Ageing after TBI: Survival & Health Issues. Is TBI a Chronic Condition?

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1 Ageing after TBI: Survival & Health Issues. Is TBI a Chronic Condition? Steven R. Flanagan, M.D. Howard A Rusk Professor and Chair Department of Rehabilitation Medicine New York University School of Medicine NYU-Langone Health

2 Traumatic Brain Injury Scope of the problem 1.4 million emergency department visits 124,000 expected to have long-term disability million with long-term disability Langlois JA et al. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention, 2004 Selassie A, et al. Incidence of Long term disability following traumatic brain injury hospitalizations, United States, J Head Trauma Rehabil 2008;23: Zaloshnja E, et al. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, J Head Trauma Rehabil 2008;23:

3 Scope of the Problem Changing demographics 2000 census: 35 million 65 years 2050: > 86 million US Census Bureau 2004

4 Ageing Population Elderly Rate of TBI-hospitalization growing faster than the population growth of this group.

5 TBI to most of the medical world

6 TBI to most of the medical world

7 TBI to most of the medical world

8 TBI to most of the medical world

Traumatic Brain Injury as a Chronic Health Condition Fig 1 One- and 2-category change in Glasgow Outcome Scale Extended<score 2 to 15 years after TBI. John D.

9 Traumatic Brain Injury as a Chronic Health Condition Fig 1 One- and 2-category change in Glasgow Outcome Scale Extended<score 2 to 15 years after TBI. John D. Corrigan, Flora M. Hammond Archives of Physical Medicine and Rehabilitation, Volume 94, Issue 6, 2013,

10 in an adult trauma patient, acute injury is not just a brief physiological setback to a healthy life, but rather signals significant long-term mortality in a large number of patients. Davidson GH et al. Long-term survival of adult trauma patients. JAMA 2011;305:

11 Proposition TBI is not just an event, similar to a broken bone that will heal over time TBI is a chronic disease, potentially impacting Life expectancy Cognitive changes over time Psychiatric disorders Seizures Neuroendocrine disorders Neurodegenerative disorders

12 Two Broad Issue re: Age and TBI Impact of older age at time of injury Survival Functional outcomes Ageing with TBI sustained earlier in life Survival Health care issues Cognitive decline/risk of dementia Quality of life

13 2008 Galveston Brain Injury Conference

14 What Is Going to Happen to Me in the Future 10, 20 Years From Now? Will I get better? Will I get worse? What will happen to me when I get old? Am I more likely to get Alzheimer s? Other dementias? Am I likely to age faster? Will I be worse off than other aged people, or will they catch up to me?

15 5 working addressed TBI and dementia Ageing with TBI: Medical focus Ageing with TBI: Cognitive focus Ageing with TBI: Social Functioning focus TBI occurring in the elderly

16 Ageing with Traumatic Brain Injury: Medical Issues Steven Flanagan, M.D. Theodore Tsaousides, Ph.D. Dana W. Moore, Ph.D. Kenneth Ottenbacher Cindy Harrison-Felix, Ph.D.

17 Overarching issue What happens to individuals with TBI from a medical perspective as they age? Are there differences from general population re: Mortality/survival Medical problems

18 Process Key words (multiple variations of) Brain injuries (e.g. brain contusion/injury/lacerations/trauma, cortical contusion, diffuse/focal brain injuries, (post-) concussive/ (post-) traumatic encephalopathy, TBI, traumatic brain injury, etc. Risk, mortality, health Age

19 Process Research manuscripts to include those 5 years post injury.

20 We were not alone IOM Report: Longterm consequences of TBI Mortality Neurocognitive Neurologic Psychiatric Social

21 Mortality

22 Mortality 3 broad sources of subjects Hospitalized Outpatient services War veterans

23 Long-term Mortality: Hospitalized Sample General Findings Mortality 2-3x general population Injury severity predominantly moderate to severe with some mild Recent evidence suggest 7-9 year reduction in life expectancy 2.23 x more likely to die than general population Harrison-Felix et al. J Neurotrauma reduction moderate TBI/ severe TBI. No reduction post mild TBI. Groswasser Z et al. Brain Inj 2018

24 Risk factors Younger population Highest Relative risk 5X expected rate More commonly due to accidental deaths Dysexecutive problems Older population Highest Absolute risk Likely related chronic medical co-morbidities. Harrison-Felix C et al. JHTR 2015

25 Increased Long-term Mortality: Hospitalized Sample Risk Factors Cause of Death Advanced age at time of Seizure injury Pneumonia Seizures Sepsis Employment status Suicide* Substance abuse Accidental Death* Physical impairments Substance abuse related* Psychiatric disorder < High school education Male *Applicable to Mild TBI McMillan TW et a.. J Neurol Neurosurg Psychiatry 2014

26 Mild TBI Increase Risk of Mortality Glasgow study >1/3 died by 15 year follow up Risk factors Alcohol/drug misuse Prior head injury or neurological hospitalization Prior physical impairment Social deprivation McMillan et al 2014 No increased risk NFL studies No increase Guskiewicz et al 2005 All cause mortality ½ national population Lehman et al 2012 Olmsted County MN No increased rate Flaada et al. 2007

27 TBI and Mortality Veterans Study TBI vs No TBI Retrospective study In veterans who did not develop dementia TBI died 2.3 years earlier compared to non- TBI Barnes DE et al. Traumatic brain injury and risk of dementia in older veterans. Neurology 2014

28 Institute of Medicine Conclusions The committee concludes, on the basis of its evaluation, that there is sufficient evidence of a causal relationship between penetrating TBI and premature mortality in survivors of the acute injury. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and premature mortality in the subset of patients who are admitted into or discharged from rehabilitation centers or receive disability services. The committee concludes, on the basis of its evaluation, that there is inadequate/insufficient evidence to determine whether an association exists between surviving 6 months or more after sustaining a mild, moderate, or severe TBI and premature mortality. Gulf War and Health: Volume 7: Long-Term Consequences of Traumatic Brain Injury

29 SPECIFIC MEDICAL CONDITIONS

30 TBI and Health Problems Veteran s study Retrospective study 189K veterans age > 55 (baseline and follow up) Vets with TBI slightly younger than those without TBI TBI had greater prevalence of Diabetes Hypertension Coronary Artery Disease Cerebrovascular Disease Depression PTSD Barnes DE et al. Traumatic brain injury and risk of dementia in older veterans. Neurology 2014

31 Traumatic brain injury and risk of dementia in older veterans. Barnes, Deborah; PhD, MPH; Kaup, Allison; Kirby, Katharine; Byers, Amy; PhD, MPH; Diaz-Arrastia, Ramon; MD, PhD; Yaffe, Kristine Neurology. 83(4): , July 22, DOI: /WNL American Academy of Neurology. Published by American Academy of Neurology. 2

32 Pituitary Dysfunction Several studies

33 Pituitary Dysfunction Sample Years Post Injury Assessment Method Outcome Bushnik with varying TBI severity 10 Serum determination and glucagon stimulation for GH Severe GHD: 39% Moderate GHD: 27% Central Hypothyroidism: 19% 40% deficient in 1 axis 44% deficient in 2 9% deficient in > 2 Bondanelli with Mildsevere TBI months (22% > 5 years post) Pituitary screen including growth hormone response to stimulation tests. 54% developed pituitary dysfunction within 5 years post-injury Hypogonadism:14% Central Hypothyroidism: 8% Prolactin abnormality: 16% Partial GHD: 20% GHD: 8%. Older age assoc w/ GHD (p<.05); Negative correlation w/ age & GH response to GH stimulation tests

34 More Recent Data Systematic Review GHD:12% Gonadotropin: 12% ACTH: 8% TSH 4% Multiple: 8% Schneider HJ et al. JAMA 2007;298:

35 Pediatric Population 1 month: 15%, 6 month: 75%, 1 year: 29% Kaulfers AM et al. J Pediatr % 1 year post Personnier et al. J Clin Endocrinol Metab 2014 Heather et al. J Clin Endocrinol Metab 2012

36 Pathology Autopsy findings Necrosis Fibrosis Infarction Hemorrhage Proposed Mechanisms Direct injury to hypothalamohypophyseal unit Ischemia Compression Hemorrhage Intracranial HTN Hypotension/Hypoxemia

37 Pituitary Dysfunction Literature suggests Common Older individuals at increased risk Can occur at various times post-injury May contribute to post-tbi morbidity Fatigue Obesity Cognitive decline Suggested guidelines for screening

38 IOM Report The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and endocrine dysfunction, particularly hypopituitarism. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and growth hormone insufficiency.

39 Neurodegenerative Diseases and TBI: Is there an association? Dementia of the Alzheimer Type Parkinson s Disease Multiple Sclerosis ALS

40 Neurodegenerative Diseases and TBI: Is there an association? Dementia of the Alzheimer Type Parkinson s Disease Multiple Sclerosis IOM concludes insufficient evidence ALS

41 Dementia of the Alzheimer Type

42 TBI-related pathology Possible contributing mechanisms to neurodegeneration Hyper-phosphorylated tau/nft Aβ deposition Hypoxia-related changes in gene expression Injury-related vascular changes Upregulation of inflammatory markers Sivanandam TM et al. Neurosci Biobehav Rev 2012

43 Dementia (as per 2008 IOM report) Significant association Plassman 2000* Schofield 1997** French 1985 Broe 1990* Heyman* Guo 2000*** Increased odds (but not reaching significance) Amaducci 1986 Broe 1990 No significance Guskiewicz 2005 *Moderate to Severe TBI **LOC > 5 minutes ***+LOC

44 TBI and Risk of Dementia of the Alzheimer Type IOM The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and dementia of the Alzheimer type. The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between mild TBI (with LOC) and dementia of the Alzheimer type. The committee concludes, on the basis of its evaluation, that there is inadequate/insufficient evidence to determine whether an association exists between mild TBI (without LOC) and dementia of the Alzheimer type.

45 Since 2008 IOM Report 11 studies* 4 supporting association Barnes 2014, Lee 2013, Wang 2012, Suhanov not supporting an association Dams-O Connor 2013, Helm conditional associations Abner 2014, Nordstrom 2014, Sundran 2007, Sayed 2013 * Scoping review Dams-O Connor 2016

46 Study Limitations Retrospective recall and # of TBI Varying levels of severity Timing of TBI, follow up and dementia onset Reverse causality Multiple contributing factors Genetics, Environmental, Co-morbidities Methodological Dementia diagnosis definitions

47 Is TBI-related Dementia AD? Similar clinical manifestations to AD But also characteristics of other neurodegenerative conditions PD ALS Other non AD dementia Similar pathological lesions Tau pathology Aβ plaques

48 Is TBI-related Dementia AD? Differences Better verbal memory More medications Poorer CV health More depression/anxiety dx Greater likelihood Falls Gait disorder Motor slowness Histopathology Location of lesions Lewy bodies CVD Hippocampal sclerosis

49 General Conclusion Many epidemiological studies provide compelling evidence that sustaining a TBI is associated with increased risk for degenerative conditions that may result in dementia including AD; however, other high-quality epidemiological studies have demonstrated no increased risk for dementia following TBI. Studies on the risk for dementia following TBI are very difficult to compare due to differences in study design, duration of follow-up, operational definition of both TBI and dementia, and differences in the extent to which other dementia risk factors are controlled. Evidence suggests TBI-related dementia may be a neurodegenerative condition distinct from AD

50 TBI and Risk of Mood Disorders The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between TBI and depression. The committee concludes, on the basis of its evaluation, that there is inadequate or insufficient evidence to determine whether an association exists between TBI and mania or bipolar disorder.

51 TBI and risk of other psychiatric disorders - IOM Aggressive Behaviors The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between TBI and subsequent development of aggressive behaviors. Additional evidence that aggression is associated with TBI primarily when frontal cortical lesions are sustained is consistent with a large literature associating frontal lobe damage with loss of behavioral control.

52 Psychosis The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between moderate or severe TBI and psychosis. However, even if the TBI is severe, the psychosis does not appear during the first post-tbi year, but rather, becomes apparent in the second and third post-tbi years.

53 Overall Conclusions Moderate to Severe TBI associated with Early mortality Poorer Quality of Life Neuroendocrine dysfunction Increased risk of Dementia Parkinsonism Depression and possibly other psychiatric disorders Association with Mild TBI less certain

54 Conclusions Individuals with TBI require long-term follow to assess for development of conditions that may develop long after the initial injury. TBI should be viewed as a chronic condition, not an event.

55 Questions? Pituitary Dysfunction Consensus guideline for assessment published Ghigo et al. Brain Injury 2005

Health and Aging after TBI: Current research and future directions

Health and Aging after TBI: Current research and future directions Kristen Dams-O Connor, PhD Associate Professor Co-Director, Brain Injury Research Center Research Director, Mount Sinai Injury Control