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2.  Self-reported concussion history: impact of providing a definition of concussion 
In recent years, the understanding of concussion has evolved in the research and medical communities to include more subtle and transient symptoms. The accepted definition of concussion in these communities has reflected this change. However, it is unclear whether this shift is also reflected in the understanding of the athletic community.
What is known about the subject
Self-reported concussion history is an inaccurate assessment of someone’s lifetime exposure to concussive brain trauma. However, unfortunately, in many cases it is the only available tool.
We hypothesize that athletes’ self-reported concussion histories will be significantly greater after reading them the current definition of concussion, relative to the reporting when no definition was provided. An increase from baseline to post-definition response will suggest that athletes are unaware of the currently accepted medical definition.
Study design
Cross-sectional study of 472 current and former athletes.
Investigators conducted structured telephone interviews with current and former athletes between January 2010 and January 2013, asking participants to report how many concussions they had received in their lives. Interviewers then read participants a current definition of concussion, and asked them to re-estimate based on that definition.
The two estimates were significantly different (Wilcoxon signed rank test: z=15.636, P<0.001). Comparison of the baseline and post-definition medians (7 and 15, respectively) indicated that the post-definition estimate was approximately twice the baseline. Follow-up analyses indicated that this effect was consistent across all levels of competition examined and across type of sport (contact versus non-contact).
Our results indicate that athletes’ current understandings of concussions are not consistent with a currently accepted medical definition. We strongly recommend that clinicians and researchers preface requests for self-reported concussion history with a definition. In addition, it is extremely important that researchers report the definition they used in published manuscripts of their work.
What this study adds to existing knowledge
Our study shows that unprompted reporting of concussion history produces results that are significantly different from those provided after a definition has been given, suggesting one possible mechanism to improve the reliability of self-reported concussion history across multiple individuals.
PMCID: PMC4019619  PMID: 24891816
concussion; self-report; sports-related concussion
3.  Angiotensin Converting Enzyme Inhibitors and the Reduced Risk of Alzheimer’s Disease in the Absence of Apolipoprotein E4 Allele 
Our cross-sectional study showed that the interaction between apolipoprotein E4 (ApoE4) and angiotensin converting enzyme (ACE) inhibitors was associated with Alzheimer’s disease (AD). The aim of this longitudinal study was to differentiate whether ACE inhibitors accelerate or reduce the risk of AD in the context of ApoE alleles. Using the longitudinal data from the National Alzheimer’s Coordinating Center (NACC) with ApoE genotyping and documentation of ACE inhibitors use, we found that in the absence of ApoE4, subjects who had been taking central ACE inhibitor use (χ2 test: 21% versus 27%, p = 0.0002) or peripheral ACE inhibitor use (χ2 test: 13% versus 27%, p < 0.0001) had lower incidence of AD compared with those who had not been taking an ACE inhibitor. In contrast, in the presence of ApoE4, there was no such association between ACE inhibitor use and the risk of AD. After adjusting for the confounders, central ACE inhibitor use (OR = 0.68, 95% CI = 0.55, 0.83, p = 0.0002) or peripheral ACE inhibitor use (OR = 0.33, 95% CI = 0.33, 0.68, p < 0.0001) still remained inversely associated with a risk of developing AD in ApoE4 non-carriers. In conclusion, ACE inhibitors, especially peripherally acting ones, were associated with a reduced risk of AD in the absence of ApoE4, but had no such effect in those carrying the ApoE4 allele. A double-blind clinical trial should be considered to determine the effect of ACE inhibitors on prevention of AD in the context of ApoE genotype.
PMCID: PMC3972060  PMID: 23948883
Alzheimer’s disease; apolipoprotein E4 allele (ApoE4); angiotensin converting enzyme (ACE) inhibitor
4.  Subclinical Hypothyroidism, Mood, and Cognition in the Elderly: A Review 
To perform a critical review of the literature on the mood and cognitive changes associated with subclinical hypothyroidism (SCH), with an emphasis on the elderly. To evaluate these data against the Consensus Statement on management of SCH from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society.
A comprehensive literature review.
SCH may be associated with an increased risk of mood and cognitive dysfunction, though the strength of this association and the efficacy of replacement hormone therapy requires further investigation.
It remains unclear whether SCH leads to significant mood and cognitive impairments in most elderly patients. More research is required to determine the nature and extent of this association and whether thyroid hormone replacement therapy is appropriate and effective in treating SCH-associated neurobehavioral impairments.
PMCID: PMC3488161  PMID: 22410877
Thyroid; Depression; Cognition; Subclinical Hypothyroidism; Dementia
5.  Angiotensin Converting Enzyme Inhibitors and Alzheimer Disease in the Presence of the Apolipoprotein E4 Allele 
The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD.
This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined.
A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08–140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education.
The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers.
PMCID: PMC3873370  PMID: 23567418
Alzheimer disease; Apolipoprotein E4 allele (ApoE4); angiotensin converting enzyme (ACE); ACE inhibitor
6.  The spectrum of disease in chronic traumatic encephalopathy 
Brain  2012;136(1):43-64.
Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I–IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I–III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer’s disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.
PMCID: PMC3624697  PMID: 23208308
axonal injury; brain trauma; frontotemporal lobar degeneration; neurodegenerative disorders; traumatic brain injury
7.  Diagnostic Accuracy Statistics for Seven Neuropsychological Assessment Battery (NAB) Test Variables in the Diagnosis of Alzheimer’s Disease 
Applied neuropsychology. Adult  2012;19(2):10.1080/09084282.2011.643947.
Neuropsychological tests are useful for diagnosing Alzheimer’s disease (AD), yet for many tests, diagnostic accuracy statistics are unavailable. We present diagnostic accuracy statistics for seven variables from the Neuropsychological Assessment Battery (NAB) that were administered to a large sample of elderly adults (n = 276) participating in a longitudinal research study at a national AD Center. Tests included Driving Scenes, Bill Payment, Daily Living Memory, Screening Visual Discrimination, Screening Design Construction, and Judgment. Clinical diagnosis was made independent of these tests, and for the current study, participants were categorized as AD (n = 65) or non-AD (n = 211). Receiver operating characteristics curve analysis was used to determine each test’s sensitivity and specificity at multiple cut points, which were subsequently used to calculate positive and negative predictive values at a variety of base rates. Of the tests analyzed, the Daily Living Memory test provided the greatest accuracy in the identification of AD and the two Screening measures required a significant tradeoff between sensitivity and specificity. Overall, the seven NAB subtests included in the current study are capable of excellent diagnostic accuracy, but appropriate understanding of the context in which the tests are used is crucial for minimizing errors.
PMCID: PMC3857936  PMID: 23373577
8.  The Structure and Validity of Self-reported Affect in Mild Cognitive Impairment and Mild Alzheimer’s Disease 
International psychogeriatrics / IPA  2011;23(6):10.1017/S104161021100041X.
This study determined the reliability, validity, and factor structure of self-report emotions in persons with mild Alzheimer’s disease (AD) and mild cognitive impairment (MCI) relative to controls.
Participants (mild AD, n = 73; MCI, n = 159; controls, n = 96) rated current emotions with the Visual Analogue Mood Scales (Stern, 1997).
Internal consistency reliabilities were comparable across groups, as were the factor structures of emotion. Persons with AD reported more negative affect (NA) than persons with MCI and controls. The emotion that most differentiated groups was confusion. NA and PA may be more bipolar in persons with AD than for persons with MCI and controls.
The underlying structure of affect was similar in persons with mild AD, MCI, and controls. Further, persons with MCI appeared to be “transitional” between cognitive health and dementia with regard to mood and affect. That is, participants with MCI tended to have affect scores that were intermediate between those with AD and controls. Implications for interventions to improve emotional well-being in AD and MCI are discussed.
PMCID: PMC3827970  PMID: 21429280
visual analogue scales; positive affect; negative affect; factor structure; emotion; self-report; dementia
9.  Commentary: Dementia has a Categorical, not Dimensional, Latent Structure 
Psychology and aging  2012;27(3):791-797.
Recently, Walters (2010) published a taxometric study suggesting a dimensional latent structure for the construct of dementia. However, because that study did not conceptualize dementia according to accepted conventions (i.e., there were no measures of cognitive change or independent functioning), its results may represent a false negative error caused by insufficient content coverage. We replicated Walters (2010), using the same taxometric methods and the same data source, but with indicators of cognitive change and functional independence. The current results support a categorical interpretation of dementia, while Walters’ (2010) results suggest that cognitive ability, rather than dementia, is dimensional in nature.
PMCID: PMC3445289  PMID: 22962922
taxometrics; latent structure; dementia; neuropsychological
10.  Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model 
Science translational medicine  2012;4(134):134ra60.
Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.
PMCID: PMC3739428  PMID: 22593173
11.  Jewish Physicians' Beliefs and Practices Regarding Religion/Spirituality in the Clinical Encounter 
Journal of religion and health  2011;50(4):806-817.
We used data from a 2003 survey of US physicians to examine differences between Jewish and other religiously affiliated physicians on 4-D of physicians' beliefs and practices regarding religion and spirituality (R/S) in the clinical encounter. On each dimension, Jewish physicians ascribed less importance to the effect of R/S on health and a lesser role for physicians in addressing R/S issues. These effects were partially mediated by lower levels of religiosity among Jewish physicians and by differences in demographic and practice-level characteristics. The study provides a salient example of how religious affiliation can be an important independent predictor of physicians' clinically-relevant beliefs and practices.
PMCID: PMC3632252  PMID: 21706257
Religion; Spirituality; Judaism; Physician; Clinical encounter
12.  Anxiety of Alzheimer’s disease patients before and after a standardized on-road driving test 
A large number of licensed elderly drivers are demented or are likely to become demented. On-road driving tests, a method often used to assess driver competency, are likely anxiety-provoking for elderly individuals. This article examines the relationship between anxiety and driving performance in a mildly demented and elderly control (EC) sample.
Anxiety ratings of fear and tension, as assessed by visual analog scales, of 84 patients clinically diagnosed with mild Alzheimer’s disease (AD) (68 safe/marginal and 16 unsafe drivers) were compared with those of 44 age- and education-equated safe/marginal EC participants, both before and after a standardized on-road driving test.
Analyses revealed significant positive correlations between AD patients’ pre–road test and post–road test tension and post–road test fear ratings and total road test score. Subsequent analyses of variance showed no significant pre–road test differences in fear ratings between the three groups but significantly higher levels of tension among the unsafe AD participants. After adjusting for baseline group differences, unsafe AD drivers experienced stable or higher anxiety levels after road test, whereas both the EC and safe/marginal AD drivers endorsed a significant reduction in anxiety.
Unlike their safe EC and safe AD driver counterparts, unsafe AD patients reported continued elevated levels of fear and tension after the road test. Given these findings, we suggest that the most appropriate time for driving instructors to counsel patients regarding their driving skills might be directly after the road test.
PMCID: PMC3598633  PMID: 19595915
Alzheimer’s disease; Driving; Road test; Anxiety; Visual analog mood scales
13.  Hypotheses on the evolution of hyaluronan: A highly ironic acid 
Glycobiology  2013;23(4):398-411.
Hyaluronan is a high-molecular-weight glycosaminoglycan (GAG) prominent in the extracellular matrix. Emerging relatively late in evolution, it may have evolved to evade immune recognition. Chondroitin is a more ancient GAG and a possible hyaluronan precursor. Epimerization of a 4-hydroxyl in N-acetylgalactosamine in chondroitin to N-acetylglucosamine of hyaluronan is the only structural difference other than chain length between these two polymers. The axial 4-hydroxyl group extends out perpendicular from the equatorial plane of N-acetylgalactosamine in chondroitin. We suspect that this hydroxyl is a prime target for immune recognition. Conversion of a thumbs-up hydroxyl group into a thumbs-down position in the plane of the sugar endows hyaluronan with the ability to avoid immune recognition. Chitin is another potential precursor to hyaluronan. But regardless whether of chondroitin or of chitin origin, an ancient chondroitinase enzyme sequence seems to have been commandeered to catalyze the cleavage of the new hyaluronan substrate. The evolution of six hyaluronidase-like sequences in the human genome from a single chondroitinase as found in Caenorhabditis elegans can now be traced. Confirming our previous predictions, two duplication events occurred, with three hyaluronidase-like sequences occurring in the genome of Ciona intestinalis (sea squirt), the earliest known chordate. This was probably followed by en masse duplication, with six such genes present in the genome of zebra fish onwards. These events occurred, however, much earlier than predicted. It is also apparent on an evolutionary time scale that in several species, this gene family is continuing to evolve.
PMCID: PMC3581078  PMID: 23315448
chondroitin; evolution; hyaluronan; hyaluronidase; immunology
14.  Long Term Consequences: Effects on Normal Development Profile after Concussion 
Each year in the United States, approximately 1.7 million people are diagnosed with a traumatic brain injury (TBI); an estimated 75% of these injuries are classified as mild TBIs (mTBI) or concussions. The symptoms of such injuries include a variety of somatic, cognitive, and behavioral deficits. While these symptoms typically resolve in a matter of weeks, both children and adults may suffer from Post-Concussion Syndrome (PCS) for months or longer. Suffering from PCS-related symptoms for an extended time may delay an individual’s return to work, adversely affect one’s quality of life, and result in additional social and economic costs. Though a consensus has not been reached on the cause of long-term PCS, it is likely that biological, physiological, psychological, and social elements all play a role in symptom persistence. Additionally, persistent PCS may adversely affect one’s developmental trajectory. The enduring effects of head trauma are not limited to PCS-related effects, however. A progressive tauopathy, chronic traumatic encephalopathy (CTE) is believed to stem from repeated brain trauma. While CTE was originally associated with boxing, it has recently been found in other cases of repetitive head injury including former football and hockey players, and professional wrestlers. In addition to this observed pathology, repetitive brain trauma is also associated with Alzheimer’s-like dementia, Parkinsonism, and motor neuron disease including Amyotrophic Lateral Sclerosis (ALS). With these significant long-term effects of head injuries, there is a clear need to develop effective diagnoses, treatments, and education plans to reduce future burden and incidence.
PMCID: PMC3208826  PMID: 22050943
concussion; development; chronic traumatic encephalopathy; postconcussion syndrome; youth
15.  Driving Scenes test of the Neuropsychological Assessment Battery (NAB) and on-road driving performance in aging and very mild dementia 
The Driving Scenes test of the new Neuropsychological Assessment Battery (NAB; [Stern, R.A., & White, T. (2003a). Neuropsychological Assessment Battery. Lutz, FL: Psychological Assessment Resources, Inc.]) measures several aspects of visual attention thought to be important for driving ability. The current study examined the relationship between scores on the Driving Scenes test and on-road driving performance on a standardized driving test. Healthy participants performed significantly better on the Driving Scenes test than did very mildly demented participants. A correlation of 0.55 was found between the brief, office-based Driving Scenes test and the 108-point on-road driving score. Furthermore, the Driving Scenes test scores differed significantly across the driving instructor’s three global ratings (safe, marginal, and unsafe), and results of a discriminant function analysis indicated that the Driving Scenes test correctly classified 66% of participants into these groups. Thus, the new NAB Driving Scenes test appears to have good ecological validity for real-world driving ability in normal and very mildly demented older adults.
PMCID: PMC3292213  PMID: 15708731
Driving; Aging; Dementia; Neuropsychology; Attention; Visual
16.  Helmets and Mouth Guards: The Role of Personal Equipment in Preventing Sport-Related Concussions 
Clinics in sports medicine  2011;30(1):145-163.
Every year, millions of athletes in the United States experience concussions. With athletes at all levels of play getting bigger, faster, and stronger, it has been suggested that newer technologies may provide an opportunity to reduce the risk and severity of these all too frequent injuries. Although helmets have been shown to decrease the rate of catastrophic head injuries, and mouth guards have decreased the risk of dental and oral injuries, the protective effect of helmets and mouth guards on concussions has not been conclusively demonstrated. In this review, the current literature pertaining to the effect that equipment has on concussions is evaluated. Understanding the role that this equipment plays in preventing concussions is complicated by many factors, such as selection bias in non-randomized studies, variations in playing style, and risk compensation in sports with mandatory protective equipment. At this point, there is little evidence supporting the use of specific helmets or mouth guards to prevent concussions outside of specific sports such as cycling, skiing, and snowboarding. Improving coach and player education about proper concussion management, encouraging neck strengthening exercises, and minimizing high-risk impacts may provide a more fruitful avenue to reduce concussions in sports.
PMCID: PMC2987604  PMID: 21074089
concussion; equipment; helmet; headgear; mouth guard; face shield; sport
17.  Chronic Traumatic Encephalopathy: A Potential Late Effect of Sport-Related Concussive and Subconcussive Head Trauma1 
Clinics in sports medicine  2011;30(1):179-xi.
Chronic traumatic encephalopathy (CTE) is a form of neurodegeneration that is believed to result from repeated head injuries. Originally termed dementia pugilistica due to its association with boxing, the neuropathology of CTE was first described by Corsellis in 1973 in a case series of 15 retired boxers. CTE has recently been found to occur following other causes of repeated head trauma, suggesting that any repeated blows to the head, such as those that occur due to American football, hockey, soccer, professional wrestling, and physical abuse, can also lead to neurodegenerative changes. These changes often include cerebral atrophy, cavum septum pellucidum with fenestrations, shrinkage of the mammillary bodies, dense tau immunoreactive inclusions (neurofibrillary tangles, glial tangles, and neuropil neurites), diffuse axonal injury, and, in some cases, a TDP-43 proteinopathy. In association with these pathological changes, affected individuals often exhibit disordered memory and executive functioning, behavioral and personality disturbances (e.g., apathy, depression, irritability, impulsiveness, suicidality), parkinsonism, and, occasionally, motor neuron disease. At the present time, there are no formal clinical or pathological diagnostic criteria for CTE, but the distinctive neuropathological profile of the disorder lends promise for future research into its prevention, diagnosis, and treatment.
PMCID: PMC2995699  PMID: 21074091
Encephalopathy; Post-Traumatic; Neurodegenerative Disorders; Concussion; Athletic Injuries; Dementia; Motor Neuron Disease
18.  Chain Gangs: New Aspects of Hyaluronan Metabolism 
Hyaluronan is a matrix polymer prominent in tissues undergoing rapid growth, development, and repair, in embryology and during malignant progression. It reaches 107 Daltons in size but also exists in fragmented forms with size-specific actions. It has intracellular forms whose functions are less well known. Hyaluronan occurs in all vertebrate tissues with 50% present in skin. Hyaluronan provides a scaffold on which sulfated proteoglycans and matrix proteins are organized. These supramolecular structures are able to entrap water and ions to provide tissues with hydration and turgor. Hyaluronan is recognized by membrane receptors that trigger intracellular signaling pathways regulating proliferation, migration, and differentiation. Cell responses are often dependent on polymer size. Catabolic turnover occurs by hyaluronidases and by free radicals, though proportions between these have not been determined. New aspects of hyaluronan biology have recently become realized: involvement in autophagy, in the pathology of diabetes., the ability to modulate immune responses through effects on T regulatory cells and, in its fragmented forms, by being able to engage several toll-like receptors. It is also apparent that hyaluronan synthases and hyaluronidases are regulated at many more levels than previously realized, and that the several hyaluronidases have functions in addition to their enzymatic activities.
PMCID: PMC3246691  PMID: 22216413
19.  Mild traumatic brain injury: a risk factor for neurodegeneration 
Recently, it has become clear that head trauma can lead to a progressive neurodegeneration known as chronic traumatic encephalopathy. Although the medical literature also implicates head trauma as a risk factor for Alzheimer's disease, these findings are predominantly based on clinical diagnostic criteria that lack specificity. The dementia that follows head injuries or repetitive mild trauma may be caused by chronic traumatic encephalopathy, alone or in conjunction with other neurodegenerations (for example, Alzheimer's disease). Prospective longitudinal studies of head-injured individuals, with neuropathological verification, will not only improve understanding of head trauma as a risk factor for dementia but will also enhance treatment and prevention of a variety of neurodegenerative diseases.
PMCID: PMC2919698  PMID: 20587081
20.  Thyroid Hormone Levels in the Prefrontal Cortex of Post-Mortem Brains of Alzheimer’s Disease Patients 
Current aging science  2008;1(3):175-181.
Converging evidence suggests a possible link between thyroid state and Alzheimer’s disease (AD), including a higher probability of dementia in individuals with higher TSH levels and a two-fold risk of AD in patients with hypothyroidism. Thyroid hormones modulate factors associated with AD, including amyloid precursor protein expression in the brain, suggesting a possible role for thyroid hormone in AD pathology. The present study is the first to directly evaluate brain thyroid hormone levels in AD. Triiodothyronine (T3) and thyroxine (T4) levels were measured with radioimmunoassay (RIA) in post-mortem samples of prefrontal cortex of patients with pathologically confirmed AD, including Braak stage I–II (n=8), Braak stage V–VI (n=8), and controls without any primary neurological disease (n=8). T4 levels did not differ between groups. T3 levels were significantly lower in Braak stage V–VI brains relative to controls, but there was no statistically significant difference between T3 levels in Braak stage I–II versus controls. Results suggest that the conversion of T4 to T3 may be affected in advanced AD, perhaps due to alterations in deiodinase activity. Reduced conversion of T4 to T3 in AD may be associated with both AD pathology and the clinical presentation of dementia.
PMCID: PMC2953721  PMID: 20021390
Thyroid hormones; thyroxine; Alzheimer’s disease; dementia
21.  TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy 
Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43 kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43–positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.
PMCID: PMC2951281  PMID: 20720505
Amyotrophic lateral sclerosis; Chronic brain injury; Motor neuron disease; Sports; Tau proteins; TDP-43
22.  Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy following Repetitive Head Injury 
Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed “dementia pugilistica” and more recently, chronic traumatic encephalopathy (CTE). We review the 47 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 professional athletes: one football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, Parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular, patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. CTE is a neuropathologically distinct, slowly progressive tauopathy with a clear environmental etiology.
PMCID: PMC2945234  PMID: 19535999
Athletes; Concussion; Dementia; Encephalopathy; Neurodegeneration; Tau protein; Traumatic brain injury
23.  Clock Drawing Test Ratings by Dementia Specialists: Interrater Reliability and Diagnostic Accuracy 
The authors aim to study subjective ratings of clock drawing test by clinicians and determine interrater reliability and diagnostic accuracy. The clock drawing test has been advocated over the Mini-Mental State Examination as an office screening test for dementia, but use of the clock drawing test by neurologists and dementia specialist clinicians has not been validated. The authors conducted a study of clock drawing test scoring by dementia specialists. The authors randomly assigned 25 clocks from each of six predetermined groups based on consensus diagnosis (cognitive comparison subjects, subjects with a memory complaint but with normal neuropsychological testing, subjects with probable and possible mild cognitive impairment, and subjects with possible and probable Alzheimer’s disease) to dementia specialists for blinded scoring using a binary yes/no impairment system and a 0–10 scale as subjectively determined by each individual clinician rater. The authors collapsed the six groups into three (comparison subjects, mild cognitive impairment patients, and Alzheimer’s disease patients) and analyzed interrater reliability, sensitivity, and specificity for consensus diagnosis of mild cognitive impairment, and Alzheimer’s disease. The authors found excellent interrater reliability, sensitivity, and specificity for predicting consensus diagnosis. The 0–10 clock drawing test rating scale was more predictive of consensus diagnosis than the binary impairment scale. Based on the five clinicians’ average dichotomous rating, the clinicians differentiated comparison and Alzheimer’s disease participants with a sensitivity of 0.75 and a specificity of 0.81. For three of the four comparisons, a cutoff score of two or greater resulted in the maximization of sensitivity and specificity for differentiating diagnostic groups. A cutoff score of four or greater maximized sensitivity (0.54) and specificity (0.74) for differentiating Alzheimer’s disease from mild cognitive impairment. Based on rating systems, clock drawing test scoring by dementia clinicians had excellent interrater reliability and sensitivity for differentiating the mild Alzheimer’s disease subjects from comparison subjects. When utilizing a binary rating scale for the clock drawing test in the absence of clinical information, dementia specialist clinicians at the Boston Medical Center were moderately sensitive and highly specific in separating mild cognitive impairment from healthy comparison subjects. These dementia clinicians were also highly sensitive and less specific in differentiating mild cognitive impairment from Alzheimer’s disease.
PMCID: PMC2938787  PMID: 20160214
24.  Predicting cognitive decline and conversion to Alzheimer's disease in older adults using the NAB List Learning test 
To validate the Neuropsychological Assessment Battery (NAB) List Learning test as a predictor of future multi-domain cognitive decline and conversion to Alzheimer's disease (AD), participants from a longitudinal research registry at a national AD Center were, at baseline, assigned to one of three groups (control, mild cognitive impairment [MCI], or AD), based solely on a diagnostic algorithm for the NAB List Learning test (Gavett et al., 2009), and followed for 1–3 years. Rate of change on common neuropsychological tests and time to convert to a consensus diagnosis of AD were evaluated to test the hypothesis that these outcomes would differ between groups (AD>MCI>control). Hypotheses were tested using linear regression models (n = 251) and Cox proportional hazards models (n = 265). The AD group declined significantly more rapidly than controls on Mini-Mental Status Examination (MMSE), animal fluency, and Digit Symbol; and more rapidly than the MCI group on MMSE and Hooper Visual Organization Test. The MCI group declined more rapidly than controls on animal fluency and CERAD Trial 3. The MCI and AD groups had significantly shorter time to conversion to a consensus diagnosis of AD than controls. The predictive validity of the NAB List Learning algorithm makes it a clinically useful tool for the assessment of older adults.
PMCID: PMC2922010  PMID: 20374677
Memory; Dementia; Differential diagnosis; Aging; Neuropsychology; Neuropsychological tests
25.  A Questionnaire for the Assessment of the Multiple Dimensions of Motion Sickness 
A limited number of attempts have been made to develop a questionnaire that assesses the experience of motion sickness. Further, many available questionnaires quantify motion sickness as a unidimensional construct
Exploratory and confirmatory factor analyses of motion sickness descriptors were used to derive and verify four dimensions of motion sickness, which were defined as gastrointestinal, central, peripheral, and sopite-related. These dimensions of motion sickness were then used to construct a motion sickness assessment questionnaire (MSAQ) that was administered to individuals who were exposed to a rotating optokinetic drum.
Total scores from the MSAQ correlated strongly with overall scores from the Pensacola Diagnostic index (r = 0.81, p < 0.001) and the Nausea Profile (r = 0.92, p < 0.001).
The MSAQ is a valid instrument for the assessment of motion sickness. In addition, the MSAQ may be used to assess motion sickness as a multidimensional rather than unidimensional construct
PMCID: PMC2910410  PMID: 11211039
factor analysis; motion sickness; questionnaire

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