Clinical Ratings of White Matter Hyperintensities, Hippocampal Ratings, and Neuropsychological Functioning from The Cache County Memory Study.

Objective: White matter burden and medial temporal atrophy are associated with cognitive health. A large epidemiological database, such as the Cache County Memory Study (CCMS), can provide additional insight into how visual clinical ratings of brain structural integrity predict cognition in older adults. Method: We used the Scheltens Ratings Scale to quantify white matter lesion burden and medial temporal atrophy in the CCMS sample to determine if these qualitative markers are predictive of memory function. We performed clinical ratings of MRI scans across two ascertainment periods among 187 community-dwelling older adults and correlated these ratings with MMSE, CERAD memory performance, and general cognitive ability. Results: Higher Scheltens ratings measuring white matter and basal ganglia hyperintensities were associated with lower memory performance (r = 0.21). The strongest correlations were observed between medial temporal atrophy and general cognition performance (r = 0.32). Conclusions: The current findings support previous research that the integrity of different regions of the brain correlate to function in a meaningful way.

MRI Clinical Ratings and Cognitive Function in a Cross-Sectional Population Study of Dementia: The Cache County Memory Study.

BACKGROUND: White matter integrity in aging populations is associated with increased risk of cognitive decline, dementia diagnosis, and mortality. Population-based data can elucidate this association. OBJECTIVES: To examine the association between white matter integrity, as measured by a clinical rating scale of hyperintensities, and mental status in older adults including advanced aging. DESIGN: Scheltens Ratings Scale was used to qualitatively assess white matter (WM) hyperintensities in participants of the Cache County Memory Study (CCMS), an epidemiological study of Alzheimer's disease in an exceptionally long-lived population. Further, the relation between Mini-Mental State Exam (MMSE) and WM hyperintensities were explored. METHOD: Participants consisted of 415 individuals with dementia and 22 healthy controls. RESULTS: CCMS participants, including healthy controls, had high levels of WM pathology as measured by Scheltens Ratings Scale score. While age did not significantly relate to WM pathology, higher Scheltens Ratings Scale scores were associated with lower MMSE findings (correlation between -0.14 and -0.22; p < .05). CONCLUSIONS: WM pathology was common in this county-wide population sample of those ranging in age from 65 to 106. Increased WM burden was found to be significantly associated with decreased overall MMSE performance.

Multivariate characterization of white matter heterogeneity in autism spectrum disorder.

The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.

Brainstem white matter integrity is related to loss of consciousness and postconcussive symptomatology in veterans with chronic mild to moderate traumatic brain injury.

We investigated associations between DTI indices of three brainstem white matter tracts, traumatic brain injury (TBI) injury characteristics, and postconcussive symptomatology (PCS) in a well-characterized sample of veterans with history of mild to moderate TBI (mTBI). 58 military veterans (mTBI: n = 38, mean age = 33.2, mean time since injury = 90.9 months; military controls [MC]; n = 20; mean age = 29.4) were administered 3T DTI scans as well as a comprehensive neuropsychiatric evaluation including evaluation of TBI injury characteristics and PCS symptoms (e.g., negative mood, dizziness, balance and coordination difficulties). Tractography was employed by seeding ROIs along 3 brainstem white matter tracts (i.e., medial lemniscus-central tegmentum tract [ML-CTT]; corticospinal tracts [CST], and pontine tegmentum [PT]), and mean DTI values were derived from fractional anisotropic (FA) maps. Results showed that there were no significant difference in FA between the MC and TBI groups across the 3 regions of interest; however, among the TBI group, CST FA was significantly negatively associated with LOC duration. Additionally, lower FA of certain tracts-most especially the PT-was significantly associated with increased PCS symptoms (i.e., more severe vestibular symptoms, poorer physical functioning, and greater levels of fatigue), even after adjusting for PTSD symptoms. Our findings show that, in our sample of veterans with mTBI, tractography-based DTI indices of brainstem white matter tracts of interest are related to the presence and severity of PCS symptoms. Findings are promising as they show linkages between brainstem white matter integrity and injury severity (LOC), and they raise the possibility that the pontine tegmentum in particular may be a useful marker of PCS symptoms. Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following the 'signature injury' of our combat-exposed veterans.

Community versus orthopaedic controls in traumatic brain injury research: how comparable are they?

BACKGROUND: Community (CC) or orthopaedic/injury (OC) control groups are typically used to evaluate the consequences of traumatic brain injuries (TBIs). Whereas CCs match for demographic variables and are readily available, OCs may additionally control for other pre- and post-injury variables but are more costly to recruit. Together, they enable an evaluation of brain- vs general-injury effects. However, the comparability of these two groups and the increase in control over confounding variables when OCs are used has rarely been examined. METHOD: The current study compared samples of CCs (n = 71) and OCs (n = 69), aged between 18-80, on a range of demographic (age, gender, education, socio-economic status), background (medical history, handedness), psychosocial (alcohol use, fatigue, pain, depression, social support, community integration, 'post-concussion' symptoms) and cognitive (motor and processing speed, memory, intellectual ability) variables. RESULTS: The two groups were comparable on all variables, except alcohol use, with the OC group having higher levels of alcohol consumption. However, alcohol use did not correlate with any other variable, including commonly used measures of outcome following TBI. CONCLUSION: The current findings suggest that an orthopaedic injury control group does not have any clear advantages over a carefully recruited community control group.

Introduction to the brain imaging and behavior special issue on neuroimaging findings in mild traumatic brain injury.

Contemporary neuroimaging methods and research findings in mild traumatic brain injury (mTBI) are reviewed in this special issue. Topics covered include structural and functional neuroimaging techniques with a particular emphasis on the most contemporary research involving magnetic resonance imaging (MRI). Future research directions as well as applied applications of using neuroimaging techniques to define biomarkers of brain injury are covered.

Intact Prototype Formation but Impaired Generalization in Autism.

Cognitive processing in autism has been characterized by a difficulty with the abstraction of information across multiple stimuli or situations and subsequent generalization to new stimuli or situations. This apparent difficulty leads to the suggestion that prototype formation, a process of creating a mental summary representation of multiple experienced stimuli that go together in a category, may be impaired in autism. Adults with high functioning autism and a typically developing comparison group matched on age and IQ completed a random dot pattern categorization task. Participants with autism demonstrated intact prototype formation in all four ways it was operationally defined, and this performance was not significantly different from that of control participants. However, participants with autism categorized dot patterns that were more highly distorted from the category prototypes less accurately than did control participants. These findings suggest, at least within the constraints of the random dot pattern task, that although prototype formation may not be impaired in autism, difficulties may exist with the generalization of what has been learned about a category to novel stimuli, particularly as they become less similar to the category's prototype.

A population-based study on the influence of brain atrophy on 20-year survival after age 85.

BACKGROUND: Individuals aged 80 years and older is the fastest growing segment of the population worldwide. To understand the biology behind increasing longevity, it is important to examine factors related to survival in this age group. The relationship between brain atrophy and survival after age 85 remains unclear. METHODS: A population-based sample (n = 239) had head CT scans at age 85 and was then followed until death. Cortical atrophy and ventricular size were assessed. Statistical analyses included Cox proportional hazards models with time to death as the outcome and considering a large number of possible confounders, including baseline cognitive function, incident dementia, and somatic disorders. RESULTS: Mean survival time (±SD) was 5.0 ± 3.6 years (range 0.10-19.8 years). Decreased survival was associated with temporal, and frontal atrophy, sylvian fissure width and a number of ventricular measures after adjustment for potential confounders. In participants without dementia at baseline (n = 135), decreased survival was associated with temporal lobe atrophy and bifrontal ratio. In those with dementia (n = 104), decreased survival was associated with third ventricle width, cella media ratio, and ventricle-to-brain and ventricle-to-cranial ratio. CONCLUSIONS: Several indices of brain atrophy were related to decreased survival after age 85, regardless of dementia status. Brain atrophy is rarely mentioned as a significant indicator of survival in the elderly, independent of traditional predictors such as cardiovascular disease or cancer. The biology behind the influence of brain atrophy on survival needs to be further scrutinized.

White matter changes in patients with hypoxic amnesia.

A deficit of declarative memory is a common sequela after a hypoxic episode. While the role of gray matter changes (i.e., atrophy of hippocampal formation) as mainly responsible for memory loss has been emphasized, the role of the white matter damage has so far been neglected. The present study was aimed at evaluating whether white matter damage, within the neural circuitry responsible for declarative memory functioning, is present in anoxic patients. We assessed, by means of voxel-based morphometry, the integrity of white matter regions in five patients with hypoxic amnesia. When anoxic patients were compared to healthy controls, significantly less white matter density was detected in the fornix, anterior portion of the cingulum bundle and uncinate fasciculus bilaterally. We conclude that cerebral hypoxia may alter, together with the hippocampi, the integrity of white matter fibers throughout the memory-limbic system.

Voxel-based analysis of diffusion tensor imaging in mild traumatic brain injury in adolescents.

BACKGROUND AND PURPOSE: DTI of normal-appearing WM as evaluated by conventional MR imaging in mTBI has the potential to identify important regional abnormalities that relate to PCS. VBA was used to examine WM changes in acute mTBI. MATERIALS AND METHODS: WM was assessed between 1 and 6 days postinjury with voxel-based DTI analyses in 10 adolescent patients with mTBI and 10 age-matched control participants. In addition to the voxel-based group, analysis used to identify brain pathology across all patients with mTBI, 2 voxel-based linear regressions were performed. These analyses investigated the relation between 1) the ADC and PCS severity scores, and 2) ADC and scores on the BSI of emotional symptoms associated with mTBI. We hypothesized that frontotemporal WM changes would relate to symptoms associated with PCS and endorsed on the BSI. RESULTS: Patients with mTBI demonstrated significant reductions in ADC in several WM regions and in the left thalamus. As expected, no increases in ADC were found in any region of interest. All injury-affected regions showed decreased radial diffusivity, unchanged AD, and increased FA, which is consistent with axonal cytotoxic edema, reflective of acute injury. CONCLUSIONS: Whole-brain WM DTI measures can detect abnormalities in acute mTBI associated with PCS symptoms in adolescents.

Decreased left posterior insular activity during auditory language in autism.

BACKGROUND AND PURPOSE: Individuals with autism spectrum disorders often exhibit atypical language patterns, including delay of speech onset, literal speech interpretation, and poor recognition of social and emotional cues in speech. We acquired functional MR images during an auditory language task to evaluate systematic differences in language-network activation between control and high-functioning autistic populations. MATERIALS AND METHODS: Forty-one right-handed male subjects (26 high-functioning autistic subjects, 15 controls) were studied by using an auditory phrase-recognition task, and areas of differential activation between groups were identified. Hand preference, verbal intelligence quotient (IQ), age, and language-function testing were included as covariables in the analysis. RESULTS: Control and autistic subjects showed similar language-activation networks, with 2 notable differences. Control subjects showed significantly increased activation in the left posterior insula compared with autistic subjects (P < .05, false discovery rate), and autistic subjects showed increased bilaterality of receptive language compared with control subjects. Higher receptive-language scores on standardized testing were associated with greater activation of the posterior aspect of the left Wernicke area. A higher verbal IQ was associated with greater activation of the bilateral Broca area and involvement of the prefrontal cortex and lateral premotor cortex. CONCLUSIONS: Control subjects showed greater activation of the posterior insula during receptive language, which may correlate with impaired emotive processing of language in autism. Subjects with autism showed greater bilateral activation of receptive-language areas, which was out of proportion to the differences in hand preference in autism and control populations.

Diffusion tensor imaging of acute mild traumatic brain injury in adolescents.

BACKGROUND: Despite normal CT imaging and neurologic functioning, many individuals report postconcussion symptoms following mild traumatic brain injury (MTBI). This dissociation has been enigmatic for clinicians and investigators. METHODS: Diffusion tensor imaging tractography of the corpus callosum was performed in 10 adolescents (14 to 19 years of age) with MTBI 1 to 6 days postinjury with Glasgow Coma Scale score of 15 and negative CT, and 10 age- and gender-equivalent uninjured controls. Subjects were administered the Rivermead Post Concussion Symptoms Questionnaire and the Brief Symptom Inventory to assess self-reported cognitive, affective, and somatic symptoms. RESULTS: The MTBI group demonstrated increased fractional anisotropy and decreased apparent diffusion coefficient and radial diffusivity, and more intense postconcussion symptoms and emotional distress compared to the control group. Increased fractional anisotropy and decreased radial diffusivity were correlated with severity of postconcussion symptoms in the MTBI group, but not in the control group. CONCLUSIONS: In adolescents with mild traumatic brain injury (MTBI) with Glasgow Coma Scale score of 15 and negative CT, diffusion tensor imaging (DTI) performed within 6 days postinjury showed increased fractional anisotropy and decreased diffusivity suggestive of cytotoxic edema. Advanced MRI-based DTI methods may enhance our understanding of the neuropathology of TBI, including MTBI. Additionally, DTI may prove more sensitive than conventional imaging methods in detecting subtle, but clinically meaningful, changes following MTBI and may be critical in refining MTBI diagnosis, prognosis, and management.

The relative contributions of brain, cerebrospinal fluid-filled structures and non-neural tissue volumes to occipital-frontal head circumference in subjects with autism.

An increased prevalence of macrocephaly defined by occipital-frontal circumference (OFC) is a consistent finding in autism. Several possible mechanisms have been proposed, the most compelling being early brain overgrowth. However, the proportion of non-neural tissues (NNT) that contribute to OFC has not been reported. Using quantitative magnetic resonance imaging (MRI) methods we analyzed the relationships between OFC and total brain (TBV), ventricular, surface cerebrospinal fluid (CSF)/meningeal, and NNT volumes in subjects with autism. Sixty male subjects (34 autistic; 26 controls) seven years of age and older were used in this study. Compared to other measures, NNT volume was most significantly related to OFC (r values > 0.8, p 0.06). In contrast, the OFC-TBV relationship was less robust in those with autism (r=0.25, p

Is performance on the Wechsler test of adult reading affected by traumatic brain injury?

OBJECTIVES: The validity of the National Adult Reading Test (NART) as a predictor of premorbid IQ when used with patients who have sustained a traumatic brain injury (TBI) has been questioned in recent years. This study examined whether performance on the Wechsler Test of Adult Reading (WTAR) is similarly affected by TBI in the first year after an injury. DESIGN AND METHOD: The WTAR scores of participants who had sustained a mild TBI (N=82), moderate TBI (N=73), severe TBI (N=61) or an orthopaedic injury (N=95) were compared (cross-sectional study). A subset of 21 mild TBI, 31 moderate TBI, 26 severe TBI and 21 control group participants were additionally reassessed 6 months later to assess the impact of recovery on WTAR scores (longitudinal study). RESULTS: The severe TBI group had significantly lower scores on the WTAR than the mild TBI, moderate TBI and control groups in the cross-sectional study, despite being matched demographically. The findings from the longitudinal study revealed a significant group difference and a small improvement in performance over time but the interaction between group and time was not significant, suggesting that the improvements in WTAR performance over time were not restricted to more severely injured individuals whose performance was temporarily suppressed. CONCLUSIONS: These findings suggest that reading performance may be affected by severe TBI and that the WTAR may underestimate premorbid IQ when used in this context, which may cause clinicians to underestimate the cognitive deficits experienced by these patients.

cerebellar atrophy after moderate-to-severe pediatric traumatic brain injury.

BACKGROUND AND PURPOSE: Although the cerebellum has not attracted the same degree of attention as cortical areas and the hippocampus in traumatic brain injury (TBI) literature, there is limited structural and functional imaging evidence that the cerebellum is also vulnerable to insult. The cerebellum is emerging as part of a frontocerebellar system that, when disrupted, results in significant cognitive and behavioral consequences. We hypothesized that cerebellar volume would be reduced in children following TBI and wished to examine the relation between the cerebellum and known sites of projection, including the prefrontal cortex, thalamus, and pons. MATERIALS AND METHODS: Quantitative MR imaging was used to measure cerebellar white and gray matter and lesion volumes 1-10 years following TBI in 16 children 9-16 years of age and 16 demographically matched typically developing children 9-16 years of age. Cerebellar volumes were also compared with volumetric data from other brain regions to which the cerebellum projects. RESULTS: A significant group difference was found in cerebellar white and gray matter volume, with children in the TBI group consistently exhibiting smaller volumes. Repeating the analysis after excluding children with focal cerebellar lesions revealed that significant group differences still remained for cerebellar white matter (WM). We also found a relation between the cerebellum and projection areas, including the dorsolateral prefrontal cortex, thalamus, and pons in 1 or both groups. CONCLUSION: Our finding of reduced cerebellar WM volume in children with TBI is consistent with evidence from experimental studies suggesting that the cerebellum and its related projection areas are highly vulnerable to fiber degeneration following traumatic insult.

Neuropsychological and information processing performance and its relationship to white matter changes following moderate and severe traumatic brain injury: a preliminary study.

Reductions in information processing speed have frequently been reported following moderate and severe traumatic brain injuries (TBIs), consistent with the effects of diffuse white matter damage. Although the corpus callosum (CC) is a common site for diffuse damage following TBI, the effects of this damage on information processing speed have not been adequately examined. This study assessed a TBI group and a matched control group on tests of attention, memory, fluency, and set shifting ability, together with reaction time (RT) tasks requiring the inter- and intrahemispheric processing of visual and tactile information. The RT tasks were designed to target the cognitive functions that are likely to be affected by diffuse white matter damage, including damage to the CC. The TBI group demonstrated deficits in verbal and visual fluency and verbal memory. They were also slower on the visual and tactile RT tasks, were more affected by task complexity, and slower on RT tasks requiring the interhemispheric transfer of information. In fact, one of the interhemispheric tactile RT tasks proved to be the most discriminating of all the cognitive and RT measures. MRIs completed on a subset of TBI participants indicated that the mean CC measurements were 5% to 19% smaller than a normative control group, with the most atrophied areas being the isthmus and anterior midbody. Although white matter atrophy was moderately related to visual and tactile RT performance, and total hippocampal volume related to memory performance, CC area was not related to many of the tasks that were designed to tap interhemispheric processing. None of the standard cognitive tests correlated with outcome in the TBI group, but 1 of the tactile RT measures was significantly related to 2 measures of outcome.

White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning.

BACKGROUND: Carbon monoxide (CO) poisoning may result in white matter hyperintensities (WMH) and neurocognitive impairments. OBJECTIVE: To assess in a prospective study WMH in CO-poisoned patients and their relationship to cognitive functioning. METHODS: Seventy-three consecutive CO-poisoned patients were studied. MR scans and neurocognitive tests were administered on day 1 (within 36 hours after CO poisoning), 2 weeks, and 6 months. Age- and sex-matched control subjects for white matter analyses only were obtained from the authors' normative imaging database. MR scans were rated for WMH in the periventricular and centrum semiovale regions, using a 4-point rating scale. Two independent raters rated the scans, and a consensus was reached. RESULTS: Thirty percent of CO-poisoned patients had cognitive sequelae. Twelve percent of the CO-poisoned patients had WMH, with significantly more periventricular, but not centrum semiovale, WMH than control subjects. The WMH in CO-poisoned patients did not change from day 1 to 6 months. Centrum semiovale hyperintensities were related to worse cognitive performance. Duration of loss of consciousness correlated with cognitive impairment at all three times. Initial carboxyhemoglobin levels correlated with loss of consciousness but not with WMH or cognitive sequelae. CONCLUSIONS: CO poisoning can result in brain injury manifested by WMH and cognitive sequelae. The WMH were not related to CO poisoning severity. The WMH occurred in both the periventricular and the centrum semiovale regions; however, only those in the centrum semiovale were significantly associated with cognitive impairments.

Brain volume, intracranial volume, and dementia.

RATIONALE AND OBJECTIVES: Using a large magnetic resonance (MR) imaging data set (n = 532), we investigated the utility of total intracranial volume (TICV) as a correction factor for head size variability when assessing total brain volume (TBV) and the subcortical volumes of the temporal horn of the lateral ventricular system and the hippocampus. METHODS: A uniform tissue segmentation procedure (analyze) was used to calculate volumes. Total brain volume was compared with TICV in 357 control subjects and 175 patients with various dementing and neuropsychiatric disorders (mixed dementia/neuropsychiatric group). These MR-based TBV/TICV relationships were compared with actual postmortem (n = 87) values obtained from a study of neurologically healthy subjects at the time of death. Comparisons were also made in which temporal horn and hippocampal volumes were corrected by TICV and TBV. Lastly, the ability of corrected TBV and temporal horn and hippocampal volumes to distinguish subjects in the mixed dementia/neuropsychiatric group from controls was examined by logistic regression. RESULTS: In the control sample, brain volume averaged 9% of TICV, regardless of age. In contrast, TBV in the mixed dementia/neuropsychiatric subjects showed, on average, a 22% reduction compared with TICV. By plotting TBV/TICV curves, highly significant but different regression lines emerged, wherein a reduction in brain volume in conditions of mixed dementia/neuropsychiatric disorder showed a distinct separation from the norm. The TBV/TICV regression line generated from MR imaging in controls did not differ from the postmortem TBV/TICV regression line. Logistic regression showed a 96% correct classification of mixed dementia/neuropsychiatric subjects from controls by using the TBV/TICV ratio. This technique has the advantage that each subject serves as his or her own control. CONCLUSIONS: In cases of dementia and neuropsychiatric disorder in persons 65 and older, TBV corrected by TICV readily differentiated this clinical population from controls. This technique is easy and simple to use and has various clinical applications. For temporal horn and hippocampal volume, corrections with TBV rather than TICV may provide more clinically meaningful corrections.

Verbal memory deficits associated with fornix atrophy in carbon monoxide poisoning.

Magnetic resonance (MR) images and neuropsychological testing data of 69 carbon monoxide (CO) poisoned patients were prospectively obtained within 1 day of CO poisoning, two weeks and six months. CO patients' Day 1 cross-sectional fornix surface area measurements, corrected for head size by using a fornix-to-brain ratio (FBR), were compared to normal age and gender-matched controls. Additionally, a within-subjects analysis was performed comparing the mean areas between CO patients' Day 1, 2 weeks and 6-month FBR. The FBR was correlated with patients' neuropsychological data. There were no significant differences between CO patients' Day 1 fornix measurements compared to normal control subjects. However, significant atrophic changes in the fornix of CO poisoned patients occurred at two weeks with no progressive atrophy at 6 months. By 6 months, CO patients showed significant decline on tests of verbal memory (when practice effects were taken into account), whereas visual memory, processing speed and attention/concentration did not decline. This study indicates that CO results in brain damage and cognitive impairments in the absence of lesions and other neuroanatomic markers.