Detection of Huntington's disease decades before diagnosis: the Predict-HD study.

OBJECTIVE: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. METHODS: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. RESULTS: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. CONCLUSIONS: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

Brain activation during face perception: evidence of a developmental change.

Behavioral studies suggest that children under age 10 process faces using a piecemeal strategy based on individual distinctive facial features, whereas older children use a configural strategy based on the spatial relations among the face's features. The purpose of this study was to determine whether activation of the fusiform gyrus, which is involved in face processing in adults, is greater during face processing in older children (12-14 years) than in younger children (8-10 years). Functional MRI scans were obtained while children viewed faces and houses. A developmental change was observed: Older children, but not younger children, showed significantly more activation in bilateral fusiform gyri for faces than for houses. Activation in the fusiform gyrus correlated significantly with age and with a behavioral measure of configural face processing. Regions believed to be involved in processing basic facial features were activated in both younger and older children. Some evidence was also observed for greater activation for houses versus faces for the older children than for the younger children, suggesting that processing of these two stimulus types becomes more differentiated as children age. The current results provide biological insight into changes in visual processing of faces that occur with normal development.

Onset and rate of striatal atrophy in preclinical Huntington disease.

BACKGROUND: Huntington disease (HD) is characterized by striatal atrophy that begins long before the onset of motor symptoms. OBJECTIVE: To determine when striatal atrophy begins, the extent and rate of atrophy before diagnosis of motor symptoms, and whether striatal atrophy can predict when symptom onset will occur. METHODS: Caudate and putamen volumes were measured on MRI scans of 19 preclinical subjects with the HD gene expansion who were very far (9 to 20 years) from estimated onset, and on serial scans from 17 preclinical subjects, six of whom were diagnosed with HD within 5 years after the initial scan. RESULTS: Striatal volumes were significantly smaller for the subjects who were very far from estimated onset than for age-matched control subjects. Statistical models fit to the longitudinal data suggest that rate of caudate atrophy becomes significant when subjects are approximately 11 years from estimated onset and rate of putamen atrophy becomes significant approximately 9 years prior to onset. In the six incident cases, caudate and putamen were approximately one-third to one-half of normal volume at diagnosis, and caudate volume alone was able to predict with 100% accuracy those subjects who would be diagnosed within 2 years of imaging. CONCLUSIONS: Striatal atrophy begins many years prior to diagnosable HD, and assessment of atrophy on MRI may be very useful in both predicting HD onset and in tracking progression in future therapeutic trials in preclinical subjects.

Caudate volume as an outcome measure in clinical trials for Huntington's disease: a pilot study.

Previous research has demonstrated that longitudinal change in caudate volume could be observed over a period of 3 years in subjects with Huntington's disease (HD). The current pilot study was designed to determine whether measurement of caudate change on magnetic resonance imaging (MRI) is a feasible and valid outcome measure in an actual clinical trial situation. We measured caudate volumes on pre- and post-treatment MRI scans from 19 patients at two sites who were participating in CARE-HD (Co-enzyme Q10 and Remacemide: Evaluation in Huntington's Disease), a 30-month clinical trial of remacemide and co-enzyme Q(10) in symptomatic patients with HD. Results from this pilot study indicated that decrease in caudate volume was significant over time. Power analysis indicated that relatively small numbers of subjects would be needed in clinical trials using caudate volume as an outcome measure. Advantages and disadvantages of using MRI caudate volume as an outcome measure are presented. We recommend the adoption of quantitative neuroimaging of caudate volume as an outcome measure in future clinical trials for treatments of HD.

An fMRI study of executive functioning after severe diffuse TBI.

PRIMARY OBJECTIVE: Preliminary study of whether severe diffuse traumatic brain injury (TBI) increases extent of frontal tissue recruited by cognitive control tasks. RESEARCH DESIGN: Functional magnetic resonance imaging (fMRI) on N-back working memory (WM)and arrows inhibition tasks in a 46 year old man who had severe diffuse TBI 1 year earlier, a 44 year old man (inhibition task) and three women (working memory task), age 20-26 years. Images were acquired by 1.5 T magnet with BOLD method and PRESTO pulse sequence and analysed using SPM. MAIN OUTCOMES AND RESULTS: Frontal activation increased under 2-back relative to 1-back condition of working memory in all participants with more extensive activation in the TBI patient relative to controls. Frontal activation increased with inhibition on the arrows task, but was greater in the TBI patient. CONCLUSION: Severe diffuse TBI results in recruitment of additional neural resources for cognitive control.

Instructional treatment associated with changes in brain activation in children with dyslexia.

OBJECTIVE: To assess the effects of reading instruction on fMRI brain activation in children with dyslexia. BACKGROUND: fMRI differences between dyslexic and control subjects have most often involved phonologic processing tasks. However, a growing body of research documents the role of morphologic awareness in reading and reading disability. METHODS: The authors developed tasks to probe brain activation during phoneme mapping (assigning sounds to letters) and morpheme mapping (understanding the relationship of suffixed words to their roots). Ten children with dyslexia and 11 normal readers performed these tasks during fMRI scanning. Children with dyslexia then completed 28 hours of comprehensive reading instruction. Scans were repeated on both dyslexic and control subjects using the same tasks. RESULTS: Before treatment, children with dyslexia showed less activation than controls in left middle and inferior frontal gyri, right superior frontal gyrus, left middle and inferior temporal gyri, and bilateral superior parietal regions for phoneme mapping. Activation was significantly reduced for children with dyslexia on the initial morpheme mapping scan in left middle frontal gyrus, right superior parietal, and fusiform/occipital region. Treatment was associated with improved reading scores and increased brain activation during both tasks, such that quantity and pattern of activation for children with dyslexia after treatment closely resembled that of controls. The elimination of group differences at follow-up was due to both increased activation for the children with dyslexia and decreased activation for controls, presumably reflecting practice effects. CONCLUSION: These results suggest that behavioral gains from comprehensive reading instruction are associated with changes in brain function during performance of language tasks. Furthermore, these brain changes are specific to different language processes and closely resemble patterns of neural processing characteristic of normal readers.

Effects of age on brain volume and head circumference in autism.

OBJECTIVE: To determine whether brain volume, as assessed on MRI scans, differs between individuals with autism and control subjects, and whether such differences are affected by age. BACKGROUND: Previous studies have found increased brain weight, head circumference, and MRI brain volume in children with autism. However, studies of brain size in adults with autism have yielded conflicting results. The authors hypothesize that enlargement of the brain may be a feature of brain development during early childhood in autism that normalizes with maturational processes. METHODS: The authors measured total brain volumes from 1.5-mm coronal MRI scans in 67 non-mentally retarded children and adults with autism and 83 healthy community volunteers, ranging in age from 8 to 46 years. Head circumference was also measured. Groups did not differ on age, sex, verbal IQ, or socioeconomic status. RESULTS: Brain volumes were significantly larger for children with autism 12 years old and younger compared with normally developing children, when controlling for height. Brain volumes for individuals older than age 12 did not differ between the autism and control groups. Head circumference was increased in both younger and older groups of subjects with autism, suggesting that those subjects older than age 12 had increased brain volumes as children. CONCLUSIONS: Brain development in autism follows an abnormal pattern, with accelerated growth in early life that results in brain enlargement in childhood. Brain volume in adolescents and adults with autism is, however, normal, and appears to be due to a slight decrease in brain volume for these individuals at the same time that normal children are experiencing a slight increase.

Brain structural abnormalities in young children with autism spectrum disorder.

OBJECTIVE: To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. METHODS: Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. RESULTS: Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. CONCLUSIONS: These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

MRI findings differentiate between late-onset schizophrenia and late-life mood disorder.

OBJECTIVES: Compare MRI scans of patients with late-onset schizophrenia, late-life depression and late-life bipolar disorder to age- and gender-matched controls. MRI head scans of 14 patients in each diagnostic group and 21 patients in the normal control group were compared. Subjects were recruited from inpatient and outpatient services. MEASURES: The CERAD MRI rating algorithm was used to rate degree of atrophy. RESULTS: Patients with bipolar and unipolar disorder had greater left sylvian fissure and left and right temporal sulcal enlargement, and more bilateral cortical atrophy than normals. Patients with late-onset schizophrenia had larger right temporal horns and larger third ventricles. These findings validate the distinctions between late-life affective disorder and late-onset schizophrenia and mirror changes reported in younger individuals. They may reflect underlying structural and functional abnormalities found in neuropathologic and functional imaging studies.

The use of herbal alternative medicines in neuropsychiatry. A report of the ANPA Committee on Research.

Growing numbers of people throughout the United States (40% in 1998) are using various forms of alternative therapies. A MEDLINE literature search of journals from the past three decades and an Internet database query were performed to determine the types and frequency of alternative therapies used, with special attention given to the herbal medicines used in neuropsychiatric disorders. Clinical effects, mechanisms of action, interactions, and adverse reactions of the herbal treatments are detailed. Objective controlled trials will be needed to establish safety and efficacy of herbal supplements. Knowledge of the properties of these therapies can improve the care of neuropsychiatric patients.

Test battery for the diagnosis of dementia in individuals with intellectual disability. Working Group for the Establishment of Criteria for the Diagnosis of Dementia in Individuals with Intellectual Disability.

A working battery of tests for the diagnosis of dementia, which is applicable to most adults with intellectual disability, is proposed by an international Working Group. The battery, reflecting contemporary research and practice findings, includes scales for informant report of functioning and tests for direct assessment. The Working Group recommends the international use of the battery both as part of ongoing and new longitudinal research, and in clinical practice. The widespread use of a common battery will enhance communication and collaborative opportunities among researchers and clinicians at various sites, and will help to standardize diagnostic protocols and research findings. The collaborative evaluation of such a battery will address one of the greatest challenges in the field, that of differentiating change associated with ageing from that associated with dementia.

Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease.

Previous research by our group demonstrated a longitudinal change in caudate volume for symptomatic subjects with Huntington's disease (HD), and suggested that volume of the caudate may be a useful outcome measure for therapeutic studies in symptomatic patients. The current study was designed to determine whether longitudinal change in caudate atrophy could be documented in presymptomatic carriers of the HD gene mutation, and to compare rate of change in these subjects with rate of change in mildly and moderately affected symptomatic patients. We measured caudate volumes on serial magnetic resonance image scans from 30 patients at three stages of HD: 10 presymptomatic; 10 with mild symptoms, as indicated by scores on the Quantified Neurological Exam (QNE) < or =35; and 10 with moderate symptoms (QNE >45). The mean interscan interval was 36 months. When analyzed separately, both symptomatic groups and the presymptomatic group demonstrated a significant change in caudate volume over time. Amount of change over time did not differ significantly among the three groups. We conclude that change in caudate volume may be a useful outcome measure for assessing treatment effectiveness in both presymptomatic and symptomatic subjects.

Elucidating the contributions of processing speed, executive ability, and frontal lobe volume to normal age-related differences in fluid intelligence.

One theory of normal cognitive aging asserts that decreases in simple processing speed mediate the age-related decline of fluid intelligence. Another possibility is that age-related atrophic changes in frontal brain structures undermine the functioning of executive abilities, thereby producing the same decline. In this study, we used principal components analysis to derive a measure of fluid-spatial intelligence in 197 normal adults between 20 and 92 years of age. Measures of perceptual comparison speed, working memory, and executive ability, as well as regional brain volumes based on high resolution magnetic resonance imaging were obtained from a subsample of 112 participants. We then conducted a series of hierarchical multiple regression analyses to test whether (1) the processing speed theory, (2) frontal-executive theory, or (3) some combination of these best accounted for age-related variation in fluid intelligence. The results showed that perceptual comparison speed, executive ability, and frontal lobe volume each made significant contributions to a regression equation that explained 57% of the variance in fluid intelligence. These findings suggest that both the processing speed and frontal-executive theory of cognitive aging are partially correct and complement one another.

Neurocognitive functioning in children with mild and moderate asthma in the childhood asthma management program. The Childhood Asthma Management Program (CAMP) Research Group.

BACKGROUND: The Childhood Asthma Management Program (CAMP) is a multicenter double-blind, randomized, placebo-controlled, clinical trial of two anti-inflammatory agents and placebo in children with mild and moderate asthma. OBJECTIVE: The interrelationship between asthma severity and neurocognitive functioning among 1041 children (age range, 5-12 years) enrolled in the CAMP trial was examined. METHODS: Asthma severity was established at baseline with a clinical history of asthma symptomatology and measures of lung function (spirometry and methacholine challenge). Diary cards were used in a screening to record nighttime awakenings and doctor contacts caused by asthma symptoms, symptom severity, and number of puffs from a rescue inhaler. All children received a comprehensive neurocognitive assessment at the end of the 28-day screening period (before randomization), including measures of intelligence, attention, memory, and academic achievement. RESULTS: Significant differences were found between children with mild and moderate asthma on lung function and symptom outcome variables (log(e)FEV(1)PC(20), DeltaFEV(1) percent predicted, change in peak flow percent predicted, nighttime awakenings caused by asthma, average symptom severity score, and average daily number of puffs from a rescue inhaler) but not on neurocognitive variables. Multiple regression analyses revealed that asthma outcomes could not be predicted by neurocognitive variables despite controlling for socioeconomic status. The prevalence of neurocognitive dysfunction, as indicated by the use of psychostimulant medication, was found to be consistent with that found in the existing literature. CONCLUSION: Mild and moderate asthma symptoms are not related to neurocognitive functioning in the children enrolled in CAMP. Mean performance on neurocognitive variables was found to be similar to that of national normative data.

Sex differences in inferior parietal lobule volume in schizophrenia.

OBJECTIVE: The inferior parietal lobule is a heteromodal association cortical region that has been implicated in the pathophysiology of schizophrenia. Inferior parietal lobule gray matter volumes have been shown to differ between healthy male and female subjects, with male subjects having larger left volumes. The authors sought to determine whether these volumetric sex differences also exist in patients with schizophrenia. METHOD: The authors used magnetic resonance imaging to measure inferior parietal lobule volumes of 15 pairs of male and female schizophrenic subjects who were individually matched to each other and to 15 pairs of healthy male and female subjects. RESULTS: Male schizophrenic patients exhibited a reversal of the normal left-greater-than-right male asymmetry in this region and had left inferior parietal lobule gray matter volumes that were significantly smaller than those of healthy male subjects. Female schizophrenic patients did not differ significantly from healthy female subjects in left or right inferior parietal lobule volume or in asymmetry. CONCLUSIONS: This study provides further evidence of brain morphology sex differences in schizophrenia that possibly contribute to the differential clinical disease expression in men and women.

MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults.

OBJECTIVE: To determine whether volumes of hippocampus and amygdala are abnormal in people with autism. BACKGROUND: Neuropathologic studies of the limbic system in autism have found decreased neuronal size, increased neuronal packing density, and decreased complexity of dendritic arbors in hippocampus, amygdala, and other limbic structures. These findings are suggestive of a developmental curtailment in the maturation of the neurons and neuropil. METHODS: Measurement of hippocampus, amygdala, and total brain volumes from 1.5-mm coronal, spoiled gradient-recalled echo MRI scans in 14 non-mentally retarded autistic male adolescents and young adults and 14 individually matched, healthy community volunteers. RESULTS: Amygdala volume was significantly smaller in the autistic subjects, both with (p = 0.006) and without (p = 0.01) correcting for total brain volume. Total brain volume and absolute hippocampal volume did not differ significantly between groups, but hippocampal volume, when corrected for total brain volume, was significantly reduced (p = 0.04) in the autistic subjects. CONCLUSIONS: There is a reduction in the volume of amygdala and hippocampus in people with autism, particularly in relation to total brain volume. The histopathology of autism suggests that these volume reductions are related to a reduction in dendritic tree and neuropil development, and likely reflect the underdevelopment of the neural connections of limbic structures with other parts of the brain, particularly cerebral cortex.

Sex differences in the inferior parietal lobule.

The inferior parietal lobule (IPL) - a neocortical region and part of the heteromodal association cortex (HASC) - has been hypothesized to exhibit sexual dimorphism, as do other HASC regions, particularly with regard to asymmetry. Using a reliable method for measuring IPL gray matter volume based upon individual sulcal-gyral landmarks, we measured this region on magnetic resonance imaging scans from a sample of 15 individually matched pairs of normal male and female subjects. Male subjects showed significantly larger left, but not right, IPL volumes when compared to females. Males also showed a leftward (left > right) asymmetry for the IPL, with a less marked opposite asymmetry in females. Such sexual dimorphisms may possibly underlie the subtle cognitive differences observed between the sexes.

MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia.

OBJECTIVE: This study sought to determine whether volumes of the hippocampus and amygdala are disproportionately smaller in subjects with Down's syndrome than in normal comparison subjects and whether volume reduction is greater in Down's syndrome subjects with dementia. METHOD: The subjects were 25 adults with Down's syndrome (eight with dementia) and 25 cognitively normal adults who were individually matched on age, sex, and race. Magnetic resonance imaging measures included volumes of the hippocampus, amygdala, and total brain. Nineteen of the Down's syndrome subjects had follow-up scans (interscan interval = 9-41 months). RESULTS: Nondemented Down's syndrome subjects had significantly smaller volumes of the hippocampus, but not the amygdala, than their comparison subjects, even when total brain volume was controlled for. Volumes of both the hippocampus and the amygdala were smaller in the demented Down's syndrome subjects than in their comparison subjects, even when total brain volume was controlled for. Age was not correlated with volume of the hippocampus or amygdala among the nondemented Down's syndrome subjects and the comparison subjects; age was correlated with volume of the amygdala, but not the hippocampus, among the Down's syndrome subjects with dementia. Changes in volume over time were not statistically significant for either the demented or the nondemented subjects. CONCLUSIONS: Hippocampal volume, while disproportionately small for brain size in individuals with Down's syndrome, remains fairly constant through the fifth decade of life in those without dementia. All subjects over age 50 who had Down's syndrome demonstrated volume reduction in the hippocampus as well as clinical signs of dementia. Dementia was also associated with volume reductions in the amygdala that exceeded reductions in total brain volume.

Mesial temporal lobe measurements on magnetic resonance imaging scans.

Changes in the mesial temporal lobe, particularly in the hippocampus, amygdala, and entorhinal cortex, are reported to occur in several neuropsychiatric conditions. Neuroimaging provides a non-invasive means of studying these changes. We present a method for reliably measuring the hippocampus, amygdala, and entorhinal cortex on MRI. The advantages of our method include high reliability, the use of orthogonal views in delineating boundaries and circumscription of measurement such that no tissue of any one anatomic structure is included in the measurement of another structure.