Steven R. Flanagan, M.D. Professor and Chair Department of Rehabilitation Medicine NYU School of Medicine  Rusk Institute ...
<ul><li>Scope of the problem </li></ul><ul><ul><li>1.4 million emergency department visits </li></ul></ul><ul><ul><ul><li>...
<ul><li>Changing demographics </li></ul><ul><ul><li>2000 census: 35 million ≥ 65 years </li></ul></ul><ul><ul><li>2050: > ...
“… in an adult trauma patient, acute injury is not just a brief physiological setback to a healthy life, but rather signal...
<ul><li>Impact of older age at time of injury </li></ul><ul><ul><li>Survival </li></ul></ul><ul><ul><li>Functional outcome...
<ul><li>Will I get better? </li></ul><ul><li>Will I get worse? </li></ul><ul><li>Will I grow to an old age? </li></ul><ul>...
<ul><li>We’re beginning to understand, but we have a long way to go. </li></ul>
<ul><li>Dementia of the Alzheimer Type </li></ul><ul><li>Parkinson’s Disease </li></ul><ul><li>Multiple Sclerosis </li></u...
<ul><li>Dementia of the Alzheimer Type </li></ul><ul><li>Parkinson’s Disease </li></ul><ul><li>Multiple Sclerosis   IOM co...
 
<ul><li>548 WWII veterans who sustained a non-penetrating TBI in 1944-45 and matched injured, non-TBI controls </li></ul><...
<ul><li>Increased risk in subjects with a history of TBI resulting in LOC of > 5 minutes (RR 4.1) and in those with TBI wi...
<ul><li>Risk of developing AD with history of TBI </li></ul><ul><ul><li>TBI (all cases): OR 4.6 </li></ul></ul><ul><ul><li...
<ul><li>Significant association </li></ul><ul><ul><li>Plassman 2000* </li></ul></ul><ul><ul><li>Schofield 1997** </li></ul...
<ul><li>The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association betwe...
<ul><li>Damage to BBB causing plasma protein leakage into the brain </li></ul><ul><li>Liberation of free oxygen radicals <...
<ul><li>Most commonly associated with professional boxing </li></ul><ul><ul><li>Exposure to repeated head trauma </li></ul...
<ul><li>The committee concludes, on the basis of its evaluation, that there is sufficient   evidence of an association bet...
 
Bower 2003 N=196 with PD.  Matched to non-PD control Rochester Epidemiology Project Hx of TBI more frequent in men with  P...
<ul><li>The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association betwe...
<ul><li>Post-TBI inflammatory cascade </li></ul><ul><li>Breakdown of BBB followed by edema, leukocyte infiltration and mic...
<ul><li>Moderate to Severe TBI associated with </li></ul><ul><ul><li>Early mortality </li></ul></ul><ul><ul><li>Poorer Qua...
<ul><li>Individuals with TBI require long-term follow to assess for development of conditions that may develop long after ...
<ul><li>Consensus guideline for assessment published </li></ul><ul><ul><li>Ghigo et al. Brain Injury 2005 </li></ul></ul>T...
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Flanagan, Steven

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  • The United States Census Bureau reported that the fastest growing portion of the population is comprised of individuals over the age of 65, with the number expected to increase by 53.2% by 2020. Therefore, an increase in both older adult survivors of TBI and elderly with new onset TBI will increase dramatically.
  • Degenerative diseases refer to nervous system disorders that result from deterioration of neurons of their myelin sheath that lead to a number of disorders such as those listed here.
  • Degenerative diseases refer to nervous system disorders that result from deterioration of neurons of their myelin sheath that lead to a number of disorders such as those listed here.
  • Progressive disorder manifested histologically by the presence of amyloid plaaques and neurofibrillary tangles in the brain.
  • Compared to injured vets without TBI, matched on age and education. Stratified by injury severity: Mild= LOC or PTA &lt; 30 minutes, Moderate= LOC or PTA of 30 minutes to 24 hours; Severe+ LOC or PTA &gt; 24 hours. Dementia determined by 3 page screening tool and assessment process, that included a telephone interview, dementia questionnaire, and clinical assessment for those who whose scores indicated dementia. Moderate and severe TBI increased risk which was significant. Limitation included reliance on medical records that were 50 years old and the fact that the authors could not rule out other factors in the development of dementia later in life.
  • Schofield: Northern Manhattan study. 271 participants. Self report of TBI with either PTA or LOC. Therefore based on self report or report of a care provider. French: case controlled study to assess factors related to DAT. N=78 veterans at a VAMC matched to controls on age, race and sex (all males). Information obtained during interviews included variables relevant to viral, genetic, and immunologic hypotheses, environmental and occupation exposures, drug use, psychological stress, smoking and alcohol use as well as hx of TBI. TBI was reported significantly more frequently in subjects than in controls with TBI occurring prior to the dx of DAT. Heyman: Case controlled study to assess risk factors for AD. N=40 with DAT matched to 80 controls on age, sex, and race. Structured interview conducted to ascertain risk factors including prior illnesses, dietary or lifestyle habirs, occupation exposure, exposure to domesticated and wild animals and family hx of DAT. Found the hx of TBI found more frequently in subjects than in controls (15% and 3.8% respectively).
  • Guo: also a case controlled study that included an investigation b/t TBI and APOE genotype. N-2,233 with AD compared to 14,688 first-degree family members and spouses. Analysis were adjusted for age, sex, and afe oat onsetl of AD. The study suggests that TBI associated with LOC significantly increased risk for AD, but not significantly different with no LOC.
  • Broe: TBI defined by LOC of at least 15 minutes. Taken as a whole, the studies generally found a strong association between moderate or severe TBI and dementia of the Alzheimer type. Studies suggested an association between mild TBI with LOC and dementia of the Alzheimer type, but mild TBI without LOC was not found to be strongly associated with dementia of the Alzheimer type. The authors found that a history of TBI increased the risk of AD (HR, 2.00; 95% CI, 1.03 – 3.90) and dementia (HR, 2.23; 95% CI, 1.30 – 3.81). Moderate TBI (HR, 2.32; 95% CI, 1.04 – 5.17) and severe TBI (HR, 4.51; 95% CI, 1.77 – 11.47) were both associated with increased risk of AD. Similarly, moderate TBI (HR, 2.39; 95% CI, 1.24 – 4.58) and severe TBI (HR, 4.48; 95% CI, 2.09 – 9.63) were both associated with dementia. There was no significant risk of AD (HR, 0.76; 95% CI, 0.18 – 3.29) or dementia (HR, 1.33; 95% CI, 0.51 – 3.47) in those with mild TBI. Except for the studies of Amaducci et al. (1986) and Broe et al. (1990), the secondary studies found an increased risk of AD after TBI. A meta-analysis of seven case – control studies supported these findings, noting that “ a history of head trauma [was] associated with a statistically significant increase in the risk for AD in the absence of a family history of dementia ” (Van Duijn et al., 1994). Guiskiewicz: No assoc with recurrent mTBI and dementia, but pro football players have earlier onset dementia than general population.
  • Findings in professional boxers demonstrate an association with the development of DP; pathology study of brains of autopsied boxers also support these findings. The evidence is less clear in amateur boxing and soccer: it is difficult to know the severity, if any, of the head injury experienced. Therefore, the committee cannot draw a conclusion about TBI and DP in general and has limited its conclusions to professional boxers.
  • The committee identified two primary studies (Bower et al., 2003; Goldman et al., 2006) and one secondary study (Taylor et al., 1999) that evaluated the association between TBI and parkinsonism. The results of all three suggested an association. Bower and colleagues (2003) conducted a case – control study of PD as related to TBI by using the medical-records linkage system of the Rochester Epidemiology Project and found that the frequency of head trauma overall was significantly higher in people with PD than in controls. An increased risk was observed in patients with mild TBI and LOC or with more severe TBI. The authors noted that the “ results suggest an association between head trauma and the later development of PD that varies with severity. ” An association was also found between mild TBI with LOC, but not without LOC. Goldman and colleagues (2006) conducted a case – control study of male twin pairs discordant for PD and found that TBI with LOC or PTA was associated with an increased risk of PD. Subjects and controls were identified from the National Academy of Sciences WWII veteran twins cohort. History of TBI was ascertained by interview. Twins were a mix of monozygotic and dizygotic. Taylor et al. (1999) conducted a case – control study to assess risk factors related to PD and found that TBI was associated with an increased risk of PD. Additional data was collected on environmental exposures, family history of illness, and comprehensvie medical history including age at onset of PD and a diagnosis of TBI, smoking, vitamin intake and depression. TBI was diagnosed if it was sever enough to cause loss of consciousness, blurred or double vision, dizziness, seizures or memory loss.
  • mTBI: Association less certain except perhaps for QOL or symptom report.
  • Flanagan, Steven

    1. 1. Steven R. Flanagan, M.D. Professor and Chair Department of Rehabilitation Medicine NYU School of Medicine Rusk Institute of Rehabilitation NYU-Langone Medical Center
    2. 2. <ul><li>Scope of the problem </li></ul><ul><ul><li>1.4 million emergency department visits </li></ul></ul><ul><ul><ul><li>124,000 expected to have long-term disability </li></ul></ul></ul><ul><ul><li>3.17 million with long-term disability </li></ul></ul>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, 2003. J Head Trauma Rehabil 2008;23:123-131 Zaloshnja E, et al. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehabil 2008;23:394-400
    3. 3. <ul><li>Changing demographics </li></ul><ul><ul><li>2000 census: 35 million ≥ 65 years </li></ul></ul><ul><ul><li>2050: > 86 million </li></ul></ul><ul><ul><ul><ul><li>US Census Bureau 2004 </li></ul></ul></ul></ul>
    4. 4. “… 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.” <ul><ul><ul><li>Davidson GH et al. Long-term survival of adult trauma patients. JAMA 2011;305:1001-1007 </li></ul></ul></ul>
    5. 5. <ul><li>Impact of older age at time of injury </li></ul><ul><ul><li>Survival </li></ul></ul><ul><ul><li>Functional outcomes </li></ul></ul><ul><li>Ageing with TBI sustained earlier in life </li></ul><ul><ul><li>Survival </li></ul></ul><ul><ul><li>Health care issues </li></ul></ul><ul><ul><li>Cognitive decline/Risk of dementia </li></ul></ul><ul><ul><li>Quality of life </li></ul></ul>
    6. 6. <ul><li>Will I get better? </li></ul><ul><li>Will I get worse? </li></ul><ul><li>Will I grow to an old age? </li></ul><ul><li>What will happen to me if and when I get old? </li></ul><ul><li>Am I more likely to get Alzheimer’s? Other dementias? </li></ul><ul><li>Am I likely to age “faster”? </li></ul><ul><li>Will I be worse off than other aged people, or will they “catch up” to me? </li></ul>
    7. 7. <ul><li>We’re beginning to understand, but we have a long way to go. </li></ul>
    8. 8. <ul><li>Dementia of the Alzheimer Type </li></ul><ul><li>Parkinson’s Disease </li></ul><ul><li>Multiple Sclerosis </li></ul><ul><li>ALS </li></ul>
    9. 9. <ul><li>Dementia of the Alzheimer Type </li></ul><ul><li>Parkinson’s Disease </li></ul><ul><li>Multiple Sclerosis IOM concludes insufficient evidence </li></ul><ul><li>ALS </li></ul>
    10. 11. <ul><li>548 WWII veterans who sustained a non-penetrating TBI in 1944-45 and matched injured, non-TBI controls </li></ul><ul><ul><li>Mild TBI: No increased risk </li></ul></ul><ul><ul><li>Moderate TBI: HR: 2.32 </li></ul></ul><ul><ul><li>Severe TBI: HR: 4.51 </li></ul></ul><ul><ul><ul><li>Plassman et al. 2000 </li></ul></ul></ul>
    11. 12. <ul><li>Increased risk in subjects with a history of TBI resulting in LOC of > 5 minutes (RR 4.1) and in those with TBI within the past 30 years (RR 5.4) </li></ul><ul><ul><li>Schofield et al 1997) </li></ul></ul><ul><li>Increased risk in subjects with TBI compared to controls (OR 4.5), attempt to control for other factors (e.g. genetics, environmental exposures) </li></ul><ul><ul><li>French et al 1985 </li></ul></ul><ul><li>History of severe TBI more frequent in DAT than controls </li></ul><ul><ul><li>Heyman et al 1984 </li></ul></ul>
    12. 13. <ul><li>Risk of developing AD with history of TBI </li></ul><ul><ul><li>TBI (all cases): OR 4.6 </li></ul></ul><ul><ul><li>TBI with LOC vs. </li></ul></ul><ul><ul><ul><li>unaffected spouse: OR 9.9 Significant </li></ul></ul></ul><ul><ul><ul><li>Parents and siblings: OR 4.0 </li></ul></ul></ul><ul><ul><li>TBI without LOC vs. </li></ul></ul><ul><ul><ul><li>unaffected spouse: OR 3.1 </li></ul></ul></ul><ul><ul><ul><li>Parents and siblings OR 2.0 </li></ul></ul></ul><ul><ul><ul><ul><li>Guo et al 2000 </li></ul></ul></ul></ul>Not significant
    13. 14. <ul><li>Significant association </li></ul><ul><ul><li>Plassman 2000* </li></ul></ul><ul><ul><li>Schofield 1997** </li></ul></ul><ul><ul><li>French 1985 </li></ul></ul><ul><ul><li>Heyman* </li></ul></ul><ul><ul><li>Guo 2000*** </li></ul></ul><ul><li>Increased odds (but not reaching significance) </li></ul><ul><ul><li>Amaducci 1986 </li></ul></ul><ul><ul><li>Broe 1990 </li></ul></ul><ul><li>No significance </li></ul><ul><ul><li>Guskiewicz 2005 </li></ul></ul>*Moderate to Sever e TBI **LOC > 5 minutes ***+LOC
    14. 15. <ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul>
    15. 16. <ul><li>Damage to BBB causing plasma protein leakage into the brain </li></ul><ul><li>Liberation of free oxygen radicals </li></ul><ul><li>Loss of brain reserve capacity </li></ul><ul><li>Deposition of beta amyloid plaque (also epileptogenic): Increased risk of AD with high plasma levels in the non-TBI population. Consentino, Arch Neurol, 2010 </li></ul><ul><li>Apoptosis </li></ul><ul><li>Other unknown factors </li></ul><ul><li>Lye, Neuropsych Review , 2000 </li></ul>
    16. 17. <ul><li>Most commonly associated with professional boxing </li></ul><ul><ul><li>Exposure to repeated head trauma </li></ul></ul><ul><li>Symptoms of impaired cognition (dementia) and motor function (parkinsonism) often appear 10-20 years post retirement </li></ul><ul><li>IOM looked predominantly at </li></ul><ul><ul><li>Profession boxing </li></ul></ul><ul><ul><li>Amateur boxing </li></ul></ul><ul><ul><li>Soccer </li></ul></ul>
    17. 18. <ul><li>The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between professional boxing and development of dementia pugilistica. </li></ul><ul><li>Evidence is less clear in amateur boxing and soccer </li></ul><ul><ul><li>Therefore the committee limited its conclusion to professional boxing </li></ul></ul>
    18. 20. Bower 2003 N=196 with PD. Matched to non-PD control Rochester Epidemiology Project Hx of TBI more frequent in men with PD (OR, 6.0) HX TBI more frequent in all cases of PD (OR, 4.3) No increased risk with mTBI without LOC Goldman 2006 93 male twin pairs discordant for PD TBI (LOC or PTA) associated with increase risk of PD (OR, 3.0) Risk greater with multiple TBI (OR, 4.3) Small # of twins concordant for PD indicated earlier onset with TBI Taylor 1999 140 with PD 147 controls Four factors associated with PD - TBI (OR, 6.23) Family history of PD (OR, 6.08 - Family history tremor (OR 3.97) - History of depression (OR, 3.01)
    19. 21. <ul><li>The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and parkinsonism. </li></ul><ul><li>The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between mild TBI (with LOC) and parkinsonism. </li></ul>
    20. 22. <ul><li>Post-TBI inflammatory cascade </li></ul><ul><li>Breakdown of BBB followed by edema, leukocyte infiltration and microglial activation </li></ul><ul><li>Up-regulation of inflammatory cytokines </li></ul><ul><ul><li>Interleukin-1, interleukin-6, TNF- α , cyclooxygenase-2 </li></ul></ul><ul><li>Disruption of mitochondrial function altered energy production, free radical production and lipid peroxidation </li></ul><ul><li>Glutamate excitotoxicity </li></ul><ul><li>Accumulation of tau and α -synuclelin (major component of Lewy bodies) </li></ul>
    21. 23. <ul><li>Moderate to Severe TBI associated with </li></ul><ul><ul><li>Early mortality </li></ul></ul><ul><ul><li>Poorer Quality of Life </li></ul></ul><ul><ul><li>Neuroendocrine dysfunction </li></ul></ul><ul><ul><li>Increased risk of </li></ul></ul><ul><ul><ul><li>Dementia </li></ul></ul></ul><ul><ul><ul><li>Parkinsonism </li></ul></ul></ul><ul><li>Association with Mild TBI less certain </li></ul>
    22. 24. <ul><li>Individuals with TBI require long-term follow to assess for development of conditions that may develop long after the initial injury. </li></ul><ul><li>TBI should be considered a chronic disease, not an event, that requires adequate resources throughout the lives of people with TBI. </li></ul>
    23. 25. <ul><li>Consensus guideline for assessment published </li></ul><ul><ul><li>Ghigo et al. Brain Injury 2005 </li></ul></ul>Thank you

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