Radiation-Induced Cognitive Impairment in Postmenopausal Female Nonhuman Primates
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Radiation-induced R di i i d d Cognitive C ii Impairment in Postmenopausal Female Nonhuman Primates Mary Lou Voytko1, Rhonda Murray1, Dan Bourland3,4, Mark Cline2, 34 Mike Robbins3,4 Departments of Neurobiology & Anatomy1, Pathology2, and Radiation Oncology3, Brain Tumor Center of Excellence4, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Radiation-induced Brain Injury ~ 30% of the ~1,600,000 new cancer patients diagnosed in 2011 in the US will develop brain metastases Brain metastases represent the most common neurological manifestation of cancer Annual incidence of brain metastases is increasing due to: i. ii ii. iii. an aging population i improved d anticancer i therapies h i for f systemic i disease di improved imaging techniques that detect smaller metastases ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Radiation-induced Brain Injury Currently ~ 200,000 patients/year receive fractionated partial or whole brain irradiation (fWBI) Cognitive impairment is observed in >50% of adult and 100% off pediatric di i brain b i tumor patients i who h are long-term l survivors i after brain irradiation Includes deficits in short-term memory (hippocampus, medial temporal lobe) and in executive and attention function (prefrontal cortex) Short-term h i interventions i have h shown h temporary efficacy, ffi but b there are no proven long-term treatments for radiation-induced cognitive impairment ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Radiation induced Brain Injury Radiation-induced days ACUTE Edema Headache D Drowsiness i Neuro. worsening years months weeks EARLY DELAYED Transient demyelination Somnolence Attention deficits Short-term memory loss LATE Vascular abnormalities Demyelination; Gliosis White matter necrosis Cognitive impairment Dementia Death ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Radiation-induced Cognitive Impairment Everything I do is slow. slow I walk walk, talk, talk and think slowly slowly. That makes it frustrating and sometimes embarrassing for me. Much of the time I can’t even remember the names of relatives and close friends. I can walk from one room off our house h tto th the other th and d arrive i nott kknowing i why h I wanted t d to get there. I am always confused. Usually I feel as though I’m in a complete fog. And I often can’t answer even simple questions. That makes it very difficult for me in social settings. settings Because I look normal and often sound normal, people assume I am normal. But I’m not. Everything is difficult for me. I am less sure of myself. I’m more emotional. I cry a lot. And I get depressed knowing kno ing that I will ill never ne er have ha e my m competence back. back Susan Sontag, g, VP,, Sontag g Foundation,, SNO Meeting, g, Toronto Canada,, 2004 ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Radiation-induced Cognitive Impairment in Women Greater impairments in cognitive function are observed in older adults following brain irradiation Female adult survivors of childhood cancer exhibit a more severe decline in cognitive function than males Limited preclinical studies indicate that pediatric and young adult females are more susceptible p to radiation-induced cognitive impairment than age-matched males ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Radiation-induced Cognitive Impairment in Women Vast majority j y of animal models use young y g adult males Rodents comprise the majority of animal models Need robust female animal models to understand how the female brain responds to fWBI In older females, also need to consider the impact p of menopause and changes in hormonal status on cognition ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Female NHP Models of Menopause, H Hormones andd Cognition C iti ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Effect of Hormonal Therapy on Cognitive Function i in i Postmenopausall NHP Experimental Design: Middle-Aged Monkeys (15-23 years of age): T i /T Train/Test Surgery + hhormones S Placebo ET E+P ICCTF International Cognition and Cancer Task Force Conference Test @ 22, 12 and T d 24 weeks March 15 15--17 th 2012 – PARIS - FRANCE Hormone Regimen Estrogen (E2) Silastic implants to maintain constant low E2 levels Day 12 receive injection of estradiol valerate Estrogen (E2) + Progesterone (P4) Silastic implants to maintain constant low E2 levels Dayy 12 receive injection j of estradiol valerate Days 16-27 oral prometrium ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Cognitive Domains Examined in Middle-Aged Female NHP Executive Function: Wisconsin Card Sorting Task ( (WCST) ) Spatial Visual Memory: Delayed Response Task (DR) Memory: Delayed Matching to Sample Task (DMS) ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Wisconsin Card Sorting Task Green + + + Triangle + + ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 + th 2012 – PARIS - FRANCE Delayed Response Task ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Delayed y Matchingg to Sample p Task + + ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Summary of Results in Middle-Aged Female NHP ET and E+P prevented the impairments in visual memory and executive function that were observed in the placebo-treated monkeys following ovariectomy Visual memory may be more sensitive than spatial memory to the loss of ovarian hormones and treatment with ET and E+P Cognitive protection provided by hormone therapy was observed within 2-12 weeks after start of hormonal therapy ET and E+P produced similar effects in all tests examined ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Effect of Hormonal Therapy on Cognitive F Function i in i fWBI fWBI-Postmenopausal P l NHP Hypothesis: Hormonal therapy will prevent/ameliorate fWBIinduced cognitive deficits in aged postmenopausal NHP ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Experimental Design Animals: 8 aged (20-25 years) OVX female rhesus NHP receiving hormone therapy for 7 years Groups: Untreated controls (4), ET alone (2), E+P (2) 2 sham-fWBI; 2 fWBI; 2 ET + fWBI; 2 E+P + fWBI fWBI 40 Gy fWBI: G 6 MV x rays (5 Gy/F, G /F 2 F/week, F/ k for f 4 weeks) k) Cognitive function tests: visual memory and spatial memory assessed 2 months prior to and monthly after fWBI for 9 months; executive function assessed 6 and 9 months ppost-fWBI ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE fWBI of the NHP Brain A A eye shield field outline S I I S P P Right Lateral Left Lateral x-ray source x-ray source Right Lateral ((view from above)) ICCTF International Cognition and Cancer Task Force Conference NHP EPID NHP EPID D linear accelerator March 15 15--17 th 2012 – PARIS - FRANCE ET Prevents/Ameliorates the fWBI-induced Acute Impairment in Visual Memory in Aged Postmenopausal NHP DMS 100 Pre-fWBI Perc cent Correct Perce ent Correct 90 100 80 70 * 90 80 70 60 60 50 50 1 100 1 short medium long Delays Post-fWBI 3 mos short medium long Delays PL-sham PL-fWBI ET-fWBI 100 Post-fWBI 9 mos * 90 Perce ent Correct 90 Perc cent Correct Post-fWBI 1 mos 80 70 60 80 70 60 50 50 1 short medium long 1 short medium long Delays ICCTF International Cognition and Cancer Task Force Conference Delays March 15 15--17 th 2012 – PARIS - FRANCE fWBI Fails to Modulate Spatial Memory in Aged Postmenopausal NHP DR Pre-fWBI 100 90 Percen nt Correct 90 Percen nt Correct Post-fWBI 1 mos 100 80 70 60 80 70 60 50 50 1 short medium long 1 Delays short medium long Delays PL-sham PL-fWBI ET-fWBI Post-fWBI 9 mos Post-fWBI 3 mos 90 90 Percentt Correct 100 Percent Correct 100 80 70 60 80 70 60 50 50 1 short medium long 1 Delays ICCTF International Cognition and Cancer Task Force Conference short medium long Delays March 15 15--17 th 2012 – PARIS - FRANCE ET Prevents/Ameliorates the fWBI-induced Impairment in Executive Function in Aged Postmenopausal NHP ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Histopathology Reveals Aging- but not fWBI d fWBI-dependent d Ch Changes Hippocampus, dentate gyrus: Focal vascular degeneration and perivascular vacuolar l degeneration d ti Thalamic blood vessel with loss of neuropil (expanded space around vessel) and hemosiderin d deposition iti (brown (b pigment) i t) ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Summary These preliminary findings suggest that fWBI of aged postmenopausal NHP leads to: An acute decrease in visual memory at 1 month post-fWBI that recovers with time A chronic decrease in executive function at 6 months post-fWBI that persists at 9 months th ET may prevent/ameliorate the chronic decrease in executive function fWBI-induced cognitive impairment is seen in the absence of fWBI-associated histopathological s op o og c changes c ges ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE
