Raquel C. Gardner

Dementia Risk After Traumatic Brain Injury vs Nonbrain Trauma: The Role of Age and Severity

IMPORTANCE Epidemiologic evidence regarding the importance of traumatic brain injury (TBI) as a risk factor for dementia is conflicting. Few previous studies have used patients with non-TBI trauma (NTT) as controls to investigate the influence of age and TBI severity. OBJECTIVE To quantify the risk of dementia among adults with recent TBI compared with adults with NTT. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study was performed from January 1, 2005, through December 31, 2011 (follow-up, 5-7 years). All patients 55 years or older diagnosed as having TBI or NTT in 2005 and 2006 and who did not have baseline dementia or die during hospitalization (n = 164,661) were identified in a California statewide administrative health database of emergency department (ED) and inpatient visits. EXPOSURES Mild vs moderate to severe TBI diagnosed by Centers for Disease Control and Prevention criteria using International Classification of Diseases, Ninth Revision (ICD-9)codes, and NTT, defined as fractures excluding fractures of the head and neck, diagnosed using ICD-9 codes. MAIN OUTCOMES AND MEASURES Incident ED or inpatient diagnosis of dementia (using ICD-9 codes) 1 year or more after initial TBI or NTT. The association between TBI and risk of dementia was estimated using Cox proportional hazards models before and after adjusting for common dementia predictors and potential confounders. We also stratified by TBI severity and age category (55-64, 65-74, 75-84, and ≥85 years). RESULTS A total of 51,799 patients with trauma (31.5%) had TBI. Of these, 4361 (8.4%) developed dementia compared with 6610 patients with NTT (5.9%) (P < .001). We found that TBI was associated with increased dementia risk (hazard ratio [HR], 1.46; 95% CI, 1.41-1.52; P < .001). Adjustment for covariates had little effect except adjustment for age category (fully adjusted model HR, 1.26; 95% CI, 1.21-1.32; P < .001). In stratified adjusted analyses, moderate to severe TBI was associated with increased risk of dementia across all ages (age 55-64: HR, 1.72; 95% CI, 1.40-2.10; P < .001; vs age 65-74: HR, 1.46; 95% CI, 1.30-1.64; P < .001), whereas mild TBI may be a more important risk factor with increasing age (age 55-64: HR, 1.11; 95% CI, 0.80-1.53; P = .55; vs age 65-74: HR, 1.25; 95% CI, 1.04-1.51; P = .02; age interaction P < .001). CONCLUSIONS AND RELEVANCE Among patients evaluated in the ED or inpatient settings, those with moderate to severe TBI at 55 years or older or mild TBI at 65 years or older had an increased risk of developing dementia. Younger adults may be more resilient to the effects of recent mild TBI than older adults.

Epidemiology of mild traumatic brain injury and neurodegenerative disease.

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinsons disease, and CTE while highlighting methodological challenges and critical future directions of research in this field. This article is part of a Special Issue entitled SI:Traumatic Brain Injury.

Development of a Brief Ataxia Rating Scale (BARS) Based on a Modified Form of the ICARS

To develop a brief ataxia rating scale (BARS) for use by movement disorder specialists and general neurologists. Current ataxia rating scales are cumbersome and not designed for clinical practice. We first modified the International Cooperative Ataxia Rating Scale (ICARS) by adding seven ataxia tests (modified ICARS, or MICARS), and observed only minimally increased scores. We then used the statistics package R to find a five‐test subset in MICARS that would correlate best with the total MICARS score. This was accomplished first without constraints and then with the clinical constraint requiring one test each of Gait, Kinetic Function‐Arm, Kinetic Function‐Leg, Speech, and Eye Movements. We validated these clinical constraints by factor analysis. We then validated the results in a second cohort of patients; evaluated inter‐rater reliability in a third cohort; and used the same data set to compare BARS with the Scale for the Assessment and Rating of Ataxia (SARA). Correlation of ICARS with the seven additional tests that when added to ICARS form MICARS was 0.88. There were 31,481 five‐test subtests (48% of possible combinations) that had a correlation with total MICARS score of ≥0.90. The strongest correlation of an unconstrained five‐test subset was 0.963. The clinically constrained subtest validated by factor analysis, BARS, had a correlation with MICARS‐minus‐BARS of 0.952. Cronbach alpha for BARS and SARA was 0.90 and 0.92 respectively; and inter‐rater reliability (intraclass correlation coefficient) was 0.91 and 0.93 respectively. BARS is valid, reliable, and sufficiently fast and accurate for clinical purposes.

Traumatic brain injury in later life increases risk for Parkinson disease

Traumatic brain injury (TBI) is thought to be a risk factor for Parkinson disease (PD), but results are conflicting. Many studies do not account for confounding or reverse causation. We sought to address these concerns by quantifying risk of PD after TBI compared to non‐TBI trauma (NTT; defined as fractures).

Intrinsic connectivity network disruption in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) has been conceptualized as a large‐scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP.

Dementia in the oldest old: a multi-factorial and growing public health issue.

The population of oldest old, or people aged 85 and older, is growing rapidly. A better understanding of dementia in this population is thus of increasing national and global importance. In this review, we describe the major epidemiological studies, prevalence, clinical presentation, neuropathological and imaging features, risk factors, and treatment of dementia in the oldest old. Prevalence estimates for dementia among those aged 85+ ranges from 18 to 38%. The most common clinical syndromes are Alzheimers dementia, vascular dementia, and mixed dementia from multiple etiologies. The rate of progression appears to be slower than in the younger old. Single neuropathological entities such as Alzheimers dementia and Lewy body pathology appear to have declining relevance to cognitive decline, while mixed pathology with Alzheimers disease, vascular disease (especially cortical microinfarcts), and hippocampal sclerosis appear to have increasing relevance. Neuroimaging data are sparse. Risk factors for dementia in the oldest old include a low level of education, poor mid-life general health, low level of physical activity, depression, and delirium, whereas apolipoprotein E genotype, late-life hypertension, hyperlipidemia, and elevated peripheral inflammatory markers appear to have less relevance. Treatment approaches require further study, but the oldest old may be more prone to negative side effects compared with younger patients and targeted therapies may be less efficacious since single pathologies are less frequent. We also highlight the limitations and challenges of research in this area, including the difficulty of defining functional decline, a necessary component for a dementia diagnosis, the lack of normative neuropsychological data, and other shortcomings inherent in existing diagnostic criteria. In summary, our understanding of dementia in the oldest old has advanced dramatically in recent years, but more research is needed, particularly among varied racial, ethnic, and socioeconomic groups, and with respect to biomarkers such as neuroimaging, modifiable risk factors, and therapy.

Cavum Septum Pellucidum in Retired American Pro-Football Players

Previous studies report that cavum septum pellucidum (CSP) is frequent among athletes with a history of repeated traumatic brain injury (TBI), such as boxers. Few studies of CSP in athletes, however, have assessed detailed features of the septum pellucidum in a case-control fashion. This is important because prevalence of CSP in the general population varies widely (2% to 85%) between studies. Further, rates of CSP among American pro-football players have not been described previously. We sought to characterize MRI features of the septum pellucidum in a series of retired pro-football players with a history of repeated concussive/subconcussive head traumas compared with controls. We retrospectively assessed retired American pro-football players presenting to our memory clinic with cognitive/behavioral symptoms in whom structural MRI was available with slice thickness ≤2 mm (n=17). Each player was matched to a memory clinic control patient with no history of TBI. Scans were interpreted by raters blinded to clinical information and TBI/football history, who measured CSP grade (0-absent, 1-equivocal, 2-mild, 3-moderate, 4-severe) and length according to a standard protocol. Sixteen of 17 (94%) players had a CSP graded ≥2 compared with 3 of 17 (18%) controls. CSP was significantly higher grade (p<0.001) and longer in players than controls (mean length±standard deviation: 10.6 mm±5.4 vs. 1.1 mm±1.3, p<0.001). Among patients presenting to a memory clinic, long high-grade CSP was more frequent in retired pro-football players compared with patients without a history of TBI.

Traumatic brain injury may increase risk of young onset dementia

Since 1906, when Alois Alzheimer first described the clinical and pathological features of Alzheimer disease (AD) in a 51-year-old woman,1 our understanding of the clinical subtypes, underlying pathologies, pathophysiologies, and risk factors for dementia has increased tremendously. By 1928, an astute pathologist reported a unique type of dementia associated with repeated traumatic brain injury (TBI) in boxers.2 A history of exposure to TBI has subsequently emerged as an important risk factor for dementia in older adults in many,3–9 but not all,10,11 epidemiological studies and meta-analyses. The contribution of TBI to young onset dementia (YOD), defined as dementia before age 65 years, has not been as thoroughly investigated. This gap is partly due to the challenges of designing a study of dementia in a population with a relatively low incidence of this outcome. The exposure rate to TBI in this population, however, is quite high. In the United States alone, TBI accounts for an estimated 1.4 million emergency department visits annually in patients younger than 65 years.12 Given the number of patients who suffer TBI and do not seek medical attention, this is likely a gross underestimate of the actual exposure rate.13 Thus, even a small increased risk of dementia in the population of TBI-exposed young adults could have important public health implications. In this issue of Annals of Neurology, Nordstrom et al14 report the results of a Swedish epidemiological study evaluating the risk of YOD after TBI in a cohort of >800,000 young men (>45,000 with TBI) followed for >3 decades. This study may be the first of its size to address this important question in a dedicated fashion. The authors report a strong dose–response association between TBI and all-cause YOD, such that more severe or frequent TBI is associated with an ever-increasing risk of all-cause YOD. After adjustment for covariates, this association and dose–response effect were attenuated, but remained significant, with a hazard ratio (HR) of 1.5 for mild TBI and 2.3 for severe TBI. In a secondary nested case–control sensitivity analysis, in which the authors used propensity score matching, the risk was even greater (HR = 1.8 for mild TBI; HR = 2.9 for severe TBI). This study has many strengths, including novelty, clinical importance, and methodological rigor. The authors employed physician-generated diagnoses of TBI, thus eliminating potential recall bias that has limited many prior studies of this topic, but missing cases that did not come to medical attention. They also included many important covariates such as baseline cognitive status, thus strengthening causality following multivariable adjustment. National databases of administrative health data present a wealth of opportunities for epidemiological research due to the sheer size of the cohorts and to the availability of long-term follow-up in many cases. These studies, however, must be interpreted in the context of potential coding idiosyncrasies—both by the providers assigning codes to the patients during an encounter and by the researchers selecting the codes to include in the study definitions. In their study, Nordstrom et al employ a TBI stratification scheme that differs from that recommended by the Centers for Disease Control and Prevention15 and implemented by many prior studies. Although this approach may limit direct comparison to prior studies, the authors’ sensitivity analysis of mortality after TBI, as well as the persistence of a dose response after adjustment for covariates, supports the clinical validity of their stratification scheme. The authors also stratified by dementia subtypes, distinguishing between AD and non-AD dementia. It is well known that general practitioners often under- or misreport dementia subtypes, potentially leading to underidentification of cases of AD within the AD cohort. Only 14 cases of AD were identified among the TBI-exposed subjects, resulting in limited power. We therefore caution readers against overinterpretation of dementia subtype results and encourage readers to focus on results for the analysis of “all cases of dementia.” Leading theories of mechanisms whereby TBI may increase risk of dementia include reduction of cognitive reserve, augmentation of incipient neurodegenerative processes, and initiation of de novo neurodegenerative processes. Although the precise underlying pathophysiological mechanisms are being investigated, there is a growing body of basic and translational research that lends support to a causal link between TBI and neurodegenerative disease. At the time of a nonpenetrating TBI, mechanical forces exerted on brain tissue may produce multifocal axonal shear injuries, which have been shown in animal studies to lead to immediate changes in axonal membrane permeability, massive calcium influx, and release of caspases and calpains that have been implicated in subsequent abnormal protein phosphorylation and aggregation.16–19 Human studies of acute TBI have revealed axonal accumulation of a number of abnormal proteins, including tau, amyloid-beta, and alpha-synuclein,20 that are implicated in a range of different neurodegenerative diseases, including chronic traumatic encephalopathy, AD, frontotemporal dementia, and Parkinson disease. Many of these abnormal proteins are known to self-propagate via cross-seeding and neuron-to-neuron transfer mechanisms,21–26 which may then seed functionally connected neuronal networks,27 thereby triggering a more widespread neurodegenerative cascade. Based on these proposed mechanisms, it stands to reason that TBI may be associated not only with late onset dementia, but also with YOD, particularly in patients with other risk factors that may promote the initiation and propagation of this cascade. For example, apolipoprotein E epsilon 4 has been shown to reduce the brain’s ability to recover post-TBI,28 and TBI sustained in childhood or adolescence may be more morbid than TBI sustained later in life.29,30 The lack of dementia in many TBI-exposed individuals, however, indicates that post-TBI neurodegeneration is a multifactorial process that is likely dependent upon number, mechanics, and timing of TBIs, individual genetics, and many other health-related, lifestyle, and environmental risk and protective factors. Overall, this is an important study by Nordstrom et al that addresses an understudied question and raises the possibility that mild or severe TBI may increase risk of YOD. As the authors point out, this is a topic that requires further examination in large prospective longitudinal studies ending in autopsy, which will inform development of diagnostic, treatment, and prevention strategies.

Evaluating and treating neurobehavioral symptoms in professional American football players: Lessons from a case series

SummaryIn the aftermath of multiple high-profile cases of chronic traumatic encephalopathy (CTE) in professional American football players, physicians in clinical practice are likely to face an increasing number of retired football players seeking evaluation for chronic neurobehavioral symptoms. Guidelines for the evaluation and treatment of these patients are sparse. Clinical criteria for a diagnosis of CTE are under development. The contribution of CTE vs other neuropathologies to neurobehavioral symptoms in these players remains unclear. Here we describe the experience of our academic memory clinic in evaluating and treating a series of 14 self-referred symptomatic players. Our aim is to raise awareness in the neurology community regarding the different clinical phenotypes, idiosyncratic but potentially treatable symptoms, and the spectrum of underlying neuropathologies in these players.

Ataxia and cerebellar atrophy--a novel manifestation of neuro-Behçet disease?

Behçet Disease (BD) is a multisystem inflammatory-vascular disorder of unknown etiology.1 Neurological involvement, or neuro-Behçet Disease (NBD), occurs in up to 49% of cases2 manifesting as primary parenchymal NBD with neurological findings and enhancing cerebral lesions, or as non-parenchymal NBD with intracranial hypertension following dural sinus thrombosis.3 We describe a case of BD with a chronic cerebellar ataxia syndrome in the absence of the characteristic mucocutaneous or brain MRI lesions, a phenomenon reported in one previous case.4 A 16-year-old woman developed presumptive rubella followed 10 days later by headache, severe limb and gait ataxia, dysarthria, diplopia, and altered mental status. Lumbar puncture revealed cerebrospinal fluid (CSF) pleocytosis. She recovered with a residual wide-based gait, dysarthria, mild diplopia, and mild arm tremor. Brain MRI at age 29 showed cerebellar atrophy. At age 34 she developed acute onset of generalized weakness, fatigue, nausea and neck tenderness, with exacerbation of her cerebellar syndrome. CSF studies were unremarkable and brain MRI was unchanged. This episode left her wheelchair bound and disabled. When examined 1 year later, she had gaze-evoked nystagmus, saccadic intrusions into pursuit eye movements, hypermetric saccades, moderate cerebellar dysarthria, severe limb dysmetria, wide-based ataxic gait with retropulsion, and right arm tremor with head titubation at rest. Strength and sensation were normal. She had patellar hyperreflexia and flexor plantar reflexes. Ophthalmological examination revealed a small nonspecific left retinal scar. Normal laboratory studies included erythrocyte sedimentation rate, anti-nuclear antibody, very long chain fatty acids, toxoplasmosis antibody, heterophile antibody, and genetic tests for Friedreich Ataxia and spinocerebellar ataxia types 1, 2, 3, 6, and 7. MRI revealed diffuse cerebellar atrophy and mild pontine atrophy (see Fig. 1). Around this time she developed severe, refractory depression. At age 36, that is, 20 years following the first episode of acute ataxia and 2 years following the second episode, she developed severe rectovaginal fistulae, large nonhealing perineal lesions, and recurrent oral lesions. Biopsy of the perineal lesion revealed dermal fibrosis, acute and chronic inflammation, and foreign body giant cell reaction, consistent with BD. High-dose prednisone was ineffective. Thalidomide 50 mg twice daily5 healed the skin lesions almost completely within 3 months, but produced peripheral neuropathy. The agent was discontinued for 2 years until she developed reactivation of the perineal ulcers. Thalidomide was then reintroduced at 50 mg weekly. Six months later, her tremor and head titubation resolved, and speech was clearer. She has remained stable for 8 years. Our patient adds to the very small literature on NBD presenting with chronic progressive ataxia and cerebellar atrophy.4,6 A 56-year-old woman with mucocutaneous symptoms for 2 decades developed ataxia6 and brain MRI revealed mild cerebellar and brainstem atrophy, but no inflammatory lesions.7 Two others presented with chronic progressive cerebellar ataxia in the absence of mucocutaneous lesions. NBD was diagnosed based on hyperintense lesions in central pons, mild pontine, and cerebellar atrophy, the presence of HLA-B51, and CSF pleocytosis in one case, and pontine and cerebellar atrophy, HLA-B51 status, and neurological improvement with methylprednisolone therapy in the other.4 In a review of 200 patients with NBD, neurological symptoms were the heralding manifestation in only 3%. The longest delay from onset of neurological symptoms to mucocutaneous lesions was 9 years.3 If the cerebellitis at age 16 in our patient was not post-viral, but the first manifestation of BD, then this represents the longest reported latency between neurological presentation of BD and the development of mucocutaneous lesions. Improvement following immune-modulating therapy highlights the importance of prompt diagnosis and treatment in cases of NBD and indicates that the neurological symptoms may potentially be modifiable years following an acute flair. In addition to the parenchymal inflammation or secondary non-parenchymal involvement in NBD, there may be a 3rd category of CNS involvement characterized by chronic progressive atrophy and degeneration. Whether this pattern of neurodegeneration is a result of a microvasculitic process, a residual inflammatory process, or a new pathogenetic mechaPublished online 28 November 2007 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21834 FIG. 1. Brain MRI of the patient. (A) T1-weighted image shows prominent cerebellar folia, indicating atrophy. (B) T2-weighted image shows a single punctate hyperintensity in right frontal lobe white matter. (C–F) T2-weighted images show diffuse cerebellar atrophy, mild pontine atrophy, and no intrinsic white matter pathology. LETTERS TO THE EDITOR 307