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 Research Center

Icahn School of Medicine at Mount Sinai

Department of Rehabilitation Medicine

New York, NY

Dams-O’Connor: Disclosures

Grant #1K01HD074651-01A1

National Institutes of Health (NIH)/National Institute of Child Health and

Development (NICHD)

Grant # 1 U01 NS086625-01

National Institutes of Health (NIH)/National Institute of Neurological Disorders and

Stroke (NINDS)

Grant #H133B040033

National Institute on Disability and Rehabilitation Research (NIDRR)

Grant #1R49CE001171-01

Centers for Disease Control and Prevention (CDC)

Post-TBI Neurodegeneration

Type of Study Primary Author Year TBI Dementia APOE 4 Interaction

Prospective Mehta 1999 No No

Prospective Katzman 1989 No N/A

Retrospective Williams 1991 No N/A

Epidemiological Schofield 1997 Yes N/A

Case Control O’Meara 1997 Yes No

Prospective Plassman 2000 Yes Inconclusive

Retrospective Mayeux 1995 Yes Yes

IOM IOM 2008 YES N/A

Retrospective Barnes 2014 Yes No

Retrospective Gardner 2014 Yes No

Retrospective Lee 2013 Yes No

Case Control Wang 2012 Yes No

Prospective Abner 2014 Conditional No

Prospective Nordstrom 2014 Conditional No

Prospective Sundstrom 2007 Conditional No

Case Control Sayed 2013 Conditional No

Prospective Helmes 2011 No No

Prospective Dams-O’Connor 2013 No No

TBI and Dementia: Inconsistent findings

Studies Finding a Relationship Between TBI and

Alzheimer’s Disease

Study Design Sample Size TBI Identification Dementia

Identification

Type of

Dementia

Barnes, Kaup

et al. (2014)

Retrospective

cohort

188,764 veterans age

55 and over and

dementia-free at

baseline

Medical record, using

ICD-9-CM codes

Medical record,

using ICD-9-CM

codes

ACD, AD

Gardner,

Burke et al.

(2014)

Retrospective

cohort

51,799 adults age 55

and over

Medical record, using

ICD-9 codes

Medical record,

using ICD-9 codes

ACD

Lee, Hou et

al. (2013)

Retrospective

cohort

28,551 with mTBI

692,382 without mTBI

National Health

Insurance claims data;

ICD-9 codes

National Health

Insurance claims

data; ICD-9 codes

ACD, AD

Wang, Lin et

al. (2012)

Retrospective

cohort,

case control

44,925 with TBI

224,625 without TBI

National Health

Insurance longitudinal

database; ICD-9-CM

National Health

Insurance

longitudinal

database; ICD-9-CM

AD, VaD,

dementia

(unspecified)

Suhanov,

Pilipenko et

al. (2006)

Case control 260 patients with AD

260 matched controls

Self-report; medical

record

DSM-IV criteria for

dementia; NINCDS-

ADRDA criteria for

AD

AD

Studies Finding a Conditional Relationship

Between TBI and Alzheimer’s Disease

Study Design Sample Size TBI

Identification

Dementia

Identification

Type of

Dementia

Abner, Nelson et

al. (2014)

Prospective

Cohort

649 adults age 60 and

over, 166 with history

of TBI

Among the 166 with

TBI, 34 met criteria for

MCI and 27 met criteria

for dementia at follow

up

Self-report

Reduced

performance on

cognitive tests;

medical records;

AD-positive

pathology

AD

Nordstrom,

Michaelsson et

al. (2014)

Prospective

Cohort

811,622 men Medical record,

using ICD-8,9,10

codes

Medical record,

using ICD-8,9,10

codes

YOD/ACD

Sundstrom,

Nilsson, et al.

(2007)

Prospective

Cohort

543 adults age 40 to 85,

181 developed dementia

Self-report;

medical record

DSM-IV criteria

for dementia

ACD

Sayed, Culver et

al. (2013)

Case

control

8381 adults with

dementia, 7862

controls; 878 had

history of TBI

Self-report Consensus-based

clinical diagnosis

AD, LBD,

VaD, FTD

Studies Finding No Relationship Between TBI

and Alzheimer’s Disease

Study Design Sample Size TBI

Identification

Dementia

Identification

Type of

Dementia

Dams-

O'Connor,

Gibbons et al.

(2013)

Prospective

Cohort

4225 dementia-free

individuals, 606

(14.3%) with history of

TBI with LOC

Self-report DSM-IV criteria

for dementia;

NINCDS-ADRDA

criteria for AD

Incident

ACD,

probable or

possible

AD

Helmes, Ostbye

et al. (2011)

Prospective

Cohort

648 (23.5%) with TBI,

2115 (76.5%) without

TBI

Medical record or

self-report or

informant report

Clinical consensus

conference, DSM-

III-R criteria

ACD

Dams-O'Connor K, Guetta G, Hahn-Ketter AE, Fedor A.

Traumatic brain injury as a risk factor for Alzheimer's disease:

current knowledge and future directions. Neurodegener Dis

Manag. 2016 Oct;6(5):417-29.

Large studies finding no association

Type of

Study

Primary

Author

Year TBI Dementia APOE 4

Interaction

Limitations

Prospective Mehta 1999 No No Short follow-up

Prospective Katzman 1989 No N/A Short follow-up

Dementia-free at

75-85

Retrospective Williams 1991 No N/A Unsystematic

Dementia Dx

Prospective,

Population-

based

Dams-

O’Connor

2013 No No Dementia-free at 65

25,569 person years of follow-up data

• TBI exposure collected prior to dementia onset (minimal

recall bias).

• Structured interview for TBI exposure, only TBI with LOC

(maximal recall).

• Strict diagnostic criteria and consensus-based diagnoses for

dementia and AD

Characterizing PTD/Late Effects of TBI

What is the clinical course?

Clinical presentation of dementia after TBI

11

National Alzheimer’s Coordinating Center (NACC) - Uniform Data set (UDS)

- 29 NIA-funded ADRCs

Study 1 (Sayed et al., 2013)

Cases Controls

Any dementia + history of TBI that

resulted in chronic deficits (n=62)

Matched sample of individuals with

Probable AD (NINDS-ADRDA) with no

TBI (n=122)

Study 2 (Dams-O’Connor et al., 2013)

Cases Controls

Any dementia + history of TBI that

resulted in LOC or chronic deficits

(n=332)

Matched sample of individuals with all-

cause dementia with no TBI (n=664)

Clinical Phenotype of Dementia after TBI (NACC) Sayed, Culver, Dams-O’Connor, Hammond, Diaz-Arrastia (2013). Journal of Neurotrauma.

12

Clinical Phenotype of Dementia after TBI (NACC) Dams-O’Connor, Spielman, Hammond, Sayed, Culver, Diaz-Arrastia (2013). Neurorehabilitation.

13

14

Neurobehavioral Characteristics of Older Veterans

with remote TBI Peltz, Gardner, Kenney, Diaz-Arrastia, Kramer, Yaffe (2016). J Head Trauma Rehab.

15

Neuropsychological Profile of Lifetime TBI

in Older Veterans Kaup, Peltz, Kenney, Kramer, Diaz-Arrastia, Yaffe (2016). JINS.

Characterizing PTD/Late Effects of TBI

What is the pathology?

Progressive PTD

• Progressive PTD with postmortem evidence of typical AD pathology

following single episode head trauma has rarely been reported. Rudelli 1982

18

Pooled results

Table4.Adjustedassociationsbetweentraumaticbraininjurywithlossofconsciousnessatanyageandneuropathologicalfindingsfromanalysisofpooleddatafromallthreestudies*

TBIwithLOC<1hr(n=176)

TBIwithLOC≥1hr(n=37)

Outcome RR(95%CI)P

value RR(95%CI)P

value

BraakStage5or6 1.02(0.79,1.33) 0.88 0.98(0.58,1.65) 0.93

CERADintermediateorfrequent 1.01(0.89,1.15) 0.88 1.00(0.79,1.27) 0.98

Amyloidangiopathy 1.08(0.99,1.19) 0.09 1.09(0.93.1.27) 0.28

Cysticinfarcts 0.90(0.73,1.12) 0.35 1.17(0.84,1.62) 0.34

Hippocampalsclerosis 0.91(0.51,1.61) 0.75 1.34(0.62,2.89) 0.45

CerebralMicroinfarcts

Any 0.94(0.76,1.15) 0.54 1.18(0.85,1.66) 0.32

Anycortical 0.90(0.68,1.19) 0.47 1.58(1.06,2.35) 0.026

Anydeep 1.02(0.78,1.33) 0.90 1.30(0.83,2.05) 0.25Lewybodies

Any 1.00(0.73,1.37) 0.99 1.44(0.87,2.39) 0.16SubstantiaNigra/Locus

Ceruleus 1.04(0.74,1.45) 0.84 1.48(0.86,2.55) 0.16

Frontalortemporalcortex 1.59(1.06,2.39) 0.025 1.75(0.82,3.77) 0.15

Amygdala/limbic 1.22(0.88,1.69) 0.24 1.16(0.59,2.27) 0.67

Exposure younger than Age 25 results

Table5.Adjustedassociationsbetweentraumaticbraininjurywithlossofconsciousnessyoungerthanage25andneuropathologicalfindingsfromjointanalysisofdatafromallthreestudies*

TBIwithLOC<1hr(n=67)

TBIwithLOC≥1hr(n=19)

Outcome RR(95%CI)P

value RR(95%CI) Pvalue

BraakStage5or6 1.00(0.66,1.52) 0.99 1.03(0.50,2.14) 0.94

CERADintermediateorfrequent

1.09(0.89,1.32) 0.41 0.91(0.62,1.35) 0.65

Amyloidangiopathy 1.07(0.89,1.29) 0.44 0.86(0.62,1.20) 0.38Cysticinfarcts 0.83(0.58,1.21) 0.33 0.84(0.45,1.60) 0.60

Hippocampalsclerosis 1.42(0.68,2.97) 0.35 1.33(0.37,4.76) 0.66CerebralMicroinfarcts

Any 1.04(0.78,1.40) 0.77 1.66(1.19,2.32) 0.003

Anycortical 1.10(0.77,1.57) 0.60 1.29(0.71,2.35) 0.41Anydeep 1.06(0.72,1.58) 0.76 1.24(0.64,2.40) 0.53

Lewybodies Any 0.95(0.56,1.62) 0.86 1.86(1.03,3.35) 0.040

SubstantiaNigraorLocusCeruleus

1.03(0.59,1.80) 0.91 1.84(0.94,3.60) 0.08

Frontalortemporalcortex 1.53(0.77,3.03) 0.23 2.53(1.02,6.24) 0.045

Amygdala/limbic 1.09(0.60,1.98) 0.78 1.77(0.86,3.64) 0.12

21

ACT, ROS, MAP

45,000 py follow-up

>1,500 ACD cases

>1,300 AD cases

1,586 autopsies

high Braak stage

High CERAD levels

Heterogeneity of Change in GOS-E score 2-15 years post TBI

Corrigan & Hammond, 2013. Traumatic Brain Injury as a chronic health condition. Archives of PM&R; 94: 1199-1201. 22

Risk Factors for Dementia

• Age: Risk of AD doubles every 5 years over age 65.

• Genetics: ApoE ɛ4

• Health: Vascular disease, high cholesterol, high blood

pressure, Type 2 diabetes, heart disease, obesity

• Lifestyle: exercise, diet, cognitive activity

• Head trauma

23 Mayeux 1995 NEUROLOGY

TBI as a Chronic Health Condition

TBI as a Chronic Disease

▶ World Health Organization:

– A chronic disease is:

• Permanent

• Caused by non-reversible pathological alterations

• Requires special training of the patient for rehabilitation

• May require a long period of observation, supervision, or care

▶ TBI is associated with:

– Long-term mortality and reduced life expectancy

– Increased incidence of:

• Seizures

• Sleep disorders

• Neurodegenerative diseases

• Neuroendocrine dysregulation

• Psychiatric diseases

• Sexual dysfunction

• Bladder and bowel incontinence

• Systematic metabolic dysregulation

25

“TBI [is] the beginning of an ongoing, perhaps lifelong process, that impacts multiple

organ systems and may be disease causative and accelerative” (Masel & DeWitt, 2000)

Guidelines for the Rehabilitation and Chronic

Disease Management of Adults with Moderate

to Severe Traumatic Brain Injury

▶ How much rehabilitation should adult patients with moderate to

severe traumatic brain injury (TBI) receive, in what setting, and

at what time?

▶ Behavioral, Cognitive, Medical, Functional, Participation/ Vocational Panels

What are the most common health conditions experienced by long-term survivors of moderate-severe TBI?

Prevalence/Incidence of Health Conditions:

Mod-Sev TBI vs. Healthy Controls (Preliminary Results)

Condition N of

Sample

N of

Cases

Prev

Incid

Seizure/Epilepsy TBI 11893 279 (22)** 2s-5p

Control 540322 1553 (8)** <1

Urinary Incontinence TBI 354 28 (12)* 6

Control 12080 192 (0)* 2

New Onset Stroke TBI 30165 1455 5

Control 120660 2903 2

Sleep changes TBI 63 50 79

Control 63 14 22

Fatigue TBI 63 12 19

Control 63 6 10

*Parcell, 2006 (n=63 TBI, 63 Controls

**Hwang 2008, n=475 TBI, 429 Homeless persons 27

Health in Adults with TBI: Sneak peak

▶ 85% of the sample (n=86) report 3 or more chronic

medical conditions (avg: 6 conditions, range 3-14)

Mount Sinai / Presentation Slide / December 5, 2012 28

Health Condition Frequency

Chronic Pain 29

Anxiety/Depression/Emotional disorder 28

Heart trouble 27

Hypertension 26

Urinary or bladder problems 21

Arthritis, bone or joint disease 20

Sciatica or recurring backache 19

Cancer 19

Diabetes or high blood sugar 14

Chronic sleep problems 10

Do health problems precede TBI? Adult Changes in Thought study

Mount Sinai BIRU

Predictors of incident TBI in older adults

▶ Older people tend to have poor functional outcomes after TBI,

and many experience deterioration in overall health after TBI.

▶ Falls are the most common cause of TBI in older adults.

▶ Older adults with mTBI have higher medical care costs in the

year before injury relative to matched controls (Unpublished

data, September 2011).

▶ Individuals presenting to hospital with mTBI are more likely

to have health problems relative to individuals with other

injuries (McMillan et al., 2014).

ExVivo

MRI

Serial Clinical Evaluations

_TBI____/____/____/____/____/____/____ Histopathology TBI

Prevention in TBI

Primary prevention aims to prevent disease or injury before it ever occurs.

This is done by preventing exposures to hazards that cause disease or injury,

altering unhealthy or unsafe behaviors that can lead to disease or injury, and

increasing resistance to disease or injury should exposure occur.

Secondary prevention aims to reduce the impact of a disease or injury that has

already occurred. This is done by detecting and treating disease or injury as

soon as possible to halt or slow its progress, encouraging personal strategies

to prevent re-injury or recurrence, and implementing programs to return

people to their original health and function to prevent long-term problems.

Tertiary prevention aims to soften the impact of an ongoing illness or injury

that has lasting effects. This is done by helping people manage long-term, often-

complex health problems and injuries (e.g. chronic diseases, permanent

impairments) in order to improve as much as possible their ability to function,

their quality of life and their life expectancy.

Guidelines for the Rehabilitation and Chronic

Disease Management of Adults with Moderate

to Severe Traumatic Brain Injury The goals of this project are to:

– Determine the evidence for various rehabilitative treatments and, based on that evidence

and/or expert opinion, make recommendations for treatment and management in various

settings;

– Document recommendations to improve quality and consistency of rehabilitation

treatment; and

– Broadly disseminate the recommendations to payer, provider, patient, and advocacy

communities in an effort to increase access to and quality of care.

Living and Aging well after TBI

▶ Cognitive Health

Yes, it can still work

MANY YEARS after

brain injury

Mount Sinai / Presentation Slide / December 5, 2012 36

Thank You

kristen.dams-o’connor@mountsinai.org

37

University of Washington Uniformed Services University

Paul Crane MD MPH of Health Sciences/CNRM

Laura Gibbons PhD C. Dirk Keene MD Dan Perl MD

Christine Mac Donald PhD Dara Dickstein PhD

Jeanne Hoffman PhD

New York Medical Examiner’s Office

Group Health Research Institute Rebecca Folkerth MD

Eric Larson MD MPH

TBIMS Collaborators

Massachusetts General Hospital/Harvard Allen Brown MD Tessa Hart PhD

Brian Edlow MD Bruce Fischl PhD John Corrigan PhD Sureyya Dikmen PhD

Ona Wu PhD Lilla Zollei Flora Hammond MD Cindy

Harrison-Felix

TBIMS Data and Statistical Center Boston University

Chris Pretz, PhD Dave Mellick, MA Ann McKee MD Jesse Mez MD

University of Pennsylvania Icahn School of Medicine at Mount Sinai

Ramon Diaz-Arrastia, MD PhD Sam Gandy MD PhD John Crary MD PhD