Traumatic Brain Injuries: Manifestations, Evaluation, Management, and Outcomes.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2024;26(3):23f03667. Author affiliations are listed at the end of this article.

Longitudinal changes in the PTSD symptom network following trauma-focused treatment in military populations: Identifying central symptoms and the role of military sexual trauma.

Posttraumatic stress disorder (PTSD) is a debilitating condition affecting military populations, with a higher prevalence compared to the general population. Despite the development of first-line trauma-focused treatments such as Cognitive Processing Therapy (CPT) and Prolonged Exposure Therapy (PE), a significant proportion of patients continue to experience persistent PTSD symptoms following treatment. This study utilized network analysis to explore the PTSD symptom network's dynamics pre- and post- trauma-focused treatment and investigated the role of military sexual trauma (MST) history in shaping the network. Network analysis is a novel approach that can guide treatment target areas. The sample was comprised of 1648 service members and veterans who participated in a two-week intensive PTSD treatment program, which included completion of evidenced-based individual therapy as well as skill-building focused group therapy. PTSD severity was assessed using the PTSD Checklist for DSM-5 at baseline and post-treatment. Network analyses revealed strong connections within symptom clusters, with negative emotions emerging as one of the most central symptoms. Interestingly, the symptom network's overall structure remained stable following treatment, whereas global strength significantly increased. MST history did not significantly impact the network's structure or its change relative to treatment. Future research should further examine whether targeting negative emotions optimizes PTSD treatment outcomes for military populations.

Telemedicine-Based Cognitive Examinations During COVID-19 and Beyond: Perspective of the Massachusetts General Hospital Behavioral Neurology & Neuropsychiatry Group.

Telehealth and telemedicine have encountered explosive growth since the beginning of the COVID-19 pandemic, resulting in increased access to care for patients located far from medical centers and clinics. Subspecialty clinicians in behavioral neurology & neuropsychiatry (BNNP) have implemented the use of telemedicine platforms to perform cognitive examinations that were previously office based. In this perspective article, BNNP clinicians at Massachusetts General Hospital (MGH) describe their experience performing cognitive examinations via telemedicine. The article reviews the goals, prerequisites, advantages, and potential limitations of performing a video- or telephone-based telemedicine cognitive examination. The article shares the approaches used by MGH BNNP clinicians to examine cognitive and behavioral areas, such as orientation, attention and executive functions, language, verbal learning and memory, visual learning and memory, visuospatial function, praxis, and abstract abilities, as well as to survey for neuropsychiatric symptoms and assess activities of daily living. Limitations of telemedicine-based cognitive examinations include limited access to and familiarity with telecommunication technologies on the patient side, limitations of the technology itself on the clinician side, and the limited psychometric validation of virtual assessments. Therefore, an in-person examination with a BNNP clinician or a formal in-person neuropsychological examination with a neuropsychologist may be recommended. Overall, this article emphasizes the use of standardized cognitive and behavioral assessment instruments that are either in the public domain or, if copyrighted, are nonproprietary and do not require a fee to be used by the practicing BNNP clinician.

Neurobiological Mechanisms Of Depression Following Traumatic Brain Injury.

OBJECTIVE: Depression is among the most pervasive and debilitating neuropsychiatric sequelae experienced by patients following a traumatic brain injury (TBI). While the individual mechanisms underlying depression and TBI have been widely studied, the neurobiological bases of depression after TBI remain largely unknown. This article highlights the potential mechanisms of action implicated in depression after TBI. RESULTS: We review putative mechanisms of action including neuroinflammation, neuroendocrine dysregulation, metabolic abnormalities, and neurotransmitter and circuitry dysfunction. We also identify the current limitations in the field and propose directions for future research. CONCLUSION: An improved understanding of the underlying mechanisms will aid the development of precision-guided and personalized treatments for patients suffering from depression after TBI.

Associations between residual hyperarousal and insomnia symptoms in veterans following a 2-week intensive outpatient program for posttraumatic stress disorder.

Many returning military service members and veterans who were deployed following the September 11, 2001, terrorist attacks (9/11) suffer from posttraumatic stress disorder (PTSD) and insomnia. Although intensive treatment programs for PTSD have shown promise in the treatment of PTSD symptoms, recent research has demonstrated that sleep disturbance shows little improvement following intensive trauma-focused treatment. The aim of the present study was to evaluate changes in self-reported insomnia symptoms among veterans and service members following participation in a 2-week intensive program for PTSD. We further aimed to investigate if residual PTSD symptoms, specifically hyperarousal, were associated with residual insomnia symptoms. Participants (N = 326) completed self-report assessments of insomnia, PTSD symptoms, and depressive symptoms at pre- and posttreatment. At pretreatment, 73.9% of participants (n = 241) met the criteria for moderate or severe insomnia, whereas at posttreatment 67.7% of participants (n = 203) met the criteria. Results of paired t tests demonstrated statistically significant differences between pre- and posttreatment Insomnia Severity Index scores; however, the effect size was small, d = 0.34. Analyses revealed that posttreatment hyperarousal symptoms were associated with posttreatment insomnia. These findings suggest that although an intensive program for service members and veterans with PTSD may significantly reduce insomnia symptoms, clinically meaningful residual insomnia symptoms remain. Further research is warranted to elucidate the association between residual hyperarousal and insomnia symptoms following intensive trauma-focused treatment.

Neuropsychiatric symptoms in a occipito-temporal infarction with remarkable long-term functional recovery.

Posterior circulation infarctions (PCI) constitute 5-25% of ischemic strokes. PCI of the occipital lobe present with a panoply of symptoms including quadrantanopsia, topographical disorientation, and executive dysfunction. Long-term cognitive recovery after PCI is not well described. However, the adult brain is remarkably plastic, capable of adapting and remodeling. We describe a 43-year-old right-handed woman who complained of black spots in both eyes, headaches, photophobia, and a feeling she would faint. Initial neurological exam and a CT scan were normal; she was diagnosed with ocular migraine. A second neurological exam a week later showed left superior quadrantopsia; an MRI scan suggested right occipito-temporal infarct. In subsequent months, the patient complained of fatigue, quadrantanopsia, memory problems, and topographical disorientation. The patient participated in multi-modality treatment, and in self-directed arts projects and physical activities. Six years later, she reported noticeable improvements in cognition and daily functioning, which were documented on neurocognitive testing. Comparison between initial and subsequent MRIs using FreeSurfer 5.3 identified neuroplastic brain changes in areas serving similar functions to the areas injured from the stroke. The case illustrates the neuropsychiatric presentation after right occipito-temporal stroke, the value of formal and self-directed cognitive rehabilitation, the extended time to cognitive recovery, and the ability of the brain to undergo neuroplastic changes.

Levodopa-Induced Dyskinesia Are Mediated by Cortical Gamma Oscillations in Experimental Parkinsonism.

BACKGROUND: Levodopa is the most efficacious drug in the symptomatic therapy of motor symptoms in Parkinson's disease (PD); however, long-term treatment is often complicated by troublesome levodopa-induced dyskinesia (LID). Recent evidence suggests that LID might be related to increased cortical gamma oscillations. OBJECTIVE: The objective of this study was to test the hypothesis that cortical high-gamma network activity relates to LID in the 6-hydroxydopamine model and to identify new biomarkers for adaptive deep brain stimulation (DBS) therapy in PD. METHODS: We recorded and analyzed primary motor cortex (M1) electrocorticogram data and motor behavior in freely moving 6-OHDA lesioned rats before and during a daily treatment with levodopa for 3 weeks. The results were correlated with the abnormal involuntary movement score (AIMS) and used for generalized linear modeling (GLM). RESULTS: Levodopa reverted motor impairment, suppressed beta activity, and, with repeated administration, led to a progressive enhancement of LID. Concurrently, we observed a highly significant stepwise amplitude increase in finely tuned gamma (FTG) activity and gamma centroid frequency. Whereas AIMS and FTG reached their maximum after the 4th injection and remained on a stable plateau thereafter, the centroid frequency of the FTG power continued to increase thereafter. Among the analyzed gamma activity parameters, the fraction of longest gamma bursts showed the strongest correlation with AIMS. Using a GLM, it was possible to accurately predict AIMS from cortical recordings. CONCLUSIONS: FTG activity is tightly linked to LID and should be studied as a biomarker for adaptive DBS. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Comparative effectiveness of prolonged exposure and cognitive processing therapy for military service members in an intensive treatment program.

OBJECTIVE: While the comparative efficacy of prolonged exposure (PE) and cognitive processing therapy (CPT) has been examined in outpatient settings, there is a dearth of literature on the relative effectiveness of these interventions when adapted for an intensive treatment format. In an expanded secondary analysis of a previous study, we sought to examine the comparative effectiveness of PE and CPT delivered in the naturalistic setting of an intensive treatment format including maintenance of outcomes through a 6-month follow-up period. METHOD: A sample of 296 veterans with posttraumatic stress disorder (PTSD) received either PE (n = 186) or CPT (n = 90), alongside other trauma-informed interventions, in a 2-week intensive clinical program. Treatment selection was determined collaboratively between patient and therapist. Our primary outcome was self-reported PTSD symptom severity (i.e., PTSD Checklist for DSM-5, PCL-5); secondarily, we examined self-reported depression (i.e., Patient Health Questionnaire) symptom severity outcomes. RESULTS: A mixed-model regression controlling for age and gender revealed a significant effect of time from baseline to endpoint (p < .001), 3-month (p < .001), and 6-month follow-up (p < .001) on PCL-5 scores but no significant effect of treatment or effect of treatment by time interaction (all ps > .05; model: Wald's χ² = 232.38, p < .001). Results were similar for depression outcomes. Attrition at posttreatment was not significantly different between groups: 7.2% for CPT and 6.5% PE (z score = 0.22). CONCLUSIONS: Both PE and CPT are associated with comparable improvements when delivered as part of a 2-week intensive outpatient program. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Telemedicine in Behavioral Neurology-Neuropsychiatry: Opportunities and Challenges Catalyzed by COVID-19.

Coronavirus 2019 (COVID-19) has profoundly impacted the well-being of society and the practice of medicine across health care systems worldwide. As with many other subspecialties, the clinical paradigm in behavioral neurology and neuropsychiatry (BN-NP) was transformed abruptly, transitioning to real-time telemedicine for the assessment and management of the vast majorities of patient populations served by our subspecialty. In this commentary, we outline themes from the BN-NP perspective that reflect the emerging lessons we learned using telemedicine during the COVID-19 pandemic. Positive developments include the ability to extend consultations and management to patients in our high-demand field, maintenance of continuity of care, enhanced ecological validity, greater access to a variety of well-reimbursed telemedicine options (telephone and video) that help bridge the digital divide, and educational and research opportunities. Challenges include the need to adapt the mental state examination to the telemedicine environment, the ability to perform detailed motor neurologic examinations in patients where motor features are important diagnostic considerations, appreciating nonverbal cues, managing acute safety and behavioral concerns in less controlled environments, and navigating intervention-based (neuromodulation) clinics requiring in-person contact. We hope that our reflections help to catalyze discussions that should take place within the Society for Behavioral and Cognitive Neurology, the American Neuropsychiatric Association, and allied organizations regarding how to optimize real-time telemedicine practices for our subspecialty now and into the future.

Marital Hypnotherapy: A Session with Milton Erickson with Commentary.

Hypnosis has primarily been used to treat individual problems. Occasionally, it has been applied to couples' problems such as infertility. We present a transcript of a treatment session of Dr. Milton Erickson in which he works with a married couple and interpret his techniques. We emphasize the following principles. Dr. Erickson's assessment was brief, just long enough to determine a general target. He used hypnotic induction to build responsiveness. He used evocative communication. He seeded ideas that, when presented later, had a powerful impact. He moved in small, strategic steps. The main intervention was designed to elicit dormant resources and adaptive states. He followed through, providing suggestions on how to use these resources. In presenting this case and our analysis of it, we highlight some of Dr. Erickson's methods and conceptualization of several intervention techniques.

Collaborative Songwriting Intervention for Veterans with Post-Traumatic Stress Disorder.

Objectives: Given that veterans are significantly more likely to suffer from post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), depression, and anxiety than civilians, yet current gold-standard treatments for PTSD are not effective for all patients, the present study sought to examine the feasibility and acceptability of a collaborative songwriting intervention (CSI) while exploring its potential effectiveness in improving physical and mental health outcomes for veterans with PTSD. Design: Ten veterans took part in the CSI. A variety of pre- and postintervention measures were administered, including the Measurement of Current Status (MOCS), the Coping Expectancies Scale (CES), the Post-traumatic Stress Disorder Checklist-Military (PCL-M), and the Patient Health Questionnaire-9 (PHQ-9). Participants also wore a Fitbit to track average heart rate, sleep, and step count. Intervention: The CSI consisted of each veteran meeting with a professional songwriter, trained specifically for co-writing original material with the veteran population. There were three phases of songwriting that took about an hour and 15 min total. Veterans were instructed to listen to their song daily for 5 weeks. Results: Participants reported that the intervention was helpful and relevant to them, and most participants (95%) would refer others to this treatment. We found that the CSI reduced participant's PTSD symptoms (d = 0.869), specifically the Numbing (d = 0.853) and Hyperarousal (d = 1.077) subscales. Depressive symptoms (d = 0.72) and stress reactivity (d = 0.785) also marginally decreased. There was no significant change in physiological data (i.e., sleep, no. of steps) from pre- to postintervention. Conclusion: These data suggest that a CSI is an acceptable intervention for veterans with PTSD that may also improve their PTSD symptoms.

Baseline Cognitive Performance and Treatment Outcomes From Cognitive-Behavioral Therapies for Posttraumatic Stress Disorder: A Naturalistic Study.

OBJECTIVE: Approximately 5%-20% of U.S. troops returning from Iraq and Afghanistan have posttraumatic stress disorder (PTSD), and another 11%-23% have traumatic brain injury (TBI). Cognitive-behavioral therapies (CBTs) are empirically validated treatment strategies for PTSD. However, cognitive limitations may interfere with an individual's ability to adhere to as well as benefit from such therapies. Comorbid TBI has not been systematically taken into consideration in PTSD outcome research or in treatment planning guidance. The authors hypothesized that poorer pretreatment cognitive abilities would be associated with poorer treatment outcomes from CBTs for PTSD. METHODS: This study was designed as a naturalistic examination of treatment as usual in an outpatient clinic that provides manualized CBTs for PTSD to military service members and veterans. Participants were 23 veterans, aged 18-50 years, with combat-related PTSD and a symptom duration of more than 1 year. Of these, 16 participants had mild TBI (mTBI). Predictor variables were well-normed objective tests of cognitive ability measured at baseline. Outcome variables were individual slopes of change of the PTSD Checklist for DSM-5 (PCL-5) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) over weeks of treatment, and of pretreatment-to-posttreatment change in PCL-5 and CAPS-5 (ΔPCL-5 and ΔCAPS-5, respectively). RESULTS: Contrary to prediction, neither pretreatment cognitive performance nor the presence of comorbid mTBI predicted poorer response to CBTs for PTSD. CONCLUSIONS: These results discourage any notion of excluding patients with PTSD and poorer cognitive ability from CBTs.

Cognitive Impairment and Predicting Response to Treatment in an Intensive Clinical Program for Post-9/11 Veterans With Posttraumatic Stress Disorder.

OBJECTIVE: This study examined whether objectively measured pretreatment cognitive impairment predicted worse response to treatment for posttraumatic stress disorder. Participants were 113 veterans and active duty service members who participated in a new multidisciplinary 2-week intensive clinical program that included individual trauma-focused cognitive-behavioral therapy, group psychotherapy, psychoeducation, skills-building groups, and complementary and alternative medicine treatments (mean age: 39.7 years [SD=8.5]; 20% women). METHODS: Prior to treatment, participants completed a brief computerized cognitive battery (CNS Vital Signs) and were operationalized as having cognitive impairment if they scored in the ≤5th percentile on two or more of five core cognitive domains. Participants completed measures of traumatic stress, depression, cognitive self-efficacy, and satisfaction with their ability to participate in social roles before and after treatment. RESULTS: There were no significant correlations between pretreatment individual cognitive test scores and change in the clinical outcome measures. One-half of the study sample (49.6%) met criteria for cognitive impairment. In a mixed multivariate analysis of variance, the interaction between cognitive impairment and time was not significant (F=0.83, df=4, 108, p=0.51), indicating that the pre- to posttreatment changes in outcome scores were not significantly different for the cognitively impaired group compared with the cognitively intact group. The multivariate main effect for time was significant (F=36.75, df=4, 108, p<0.001). Follow-up univariate tests revealed significant improvement in traumatic stress, depression, cognitive self-efficacy, and satisfaction with social roles after treatment. CONCLUSIONS: Cognitive impairment was not associated with worse response to treatment in veterans with severe and complex mental health problems. Veterans with and without cognitive impairment reported large improvements in symptoms and functioning after treatment.

Cortical thickness alterations linked to somatoform and psychological dissociation in functional neurological disorders.

BACKGROUND: Links between dissociation and functional neurological disorder (FND)/conversion disorder are well-established, yet the pathophysiology of dissociation remains poorly understood. This MRI study investigated structural alterations associated with somatoform and psychological dissociation in FND. We hypothesized that multimodal, paralimbic cingulo-insular regions would relate to the severity of somatoform dissociation in patients with FND. METHODS: FreeSurfer cortical thickness and subcortical volumetric analyses were performed in 26 patients with motor FND and 27 matched healthy controls. Patients with high dissociation as measured by the Somatoform Dissociation Questionnaire-20 (SDQ) or Dissociative Experiences Scale (DES) were compared to controls in stratified analyses. Within-group analyses were also performed with SDQ and DES scores in patients with FND. All cortical thickness analyses were whole-brain corrected at the cluster-wise level. RESULTS: Patients with FND and high somatoform dissociation (SDQ > 35) showed reduced left caudal anterior cingulate cortex (ACC) cortical thickness compared to controls. In within-group analyses, SDQ scores inversely correlated with left caudal ACC cortical thickness in patients with FND. Depersonalization/derealization scores positively correlated with right lateral occipital cortical thickness. Both within-group findings remained statistically significant controlling for trait anxiety/depression, borderline personality disorder and post-traumatic stress disorder, adverse life events, and motor FND subtypes in post-hoc analyses. CONCLUSION: Using complementary between-group and within-group analyses, an inverse association between somatoform dissociation and left caudal ACC cortical thickness was observed in patients with FND. A positive relationship was also appreciated between depersonalization/derealization severity and cortical thickness in visual association areas. These findings advance our neuropathobiological understanding of dissociation in FND. Hum Brain Mapp 39:428-439, 2018. © 2017 Wiley Periodicals, Inc.

Sleep Patterns and Neuropsychiatric Symptoms in Hospitalized Patients With Dementia.

The authors examined 28 dementia inpatients receiving treatment as usual. Beginning-to-end differences in neuropsychiatric symptoms and actigraphic sleep patterns were measured. Using a mixed-model, the authors regressed neuropsychiatric symptoms on average sleep minutes (between-subjects effect) and each night's deviation from average (within-subject effect). Sleep did not significantly differ from beginning to end of participation, whereas neuropsychiatric symptoms did. Average sleep minutes predicted average neuropsychiatric symptoms (p=0.002), but each night's deviation from the average did not predict next day's symptoms (p=0.90). These findings raise questions about the immediate benefits of treating sleep-wake disturbances on neuropsychiatric symptoms in hospitalized inpatients with dementias.

Positive Association Between Nightmares and Heart Rate Response to Loud Tones: Relationship to Parasympathetic Dysfunction in PTSD Nightmares.

Seventy-three women with posttraumatic stress disorder (PTSD) resulting from rape or physical assault participated in a loud-tone procedure, while skin conductance (SC), heart rate, and electromyogram responses were recorded. Pearson correlations were examined between each psychophysiological response and Clinician-Administered PTSD Scale (CAPS) symptom scores. Significant correlations were adjusted for each remaining individual PTSD symptom score. Heart rate response (HRR) significantly correlated with CAPS total score and with CAPS nightmares. The relationship between HRR and nightmares remained significant after controlling for each of the other 16 individual PTSD symptoms, for the remaining reexperiencing cluster, and for CAPS total score. The zero-order correlations between SC response and nightmares and between electromyography response and nightmares were both not significant. The association of nightmares with larger HRR in the absence of an association with larger SC response likely reflects reduced parasympathetic tone. Thus, our findings indirectly support a role for reduced parasympathetic tone in PTSD nightmares.

Mixed-Handedness in Identical Twins Discordant for Combat Exposure in Vietnam: Relationship to Posttraumatic Stress Disorder.

This study evaluated the degree of mixed-handedness in predominantly right-handed Vietnam combat veteran twins and their identical, combat-unexposed cotwins. The "high-risk" cotwins of combat veterans with combat-related posttraumatic stress disorder (PTSD) had more mixed-handedness (i.e., less right-handedness) than the "low-risk" cotwins of combat veterans without PTSD. Self-reported combat exposure in combat-exposed twins was a mediator of the association between handedness in their unexposed cotwins and PTSD in the twins themselves. We conclude that mixed-handedness is a familial risk factor for combat-related PTSD. This risk may be mediated in part by a proclivity for mixed-handed soldiers and Marines to experience heavier combat.

Evaluation and treatment of migraine in the emergency department: a review.

Head pain is the fifth most common reason for emergency department (ED) visits. It is second only to focal weakness as the most common reason for neurological consultation in the ED. This manuscript reviews how patients with migraine, the most common primary headache disorder for which patients seek medical treatment, are managed in the ED. We discuss existing guidelines for head imaging in patients with migraine, recommended pharmacologic treatments, and current treatment trends. We also review studies evaluating the discharge care of migraine patients in the ED. With the goal of standardizing, streamlining, and optimizing ED-based migraine care, we offer ideas for future research to improve the evaluation, treatment, and discharge care of patients who present to an ED with acute migraine.

Influence of psychiatric comorbidities in migraineurs in the emergency department.

OBJECTIVE: To examine how psychiatric comorbidities in migraineurs in the emergency department (ED) affect healthcare utilization and treatment tendencies. METHOD: This is a cross-sectional analysis of 2872 patients who visited our ED over a 10-year period and were given a principal diagnosis of migraine. RESULTS: Compared to migraineurs without a psychiatric comorbidity, migraineurs with a psychiatric comorbidity had about three times more ED visits, six times more inpatient hospital stays and four times more outpatient visits. Migraineurs with psychiatric comorbidities received narcotics in the ED more often than migraineurs without psychiatric comorbidities (P<0.0001). In addition, migraineurs with psychiatric disorders were more likely to have a computed tomography scan of the head [Risk Ratio (RR) 1.42 (95% confidence interval (CI)=1.28-1.56, P<0.001)] or a magnetic resonance image of the brain [RR 1.53 (95% CI=1.33-1.76, P<0.001)] than patients without a psychiatric disorder when visiting our hospital center. CONCLUSIONS: Migraineurs with psychiatric comorbidity who visit the ED have different healthcare utilization tendencies than migraineurs without psychiatric comorbidity who visit the ED. This is seen in the frequency of ED visits, outpatient visits and inpatient stays, in the medications administered to them and in the radiology tests they undergo.

Stress, PTSD, and dementia.

The physiological consequences of acute and chronic stress on a range of organ systems have been well documented after the pioneering work of Hans Selye more than 70 years ago. More recently, an association between exposure to stressful life events and the development of later-life cognitive dysfunction has been proposed. Several plausible neurohormonal pathways and genetic mechanisms exist to support such an association. However, many logistical and methodological barriers must be overcome before a defined causal linkage can be firmly established. Here the authors review recent studies of the long-term cognitive consequences of exposures to cumulative ordinary life stressors as well as extraordinary traumatic events leading to posttraumatic stress disorder. Suggestive effects have been demonstrated for the role of life stress in general, and posttraumatic stress disorder in particular, on a range of negative cognitive outcomes, including worse than normal changes with aging, Alzheimer's disease, and vascular dementia. However, given the magnitude of the issue, well-controlled studies are relatively few in number, and the effects they have revealed are modest in size. Moreover, the effects have typically only been demonstrated on a selective subset of measures and outcomes. Potentially confounding factors abound and complicate causal relationships despite efforts to contain them. More well-controlled, carefully executed longitudinal studies are needed to confirm the apparent association between stress and dementia, clarify causal relationships, develop reliable antemortem markers, and delineate distinct patterns of risk in subsets of individuals.