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    3 Comments for this article
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    PTSD and dementia in Holocaust survivors
    Teresa Biermann, M.D.; Dr. med. | Department of Psychiatry and Psychotherapy, University Hospital of Erlangen, Germany,
    Yaffe et al.1 reported on the markedly increased risk of dementia from all origins in veterans suffering from posttraumatic stress disorder (PTSD). In this predominantly male and impressively large veteran cohort, those diagnosed with a PTSD were at a nearly 2-fold higher risk of developing dementia compared to those without. Reasons for this finding include poorer performance in cognitive testing as a risk factor, chronic stress damaging the hippocampus, alterations in the hypothalamic-pituitary -adrenal axis and proinflammatory cytokines, some kind of over reporting bias, or an increased non-specific vulnerability to several neuro psychiatric disorders caused by PTSD. A large body of research has been undertaken to prove the association between PTSD and altered brain structures such as decreases in hippocampus volume. In veterans as well as in Holocaust survivors, PTSD is associated with substantial impairments in learning, free and cued recall, and recognition memory compared to respective non-exposed subjects though findings on hippocampus volume loss have been contradictory.2
    Within the context of internal research 93 Holocaust survivors suffering from PTSD have been examined who were found to be strongly at risk for late-onset schizophrenia mainly explained by the stress diathesis model 3: All of these patients surviving the Holocaust suffered from PTSD, 70% had an anxiety disorder, and 50.5% had major depression and personality changes following extreme exposure to traumatisation. They were diagnosed with somatic diseases as well: gastrointestinal (47.3%), cardiovascular (17%) and chronic infectious diseases (22.6%). Patients suffered on average from 4.5 (Standard Deviation SD ± 1.8) somatic diagnoses as well as 1.8 (SD ± 0.5) psychiatric diagnoses. In 14% a diagnosis of dementia was ascertained according to ICD-10 criteria. Vascular dementia (66%) dominated in comparison to Alzheimer’s dementia (23%) and other subtypes (11%). The preference for vascular dementia in this group of 93 survivors of the Holocaust with PTSD differs from the results of the exhaustive analysis of veterans with PTSD. Explanations for the phenomena of an increased dementia rate are manifold. It might be speculated that different causes of traumatisation might lead to different subtypes of psychiatric disease. Even if veterans seem to be a relatively homogenous collective of patients having suffered from comparable experiences during a defined time frame, possibly their traumas differ in some way. This difference might account for different explanations of different pathophysiologic explanations for the genesis of dementia or other neurodegenerative diseases.
    Yours sincerely, Dr. med. Teresa Biermann Prof. Wolfgang Sperling
    References:
    1. Yaffe K, Vittinghoff E, Lindquist K, et al. Posttraumatic stress disorder and risk of dementia among US veterans. Arch Gen Psychiatry. Jun;67(6):608-613.
    2. Golier JA, Harvey PD, Legge J, Yehuda R. Memory performance in older trauma survivors: implications for the longitudinal course of PTSD. Ann N Y Acad Sci. Jul 2006;1071:54-66.
    3. Reulbach U, Bleich S, Biermann T, Pfahlberg A, Sperling W. Late- onset schizophrenia in child survivors of the holocaust. J Nerv Ment Dis. Apr 2007;195(4):315-319.

    Conflict of Interest: None declared
    CONFLICT OF INTEREST: None Reported
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    Enkephalin may be a contributing factor in developing Alzheimer's disease in PTSD patients
    Xing-Xing Sun, M.D. | School of Stomatology, Fourth Military Medical University,
    In a recent paper, Yaffe et al reported that older veterans who suffered from posttraumatic stress disorder (PTSD) were almost twice as likely to develop Alzheimer's disease and other age-related dementias as veterans without PTSD.(1) How to reduce the increased risk of dementia associated with PTSD would be an important problem for doctors to address. The enkephalin pathway could illustrate the relationship between PTSD and dementias. Reduction of the production of enkephalin in exposure to traumatic stress and enkepahlin signaling may be a new target for curing dementias.(2)
    PTSD is a severe anxiety disorder that can be caused by
    exposure to traumatic stress. Under the traumatic stress, enkephalin can be elevated or the enkephalinergic neurons can be activated in certain brain areas such as hypothalamus and hippocampus in rats.(3) On the other hand, enkephalin is involved in many functions that are affected by Alzheimer's disease and other neurodegenerative diseases. It was found that there are increased levels of preproenkephalin mRNA and enkephalin in brain regions important for memory that are affected in early stages of Alzheimer's disease, and modulating the activity of enkephalin peptides in the brain could relieve the symptoms of Alzheimer's disease in mice.(4) We propose that the enkephalin generated under the traumatic stress may be a contributing factor in the development of Alzheimer’s disease.
    The enkephalin pathway may be a tentative point to prevent patients with PTSD from developing Alzheimer’s disease. Neprilysin, which could dissolve generated enkephalin in the central nervous system, was proven to be useful and has been widely used in clinical treatment for reducing the syndrome of Alzheimer’s disease. However, reduction of enkephalin and inhibition of the enkephalin pathway may also be harmful to veterans under traumatic stress (such as in battle, or when wounded), for enkephalin generated in the brain, especially in the hypothalamus and thalamus, seems to be associated with analgesia.(5) Considering this side effect, patients can be given agonists of µ-receptor at the same time to relieve pain, for there is no conclusive evidence that activation of µ- receptor increases the possibility of developing Alzheimer’s disease in patients with PTSD. This letter just provides a tentative point illustrating a relationship between PTSD and Alzheimer’s disease and a possible treatment to slow or stop the process, which requires further studies for proof.
    No relevant conflicts of interest.
    Xing-Xing Sun, MD* Hao Xu, MD* Ting-Ting Du, MD# Jing Chen, MD, PhD candidate** Sheng-Xi Wu, MD, PhD, professor Li-Xian Xu, MD, PhD, Professor
    *Department of Anesthesiology, School of Stomatology **Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, PR China. #Tongji medical college of huazhong university of science & technology, Wuhan, PR China.
    Correspondence: Sheng-Xi Wu MD, PhD, Unit for Evidence-Based Medicine, Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University;
    Li-Xian Xu, MD, PhD, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University
    REFERENCES
    1.Yaffe K, Vittinghoff E, Lindquist K, et al. Posttraumatic stress disorder and risk of dementia among US veterans. Arch Gen Psychiatry. 2010;67(6):608-613.
    2.Meilandt WJ, Yu G-Q, Chin J, et al. Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci. 2008;28(19):5007-5017.
    3.Dumont EC, Kinkead R, Trottier JF, Gosselin I, Drolet G. Effect of chronic psychogenic stress exposure on enkephalin neuronal activity and expression in the rat hypothalamic paraventricular nucleus. J Neurochem. 2000;75(5):2200-11.
    4.Meilandt WJ, Yu GQ, Chin J, Roberson ED, Palop JJ, Wu T, Scearce- Levie K, Mucke L.Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci. 2008;28(19):5007-17.
    5. Kurumaji A, Takashima M, Shibuya H. Cold and immobilization stress -induced changes in pain responsiveness and brain Met-enkephalin-like immunoreactivity in the rat. Peptides. 1987;8(2):355-9.

    Conflict of Interest: None declared
    CONFLICT OF INTEREST: None Reported
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    PTSD and Dementia
    Sebastian K. Kreil, MD | University of Erlangen-Nuremberg, Psychiatric Clinic, Schwabachanlage 6, 91054 Erlangen, Germany,
    Yaffe et al. came to the result that veterans with PTSD had a 7-year cumulative incident dementia rate of 10.6%, whereas those without had a rate of 6.6% (P < .001). In a predominantly male veteran cohort, those diagnosed as having PTSD were at a nearly 2-fold-higher risk of developing dementia compared with those without PTSD. No consistent pattern was seen, other than that PTSD was associated with a higher risk of dementia among all dementia subtypes (Patients with PTSD: Alzheimer hazard ratio 1.71 [confidence interval 95%], Frontotemporal dementia 2.19, Senile dementia 2.03, vascular dementia 1.69, Lewy body dementia 2.05). In another study with Holocoaust survivors with PTSD older age and smaller left hippocampal volume were more strongly associated in the PTSD+ group than in the PTSD- groups (Yehuda et al., 2007). Within the context of internal research, 93 Holocaust survivors suffering from posttraumatic stress disorder have been examined in our own sample. Patients suffered on average from 4.5 (standard deviation 1.8) somatic diagnoses as well as 1.8 (standard deviation 0.5) psychiatric diagnoses. A diagnosis of dementia was ascertained according to ICD-10 criteria in 14%. Vascular dementia (66%) dominated over Alzheimer`s dementia (23%) and other subtypes (11%). Patients with PTSD and dementia in our group showed an increase in hypertension, chronic gastrointestinal, and infectious diseases in comparison with other PTSD-patients (Sperling, Kreil, & Biermann, 2011). In veterans, hypertension was found in 65.3% of PTSD subjects, while chronic gastrointestinal and infectious diseases have not been described (Yaffe et al., 2010). The high rate of vascular dementia in our group in comparison to veterans with similarly increased rates of hypertension might therefore be explained by the interaction of chronic infectious diseases, hypertension, and the atherogenic risk in PTSD victims of the Holocaust (Sperling, et al.,2011). It can be supposed that hyperactivity of the sympathoadrenal axis might contribute to vascular disease through the effects of the catecholamines in this group (Bedi & Arora,2007).
    References:
    Bedi, U. S., & Arora, R. (2007). Cardiovascular manifestations of posttraumatic stress disorder. J Natl Med Assoc, 99(6), 642-649.
    Sperling, W., Kreil, S. K., & Biermann, T. (2011). Posttraumatic stress disorder and dementia in holocaust survivors. J Nerv Ment Dis, 199(3), 196-198.
    Yaffe, K., Vittinghoff, E., Lindquist, K., Barnes, D., Covinsky, K. E., Neylan, T., et al.(2010). Posttraumatic stress disorder and risk of dementia among US veterans. Arch Gen Psychiatry, 67(6), 608-613.
    Yehuda, R., Golier, J. A., Tischler, L., Harvey, P. D., Newmark, R., Yang, R. K., et al.(2007). Hippocampal volume in aging combat veterans with and without posttraumatic stress disorder: relation to risk and resilience factors. J Psychiatr Res, 41(5), 435-445.

    Conflict of Interest: None declared
    CONFLICT OF INTEREST: None Reported
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    Original Article
    June 2010

    Posttraumatic Stress Disorder and Risk of Dementia Among US Veterans

    Author Affiliations

    Author Affiliations: Departments of Psychiatry (Drs Yaffe, Barnes, Neylan, and Marmar and Ms Kluse), Neurology (Dr Yaffe), Epidemiology and Biostatistics (Drs Yaffe and Vittinghoff), and Medicine (Ms Lindquist and Dr Covinsky), School of Medicine, University of California, San Francisco, and San Francisco Veterans Affairs Medical Center (Drs Yaffe, Covinsky, Neylan, and Marmar).

    Arch Gen Psychiatry. 2010;67(6):608-613. doi:10.1001/archgenpsychiatry.2010.61
    Abstract

    Context  Posttraumatic stress disorder (PTSD) is highly prevalent among US veterans because of combat and may impair cognition.

    Objective  To determine whether PTSD is associated with the risk of developing dementia among older US veterans receiving treatment in the Department of Veterans Affairs medical centers.

    Design  A stratified, retrospective cohort study conducted using the Department of Veterans Affairs National Patient Care Database.

    Setting  Department of Veterans Affairs medical centers in the United States.

    Participants  A total of 181 093 veterans 55 years or older without dementia from fiscal years 1997 through 2000 (53 155 veterans with and 127 938 veterans without PTSD).

    Main Outcome Measures  During the follow-up period between October 1, 2000, and December 31, 2007, 31 107 (17.2%) veterans were ascertained to have newly diagnosed dementia according to International Classification of Diseases, Ninth Revision, Clinical Modification codes.

    Results  The mean baseline age of the veterans was 68.8 years, and 174 806 (96.5%) were men. Veterans with PTSD had a 7-year cumulative incident dementia rate of 10.6%, whereas those without had a rate of 6.6% (P < .001). With age as the time scale, Cox proportional hazards models indicated that patients with PTSD were more than twice as likely to develop incident dementia compared with those without PTSD (hazard ratio, 2.31; 95% confidence interval, 2.24-2.39). After multivariable adjustment, patients with PTSD were still more likely to develop dementia (hazard ratio, 1.77; 95% confidence interval, 1.70-1.85). Results were similar when we excluded those with a history of head injury, substance abuse, or clinical depression.

    Conclusions  In a predominantly male veteran cohort, those diagnosed as having PTSD were at a nearly 2-fold-higher risk of developing dementia compared with those without PTSD. Mechanisms linking these important disorders need to be identified with the hope of finding ways to reduce the increased risk of dementia associated with PTSD.

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