, n (%) | 10 (55.6) | 132 (22.6) | 0.01 |
| Primary clinical diagnoses at 1st visit/CDR-GS 0.5, n (%) | |||
| AD | 4 (22.2) | 179 (30.6) | 0.76 |
| DLB | 0 (0.0) | 21 (3.6) | 1.00 |
| CVD | 1 (5.6) | 28 (4.8) | 0.84 |
| FTD2 | 6 (33.3) | 202 (34.5) | 0.57 |
Includes self-reported, bipolar disorder, schizophrenia, anxiety, OCD, developmental neuropsychiatric disorders, and other psychiatric disorders
Includes MSA, PSP, CBD, FTLD with motor neuron disease (e.g., ALS, and other FTLD including bvFTD and PPA
Bold values indicate significance at the 0.05 level
Abbreviations: Yrs: Years; SD: Standard deviation; APOE: Apolipoprotein E; BMI: Body Mass Index; GDS: Geriatric Depression Scale; CDR-GS: Clinical Dementia Rating Global Score; AD: Alzheimer’s disease; DLB: Dementia with Lewy bodies; CVD: Cardiovascular dementia; FTD: Fronto-temporal dementia; PTSD: Post-traumatic stress disorder.
Figure 1 shows the change in total NPI-Q mean neuropsychiatric scores. The PTSD+ and PTSD- groups did not differ with respect to the total NPI-Q mean neuropsychiatric scores. Supplemental Digital Content Table 1 shows no group differences in the change in individual NPI-Q mean neuropsychiatric scores. Supplemental Digital Content Table 2 shows group differences in annual rates of change of total and individual symptoms and indicates a similar pattern to Supplemental Digital Content Table 1.
Figure 1.
Difference in mean total change of neuropsychiatric symptoms by PTSD history
Conclusions
This is among the first studies to assess the change in neuropsychiatric symptoms among people who develop cognitive impairment and have a history of PTSD. Our study overcomes limitations of previous studies by not limiting the sample to Veteran Affairs clinics, including a modestly larger sample, using a prospective design, and using a summary score of a wide range of neuropsychiatric symptoms as the outcome. We hypothesized that people who develop cognitive impairment and have a history of PTSD would have more neuropsychiatric symptom worsening than those without a history of PTSD. Contrary to our hypothesis, we found that neuropsychiatric symptom worsening from a cognitively normal to a cognitively impaired stage did not differ between individuals with and without a history of PTSD.
Our hypothesis was based on a model where cognitive impairment triggers previous PTSD symptoms and impair individuals’ ability to cope with them.3 Our results are not in line with several observations of reported PTSD relapse or worsening among individuals with dementia in case series and reports,1 and a retrospective study reporting a higher percentage of disruptive behaviors among PTSD+ individuals with dementia.6 However, results are consistent with one retrospective and one prospective study where aggression, agitation, and paranoia did not differ among PTSD+ and PTSD- patients with dementia.4,5 An explanation could be that cognitive decline eliminates triggers that lead to PTSD-related symptoms. However, these memories are deeply rooted in limbic areas, which tend to be preserved until more severe stages.2,3 The very mild/questionable nature of participants’ cognitive impairment (CDR-GS=0.5) might account for these null findings, as it might be too mild to impact PTSD symptoms. Alternatively, several participants identified as PTSD- might have been undiagnosed PTSD+ or experienced subthreshold levels of PTSD. However, such a high rate of undiagnosed or subthreshold PTSD is unlikely in the general population. A higher prevalence of certain cognitive impairment etiologies (e.g., Alzheimer’s disease or Frontotemporal dementia) in the non-PTSD group could have explained the lack of differences in neuropsychiatric symptoms compared to the PTSD group. However, groups did not differ with respect to etiology.
Other study limitations include a sample of PTSD+ individuals that is relatively small, a non-probabilistic sampling approach, and reliance on the participants and their informants’ disclosure of PTSD diagnosis history. Future studies should address these limitations, and especially, achieving a larger sample of PTSD+ individuals who were assessed at more severe cognitive impairment stages than a 0.5 in the CDR-GS. Achieving a larger sample might be possible after several years in the NACC database. These future studies might also differentiate between those whose PTSD symptoms remitted and those whose PTSD symptoms continued into older age. Samples in the future also will need to be diverse, given the high percentage of individuals with a history of PTSD from ethnoracially minoritized backgrounds in our sample, and the high dementia risk found in these groups. This line of research could have implications for addressing overall health disparities for minoritized groups.
Supplementary Material
Acknowledgements:
This work was supported by grants from the National Institutes of Health, including K01MD014177 and R21AG065755 (Dr. Perales-Puchalt) and K01AG056669 and R24AG066599 (Dr. Jason Flatt). The NACC database is funded by the National Institutes of Health grant U24 AG072122. NACC data are contributed by the National Institutes of Health-funded ADRCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD). We thank the participants for their engagement in ADRC research studies.
Footnotes
Conflicts of interest and source of funding
JPP and his institution are currently receiving grants from the NIH (K01MD014177, R21AG065755 and P30 AG035982). OLM and her institution are currently receiving grants from the NIH (R01AG067541, P30AG072972). WAK and his institution are currently receiving grants from the NIH, principally U24 AG072122. For the remaining authors none were declared.
Contributor Information
Jaime Perales-Puchalt, University of Kansas, Department of Neurology, University of Kansas Alzheimer’s Disease Research Center, Fairway, KS.
Kathryn Gauthreaux, University of Washington, National Alzheimer’s Coordinating Center (NACC), Seattle, WA.
Jason D. Flatt, University of Nevada, Las Vegas, School of Public Health, Las Vegas, NV.
Oanh L. Meyer, University of California, Davis School of Medicine, Department of Neurology, Alzheimer’s Disease Research Center, Sacramento, CA.
Walter A. Kukull, University of Washington, National Alzheimer’s Coordinating Center (NACC), Seattle, WA.
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