Teemu M. Luoto

Apolipoprotein E―Dependent Accumulation of Alzheimer Disease―Related Lesions Begins in Middle Age

To study the prevalence and age dependency of senile plaques (SP) and neurofibrillary tangles (NFT), the brain changes characteristic of Alzheimer disease (AD), and their association with apolipoprotein E (APOE) genotypes in a community‐dwelling normal population.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gene Is a Risk Factor of Large-Vessel Atherosclerosis Stroke

Background/Purpose Genetic variation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene has been recently identified as an important determinant of plasma LDL-cholesterol and severity of coronary heart disease. We studied whether the PCSK9 gene is linked to the risk of ischemic stroke (IS) and with the development of intracranial atherosclerosis. Methods/Results The pivotal E670G polymorphism, tagging an important haplotype of the PCSK9 gene, was genotyped in two independent studies. The Belgium Stroke Study included 237 middle aged (45–60) Belgian patients, with small-vessel occlusion (SVO) and large-vessel atherosclerosis stroke (LVA), and 326 gender and ethnicity matched controls (>60 yrs) without a history of stroke. In multivariate analysis the minor allele (G) carriers appeared as a significant predictor of LVA (OR = 3.52, 95% CI 1.25–9.85; p = 0.017). In a Finnish crossectional population based consecutive autopsy series of 604 males and females (mean age 62.5 years), G-allele carriers tended to have more severe allele copy number-dependent (p = 0.095) atherosclerosis in the circle of Willis and in its branches. Conclusion Our findings in this unique combination of clinical and autopsy data, provide evidence that PCSK9 gene associates with the risk of LVA stroke subtype, and suggest that the risk is mediated by the severity of intracranial atherosclerosis.

Who Gets Recruited in Mild Traumatic Brain Injury Research

Selection bias, common in traumatic brain injury research, limits the clinical usefulness and generalizability of study findings. The purpose of this study was to examine the effect of different inclusion and exclusion criteria on patient enrollment, and the implications for generalizability, in a mild traumatic brain injury (MTBI) study. The study was conducted at the emergency department (ED) of Tampere University Hospital. Our aim was to study outcome from MTBI in patients who do not have pre-existing conditions or other confounding factors. For this, all consecutive patients with acute head trauma (n=1344) were screened. The study design included three inclusion criteria and nine exclusion criteria. The World Health Organization Collaborating Center for Neurotrauma Task Force criteria for MTBI were used. Of all patients screened, 934 (69.5%) fulfilled the MTBI criteria. For those fulfilling the MTBI criteria, various inclusion and exclusion criteria were applied in order to yield those eligible for the outcome study. Applying these criteria excluded 95.1% of MTBI patients, leaving only 46 patients in the final sample. The final sample and the excluded patients with MTBI significantly differed in age, mechanism of injury, and injury severity characteristics. Many studies recruit fundamentally biased samples that are not generalizable to the population of persons who sustain an MTBI. Studying carefully selected samples is often necessary to address specific research questions, but such studies have serious limitations in terms of translating research findings into clinical practice.

Acute mild traumatic brain injury is not associated with white matter change on diffusion tensor imaging

This study was designed to (i) evaluate the influence of age on diffusion tensor imaging measures of white matter assessed using tract-based spatial statistics; (ii) determine if mild traumatic brain injury is associated with microstructural changes in white matter, in the acute phase following injury, in a large homogenous sample that was carefully screened for pre-injury medical, psychiatric, or neurological problems; and (iii) examine if injury severity is related to white matter changes. Participants were 75 patients with acute mild traumatic brain injury (age = 37.2 ± 12.0 years, 45 males and 30 females) and 40 controls (age = 40.6 ± 12.2 yrs, 20 males and 20 females). Age effects were analysed by comparing control subgroups aged 31-40, 41-50, and 51-60 years against a group of 18-30-year-old control subjects. Widespread statistically significant areas of abnormal diffusion tensor measures were observed in older groups. Patients and controls were compared using age and gender as covariates and in age- and gender-matched subgroups. Subgroups of patients with more severe injuries were compared to age-and gender-matched controls. No significant differences were detected in patient-control or severity analyses (all P-value > 0.01). In this large, carefully screened sample, acute mild traumatic brain injury was not associated with diffusion tensor imaging abnormalities detectable with tract-based spatial statistics.

Recovery from Mild Traumatic Brain Injury in Previously Healthy Adults.

This prospective longitudinal study reports recovery from mild traumatic brain injury (MTBI) across multiple domains in a carefully selected consecutive sample of 74 previously healthy adults. The patients with MTBI and 40 orthopedic controls (i.e., ankle injuries) completed assessments at 1, 6, and 12 months after injury. Outcome measures included cognition, post-concussion symptoms, depression, traumatic stress, quality of life, satisfaction with life, resilience, and return to work. Patients with MTBI reported more post-concussion symptoms and fatigue than the controls at the beginning of recovery, but by 6 months after injury, did not differ as a group from nonhead injury trauma controls on cognition, fatigue, or mental health, and by 12 months, their level of post-concussion symptoms and quality of life was similar to that of controls. Almost all (96%) patients with MTBI returned to work/normal activities (RTW) within the follow-up of 1 year. A subgroup of those with MTBIs and controls reported mild post-concussion-like symptoms at 1 year. A large percentage of the subgroup who had persistent symptoms had a modifiable psychological risk factor at 1 month (i.e., depression, traumatic stress, and/or low resilience), and at 6 months, they had greater post-concussion symptoms, fatigue, insomnia, traumatic stress, and depression, and worse quality of life. All of the control subjects who had mild post-concussion-like symptoms at 12 months also had a mental health problem (i.e., depression, traumatic stress, or both). This illustrates the importance of providing evidence-supported treatment and rehabilitation services early in the recovery period.

Large Vessel Cerebral Atherosclerosis Is Not in Direct Association with Neuropathological Lesions of Alzheimer’s Disease

Introduction: Cerebral hypoperfusion caused by large vessel atherosclerosis has been suggested to be associated with the pathogenesis of sporadic Alzheimer’s disease (AD). Atherosclerosis and AD share risk factors such as age, diabetes, hypercholesterolemia, hypertension and apolipoprotein E ε4 (APOE ε4) allele. We studied the association between atherosclerosis of the circle of Willis (CW) and AD neuropathology in a large autopsy sample. Methods: The present study comprised a consecutive autopsy series (n = 466) representing noninstitutionalized general population aged 50 years and over (mean 70.8, SD 11.5 years). The atherosclerosis of CW was scored semiquantitatively and the amyloid plaque (AP) load in the frontal cortex and the number of neurofibrillary tangles (NFT) in the hippocampus were measured. Results: In a linear regression model, AP percentage area was associated with age (p < 0.0001) and APOE ε4 allele (p < 0.0001), but not with CW score (p = 0.70) or gender (p = 0.11). Similarly, the NFT count was predicted only by age (p > 0.0001), and not by CW score (p = 0.36), gender (p = 0.41) or APOE ε4 allele (p = 0.072). Conclusion: Our results suggest that cerebral large vessel atherosclerosis is not in direct association with APs or NFTs – hallmarks of AD neuropathology.

Assessment of mild traumatic brain injury with the King-Devick Test in an emergency department sample.

Abstract Objective: The King-Devick Test® (K-D) is a brief measure of cognitive processing speed and rapid gaze shifting that appears sensitive to the effects of sport-related concussion. This study evaluated its diagnostic and incremental validity in civilian patients with mild traumatic brain injury (MTBI). Methods: Participants with MTBI (n = 26) and controls with non-head injuries (n = 33) were prospectively recruited from an Emergency Department (ED). They underwent a clinical evaluation including the K-D test and the Sport Concussion Assessment Tool 2 (SCAT2). Magnetic resonance imaging (MRI) was conducted within 10 days post-injury. Results: The patients with MTBI differed from those without MTBI on components of the SCAT2, including the Symptom Scale (Cohen’s d = 1.02–1.15, p < 0.001) and Standardized Assessment of Concussion (d = 0.81, p = 0.004), but not the K-D test (d = 0.40, p = 0.148). In a logistic regression analysis, the K-D Test did not contribute over and above these two measures in predicting group membership (MTBI vs. control), p = 0.191. Low K-D Test scores in the MTBI group (<1 SD below controls) were not associated with poor SCAT2 performance, loss of consciousness or traumatic abnormalities on MRI, suggesting these cases may have been false positives. Conclusions: The present findings do not support the K-D Test for the assessment of civilian MTBI in an ED setting.

Resilience is associated with outcome from mild traumatic brain injury

Resilient individuals manifest adaptive behavior and are better able to recover from adversity. The association between resilience and outcome from mild traumatic brain injury (mTBI) is examined, and the reliability and validity of the Resilience Scale and its short form in mTBI research is evaluated. Patients with mTBI (n=74) and orthopedic controls (n=39) completed the Resilience Scale at one, six, and 12 months after injury. Additionally, self-reported post-concussion symptoms, fatigue, insomnia, pain, post-traumatic stress, and depression, as well as quality of life, were evaluated. The internal consistency of the Resilience Scale and the short form ranged from 0.91 to 0.93 for the mTBI group and from 0.86 to 0.95 for controls. The test-retest reliability ranged from 0.70 to 0.82. Patients with mTBI and moderate-to-high resilience reported significantly fewer post-concussion symptoms, less fatigue, insomnia, traumatic stress, and depressive symptoms, and better quality of life, than the patients with low resilience. No association between resilience and time to return to work was found. Resilience was associated with self-reported outcome from mTBI, and based on this preliminary study, can be reliably evaluated with Resilience Scale and its short form in those with mTBIs.

Associations of apolipoprotein E gene with ischemic stroke and intracranial atherosclerosis

The apolipoprotein E (APOE) ɛ4 allele is associated with elevated cholesterol and risk of atherosclerosis. However, its role in ischemic stroke (IS) remains controversial. We investigated a possible link between IS or the severity of intracranial atherosclerosis and the APOE promoter polymorphisms −219G/T and +113G/C, involved in regulating APOE transcription. We genotyped subjects from a multicentric Belgian case–control study, including 237 middle-aged patients with IS due to small- or large-vessel atherosclerotic stroke and 326 ethnicity- and gender-matched controls and a Finnish autopsy series of 1004 non-stroke cases, who had received a quantitative score of atherosclerosis in the circle of Willis. The APOE ɛ4+ genotype did not associate with IS, but was related to more severe intracranial atherosclerosis score in men (5.4 vs 4.6, P=0.044). Within the most common APOE ɛ3/ɛ3 genotype group, the risk of IS associated with the G-allele of the tightly linked −219G/T (OR=6.2; 95% CI: 1.6–24.3, P=0.009) and +113G/C (OR=7.1; 95% CI: 1.7–29.9, P=0.007) promoter polymorphisms. There was no difference in the severity of intracranial atherosclerosis between −219G/G genotype carriers and non-carriers. This study suggests a multifaceted role of apoE on the risk of cerebrovascular diseases. The APOE ɛ4+ genotype did not predict the risk of IS but was associated with severity of subclinical intracranial atherosclerosis in men on the autopsy study. In contrast, the promoter variants were significant predictors of IS, suggesting that quantitative rather than qualitative variation of apoE is related to IS.

Sport Concussion Assessment Tool 2 in a civilian trauma sample with mild traumatic brain injury

The aim of the study was to evaluate the validity of the Sport Concussion Assessment Tool-Second Edition (SCAT2) in patients with acute mild traumatic brain injuries (mTBIs) in a civilian trauma setting. In addition, the SCAT2 was compared to the Military Acute Concussion Evaluation (MACE). All the participants of the study were prospectively recruited from the emergency department of Tampere University Hospital (Tampere, Finland). Patients (n=49) between the ages of 18 and 60 years, with no premorbid medical or psychiatric conditions, who met the World Health Organization criteria for mTBI, were enrolled. Trauma controls (n=33) were recruited using similar study criteria. The main measures of the study consisted of SCAT2, MACE, and mTBI severity markers, including neuroimaging (computed tomography and conventional magnetic resonance imaging [MRI]), and 1-month clinical outcomes (postconcussion syndrome diagnosis and return to work status). The scoreable components of the SCAT2 performed variably across five dimensions of validity (diagnostic, criterion, divergent, predictive, and responsiveness). The Standardized Assessment of Concussion component reasonably discriminated mTBI patients from controls, was associated with MRI lesions, improved over time, and predicted return to work. Symptom scores differentiated patients with mTBIs from controls, and elevated initial symptom scores in patients with mTBI were associated with a greater risk of persistent postconcussion symptoms. The SCAT2 was superior to the MACE. The SCAT2 appears useful for detecting acute mTBI-related symptoms and cognitive impairment, refining prognosis, and monitoring recovery.