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Appendix e-1SUPPLEMENTAL METHODSPET Brain Imaging30 to 60 minute standard uptake value ratios were calculated for all 18F-FDG scans normalized to mean activity in the pons.e1 18F-AV-45 images were analyzed as 50 to 70 minute standard uptake value ratios normalized to mean activity in the whole cerebellum.e2 11C-PiB data were analyzed as 90-minute distribution volume ratio using Logan graphical analysis, with cerebellum gray matter as the reference region.e3Clinical and neuropsychological assessmentsAll patients were evaluated by a behavioral neurologist with a one to two hour medical interview and neurological examination. Most patients were accompanied by an informant who provided additional information. Eight patients underwent at least one follow-up examination one to three years after the baseline evaluation. All patients were evaluated by a neuropsychologist who administered a standardized battery of tests assessing an array of cognitive realms. All patients received a test of global cognitive function with either the Mini-Mental State Exam (MMSE) (n=13) or the Montreal Cognitive Assessment (MoCA) (n=1). All patients received the California Verbal Learning Test - Second Edition (CVLT)e4 16-word list (n=11) or 9-word list (n=3), which is a test of verbal episodic memory. All patients received visual memory testing via the Benson Figure Test Copy and 15-minute Recall (n=10)e5 or a more complex version of this test (n=4). All patients received the Trailmaking test from either Delis KaplanExecutive Function System (D-KEFS)e6 (n=10) or modified trailmakinge7 (n=4), which are tests of executive function. Digit Span Backward, a test of working memory, was recorded as the maximum achieved span for all patients. All patients had assessment of D-word or F-word fluency and design fluency (from D-KEFS Condition 1), defined as the number of words or designs generated in 1 minute, as additional tests of executive function. All but one patient had assessment of animal fluency, defined as the number of animals generated in 1 minute, which tests verbal semantic fluency. The modified Boston Naming Test (BNT), a 15-item confrontation naming teste7, was administered to 14 patients. Number-Location, a spatial localization test from the Visual Object and Space Perception Batterye8, was administered to 12 patients. The Geriatric Depression Scalee9 was administered to 13 patients.SUPPLEMENTAL RESULTSChronic post-concussive syndrome vignetteCase 2: This is a left-handed man in his 30s who presented with six years of progressive forgetfulness and frequent post-concussive symptoms of headache and feeling “dazed” after hits to the head during play that began four years into his professional football career. While he was initially able to compensate for his forgetfulness by taping a “cheat sheet” to his forearm, the symptoms progressed, became noticeable to his colleagues and coaches, began to affect his ability to perform instrumental acts of daily living, and ultimately prompted him to retire from football and seek assistance maintaining his household, paying bills, and driving. He became increasingly depressed and irritable, had fleeting suicidal ideations, developed insomnia, and experienced increasingly frequentsevere migrainous headaches lasting hours to days that were associated with brief episodic vertigo, tinnitus, dysarthria, left hand tremors and clumsiness, diplopia, and a visual aura of squares and dots of light. The headaches were associated with photophobia, phonophobia, nausea, hyperacusis, bilateral cranial autonomic symptoms, and were occurring more than 15 times per month. Tackle football exposure began in elementary school and continued until his retirement from professional football two years prior to presentation. On exam, he had mild word-finding difficulty with occasional paraphasic errors and a flat affect. Neuropsychological testing revealed variable attention, low- average episodic memory, impaired phonemic fluency, and depression. Normal or unremarkable studies included routine dementia labs (TSH, free T4, B12, methylmalonic acid, homocysteine, RPR, HIV, hemoglobin A1c), hypercoagulable panel, routineelectro-encephalogram, and brain MRI with MR angiogram. A brief trial of lamotrigine for possible focal epilepsy was ineffective. All symptoms and functional status improved with initiation of flunarizine 5mg daily and a five-day treatment with intravenous dihydroergotamine for a presumptive diagnosis of post-traumatic migraine. Repeat neuropsychological testing one year later revealed improvement in all areas except stable impairment in phonemic fluency. With repeat five-day intravenous dihydroergotamine treatment every 10 to 12 months and continued flunarizine 5mg daily, his migraine symptoms remained well-controlled and his cognitive functioning remained stable for more than one year. At last follow-up two years after baseline evaluation, however, memory and executive functioning were declining subjectively and objectively and he had developed a new symptom of increasingly frequent brief confusional episodes lastingthree to five minutes upon awakening in the morning. Inpatient video EEG and sleep study are pending.Behavior/mood syndrome vignetteCase 8: This is a left-handed man in his 50s who presented with eight years of increasing frequency of rage attacks that began more than 30 years after initial exposure to professional football. His first attack occurred when he struck his wife in the face during an argument. He had no recollection of this altercation the following day. Attacks often occurred in the setting of alcohol consumption, lasted one hour, were followed by fatigue and total amnesia for the event, and gradually increased in frequency until they were occurring every one to two months by the time of presentation. He also reported anhedonia, insomnia, and two years of stooped posture and mild hand tremors. He was functionally unimpaired. Football exposure began in high school, totaled more than 15 years including more than five years in a professional league, and was followed by three years of work in an occupation that exposed him to high risk of further TBI. During this time he sustained many head traumas and at least two concussions diagnosed by a physician. Physical exam was notable for hypomimia, hypophonia, asymmetrical cogwheel rigidity and bradykinesia, bilateral fine postural hand tremor, absent deep tendon reflexes, reduced vibratory sensation in the toes, and a mildly wide-based gait with a stooped posture. On neuropsychological testing, his verbal fluency was impaired, and his false positive rate on delayed verbal memory recognition testing was slightly elevated. Depression was mild. Processing speed, visual memory, set-shifting, design fluency, visuospatial skills, and confrontation naming were intact. Laboratory testing forreversible causes of dementia was unremarkable. MRI brain revealed a CSP and mild generalized atrophy. Over the subsequent two years of follow-up, rage attacks increased in frequency and intensity until they were occurring several times per week. The patient was admitted for three days of video EEG telemetry which did not capture any attacks. Alcohol abstention was recommended, a trial of lamotrigine was initiated and tritrated up to 75mg each morning and 150mg each evening, at which point the patient reported near total resolution of rage attacks despite continued daily alcohol consumption. Cognitive symptoms have continued to progress, however, and the patient met criteria for mild dementia three years after presentation.Cognitive syndrome vignetteCase 13: This is a right-handed man in his 70s who presented with two years of progressive short-term memory decline accompanied by mild navigational difficulties and mild apathy, but no frank depression, irritability, or insomnia. At the time of presentation, he was compensating well with notes and calendars and was not functionally impaired. Tackle football exposure began in high-school, continued through college, and for 9 years in a professional league. He additionally served several tours of duty in the military which involved jumping out of planes, but he was not involved in combat. He reported multiple head injuries during his football career including several concussions, at least 2 of which prompted hospitalization. Physical exam was notable for mild disinhibition with occasional use of profanity, but otherwise appropriate and socially engaged demeanor, occasional self-repetition, hypophonia, mild diffuse limb rigidity without cogwheeling or tremors, reduced bulk in intrinsic hand and foot muscles, tracedeep tendon reflexes, and slightly stooped posture. Neuropsychological testing was notable for markedly impaired episodic memory and mildly impaired working memory, semantic/phonemic fluency, and visuospatial construction. CT brain showed moderate confluent periventricular and patchy subcortical white matter hypodensities, mild global atrophy, moderate hippocampal atrophy, and a large CSP. A trial of donepezil did not produce any symptomatic improvement. FDG-PET showed medial temporal hypometabolism and Amyloid-PET was negative (Fig 1, main text). Over two and a half years of follow-up, he became gradually more impaired, ultimately meeting criteria for dementia. Approximately four and half years after symptom onset, he died. Brain autopsy performed by the UCSF Pathology Department and confirmed by the UCSF Alzheimer’s Disease Research Center Brain Bank revealed tau and TDP-43 pathology primarily involving neurons and astrocytes of the hippocampus/medial temporal lobe and brainstem nuclei (Fig. 2, main text). These findings were considered most consistent with chronic traumatic encephalopathy (CTE) versus less likely primary age-related tauopathy(PART).e10 There were also neuronal alpha-synuclein aggregates in multiple brainstemregions. Additionally, multiple acute and evolving infarcts were seen which may have contributed to death, but were considered unlikely to have contributed to the chronic cognitive decline. There was a paucity of amyloid plaques in cerebral cortex. Focal amyloid angiopathy and beta-amyloid positive protein aggregates were identified in scattered dystrophic axons in subcortical white matter, especially in regions close to the acute and evolving infarcts.e-ReferencesMinoshima S, Frey KA, Foster NL, Kuhl DE. Preserved pontine glucose metabolism in Alzheimer disease: a reference region for functional brain image (PET) analysis. Journal of computer assisted tomography 1995;19:541-547.Clark CM, Pontecorvo MJ, Beach TG, et al. Cerebral PET with florbetapircompared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 2012;11:669-678.Rabinovici GD, Rosen HJ, Alkalay A, et al. Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology 2011;77:2034-2042.Delis DC, Wetter SR, Jacobson MW, et al. Recall discriminability: utility of a new CVLT-II measure in the differential diagnosis of dementia. Journal of theInternational Neuropsychological Society : JINS 2005;11:708-715.Possin KL, Laluz VR, Alcantar OZ, Miller BL, Kramer JH. Distinctneuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer's disease and behavioral variant frontotemporal dementia. Neuropsychologia 2011;49:43-48.Delis DC, Kramer JH, Kaplan E, Holdnack J. Reliability and validity of the Delis-Kaplan Executive Function System: an update. Journal of the International Neuropsychological Society : JINS 2004;10:301-303.Kramer JH, Jurik J, Sha SJ, et al. Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cognitive andbehavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology 2003;16:211-218.Quental NB, Brucki SM, Bueno OF. Visuospatial function in early Alzheimer's disease--the use of the Visual Object and Space Perception (VOSP) battery. PloS one2013;8:e68398.Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatricdepression screening scale: a preliminary report. Journal of psychiatric research 1982;17:37-49.Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol2014;128:755-766. ................
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