Brain disease and molecular analysis in myotonic dystrophy

Abnormal amplification of a CTG repeat on chromosome 19 is the molecular basis of myotonic dystrophy (DM). Expansion of the repeat has been correlated with severity of several clinical features of the disease. We performed extensive cognitive testing, cerebral magnetic resonance imaging (MRI) and a molecular analysis in 28 cases of DM to determine the relationship between the molecular defect and brain disease. Performance in two or more cognitive tests was pathological in 10 cases. Fourteen patients had subcortical white matter lesions on MRI, 14 had cerebral atrophy. Amplification of the CTG repeat showed a strong correlation with cognitive test deficits when exceeding a length of over 1000 trinucleotides. MRI lesions were associated with impaired psychometric performance, but MRI and molecular findings were only weakly related. Disease duration influenced the appearance and amount of white matter lesions on MRI. Quantification of CTG repeat size may allow an early estimate on the probability of brain involvement in DM; cognitive dysfunction is associated with white matter lesions and cerebral atrophy later on in the course.     

Anterior temporal white matter lesions in myotonic dystrophy with intellectual impairment: an MRI and neuropathological study

We studied 12 patients with myotonic dystrophy using MRI and the Mini-mental state examination (MMSE), to see it specific MRI findings were associated with intellectual impairment. We also compared them with the neuropathological findings in an autopsy case of MD with intellectual impairment. Mild intellectual impairment was found in 8 of the 12 patients. On T2-weighted and proton density-weighted images, high-intensity areas were seen in cerebral white matter in 10 of the 12 patients. In seven of these, anterior temporal white-matter lesions (ATWML) were found; all seven had mild intellectual impairment (MMSE 22-26), whereas none of the four patients with normal mentation had ATWML. In only one of the eight patients with intellectual impairment were white-matter lesions not found. Pathological findings were severe loss and disordered arrangement of myelin sheaths and axons in addition to heterotopic neurons within anterior temporal white matter. Bilateral ATWML might be a factor for intellectual impairment in MD. The retrospective pathological study raised the possibility that the ATWML are compatible with focal dysplasia of white matter.     

Somatic mosaicism of p(CTG)n expansion in a case of myotonic dystrophy with parotid tumor

Myotonic dystrophy (MD) is an autosomal dominant systemic disorder with an unstable expansion of the CTG triplet repeat in the 3'-untranslated region of the gene encoding myotonine protein kinase (DMPK) which maps to chromosome 19q13.3. Somatic mosaicism of CTG repeats in MD has been reported; and it has been observed that CTG repeats in tumor tissues associated with MD are more expanded than the other tissues. It is not rare that parotid tumors are found in patients with MD. We performed Southern blot analysis for tissues from the parotid tumor, the normal parotid gland, the skeletal muscles, and the leukocyte from a 60-year-old patient with MD. CTG repeat was most expanded in the parotid tumor, and the normal parotid gland had longer expansion of CTG repeat than the skeletal muscles. The leukocyte had the shortest expansion of CTG repeat. The expansion of CTG repeat in the parotid tumor may be related to active cell division and may underlie the occurrence of tumors in MD.     

White matter atrophy, ventricular dilation, and intellectual functioning following traumatic brain injury.

Examined the role in traumatic brain injury (TBI) of injury severity measured by the Glasgow Coma Scale (GCS), white matter atrophy identified by various magnetic resonance imaging (MRI) morphometric techniques, and postinjury intellectual functioning measured with the Wechsler Adult Intelligence Scale—Revised (WAIS—R). MR images of 31 female and 33 male TBI patients were used to calculate corpus callosum (CC) areas, ventricular volumes (estimates of white matter loss), and parenchymal volumes. Results indicated that the men were on the average more severely injured, as indicated by significantly lower GCS scores. CC size correlated significantly with the ventricle-to-brain ratio (VBR), but no significant correlations were found between CC size and WAIS—R scores. Significant correlations were found for men only between VBR and Performance IQ and between VBR and the Digit Symbol subtest of the WAIS—R. Implications for the roles of white matter atrophy and intellectual functioning in TBI are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"White matter atrophy, ventricular dilation, and intellectual functioning following traumatic brain injury": Correction.

Reports an error in the original article by S. C. Johnson et al (Neuropsychology, 1994[July], Vol 8[3], 301–315). On page 309, Figure 2 was printed upside down. Figures are provided in the correct position. (The following abstract of this article originally appeared in record 1994-38110-001.) Examined the role in traumatic brain injury (TBI) of injury severity measured by the Glasgow Coma Scale (GCS), white matter atrophy identified by various magnetic resonance imaging (MRI) morphometric techniques, and postinjury intellectual functioning measured with the Wechsler Adult Intelligence Scale—Revised (WAIS—R). MR images of 31 female and 33 male TBI patients were used to calculate corpus callosum (CC) areas, ventricular volumes (estimates of white matter loss), and parenchymal volumes. Results indicated that the men were on the average more severely injured, as indicated by significantly lower GCS scores. CC size correlated significantly with the ventricle-to-brain ratio (VBR), but no significant correlations were found between CC size and WAIS—R scores. Significant correlations were found for men only between VBR and Performance IQ and between VBR and the Digit Symbol subtest of the WAIS—R. Implications for the roles of white matter atrophy and intellectual functioning in TBI are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Improved peripheral nerve conduction, EEG and verbal IQ after bone marrow transplantation for adult metachromatic leukodystrophy

A 28-year-old woman with a 4 year history of slowly progressing 'frontal dementia' was diagnosed as having adult metachromatic leukodystrophy and was followed for 4 years after bone marrow transplantation (BMT). MRI, neurophysiological tests (EEG, ENeG, VEP, SEP and BAEP) and neuropsychological assessment were performed before, and repeatedly after BMT. MRI showed symmetrical white matter lesions in the frontal and parieto-occipital lobes and in the corpus callosum. EEG showed frontal and temporal slow wave abnormalities and nerve conduction was slow. Neuropsychological tests showed cognitive impairment in executive functions, decline in visuospatial-constructive and spatial memory tasks and disorganized thinking. IQ was low (52), with slightly better values for verbal IQ than for performance IQ. After BMT, the patient was followed for 4 years. Clear improvements were seen in EEG, in peripheral nerve conduction and in neuropsychological tests (especially in verbal IQ). MRI findings were unchanged. We believe that the improvement in our patient resulted from the bone marrow transplantation.     

Meta-Analysis of Intellectual and Neuropsychological Test Performance in Attention-Deficit/Hyperactivity Disorder.

Cognitive measures are used frequently in the assessment and diagnosis of attention-deficit/hyperactivity disorder (ADHD). In this meta-analytic review, the authors sought to examine the magnitude of differences between ADHD and healthy participants on several commonly used intellectual and neuropsychological measures. Effect sizes for overall intellectual ability (Full Scale IQ; FSIQ) were significantly different between ADHD and healthy participants (weighted d = .61). Effect sizes for FSIQ were significantly smaller than those for spelling and arithmetic achievement tests and marginally significantly smaller than those for continuous performance tests but were comparable to effect sizes for all other measures. These findings indicate that overall cognitive ability is significantly lower among persons with ADHD and that FSIQ may show as large a difference between ADHD and control participants as most other measures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy. Influence of CAG repeat size on MRI findings

To elucidate how the size of the expanded CAG repeat of the gene for dentatorubral pallidoluysian atrophy (DRPLA) and other factors affect the atrophy of the brainstem and cerebellum, and the appearance of high-intensity signals on T2-weighted MRI of the cerebral white matter of patients with DRPLA, we quantitatively analyzed the MRI findings of 26 patients with DRPLA, the diagnosis of which was confirmed by molecular analysis of the DRPLA gene. When we classified the patients into two groups based on the size of the expanded CAG repeat of the DRPLA gene (group 1, number of CAG repeat units > or = 66; group 2, number of CAG repeat units < or = 65), we found strong inverse correlations between the age at MRI and the areas of midsagittal structures of the cerebellum and brainstem in group 1 but not in group 2. Multiple regression analysis, however, revealed that both the patient's age at MRI and the size of the expanded CAG repeat correlated with the areas of midsagittal structures. Involvement of the cerebral white matter as detected on T2-weighted images was observed more frequently in patients belonging to group 2 than in group 1 patients. Furthermore it was demonstrated that high-intensity signals can be detected on T2-weighted images of the cerebral white matter of patients with a largely expanded CAG repeat (group 1) in their thirties. These results suggest that patient age as well as the size of the expanded CAG repeat are related to the degree of atrophy of the brainstem and cerebellum, and the white matter changes in patients with DRPLA.     

Reading and arithmetic in adolescents with autism spectrum disorders: Peaks and dips in attainment.

In describing academic attainment in autism spectrum disorders (ASD), results are typically reported at the group mean level. This may mask subgroups of individuals for whom academic achievement is incommensurate with intellectual ability. The authors tested the IQ, literacy, and mathematical abilities of a large group (N = 100) of adolescents (14–16 years old) with ASD. Seventy-three percent of the sample had at least one area of literacy or mathematical achievement that was highly discrepant (approximately 14 standard score points) from full-scale IQ (FSIQ). The authors focused on four subgroups with either word reading (“Reading Peak” and “Reading Dip”) or arithmetic (“Arithmetic Peak” and “Arithmetic Dip”) higher or lower than FSIQ. These subgroups were largely mutually exclusive and were characterized by distinct intellectual profiles. The largest was the “Arithmetic Peak” subgroup of participants, who presented with average intellectual ability alongside superior arithmetic skills and who were predominantly in a mainstream educational setting. Overall, the most pervasive profile was discrepantly poor reading comprehension, which associated with severity of social and communication difficulties. The high rate of uneven academic attainment in ASD has implications for educational practice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic carbon disulfide encephalopathy

To understand central nervous damage after long-term exposure to carbon disulfide (CS2), 10 patients who had polyneuropathy with various neuropsychiatric symptoms in a viscose rayon plant were studied. Clinical and laboratory examinations including electroencephalography (EEG), brain computed tomography (CT), brain magnetic resonance images (MRI), and carotid duplex sonography were carried out. Clinically, headache, unpleasant dreams, memory impairment, fatigue, anorexia and emotional lability were common in these patients while 2 patients had stroke episodes. EEGs were all normal. Brain CT scan showed mild cortical atrophy in 3 and low density lesions in the basal ganglia in 3. Brain MRI studies also disclosed mild cortical atrophy in 4 and multiple lesions involving the basal ganglia and corona radiata in 4. Carotid duplex sonography revealed mild atherosclerosis with plaques (< 20% stenosis) of extracranial vessels in 6. However there was no significant difference in flow velocities and flow volumes in the extracranial carotid arteries between patients and the normal controls. Interestingly, 2 patients had multiple brain lesions in the subcortical white matter but without strokes. In conclusion, encephalopathy with possible strokes may occur after chronic exposure to CS2, as well as polyneuropathy. The lesions usually involve the basal ganglia and subcortical white matter. Furthermore, MRI study may detect brain lesions particularly in the subcortical white matter areas before the occurrence of stroke.     

Magnetic resonance in HTL-I associated myelopathy. Leukoencephalopathy and spinal cord atrophy

Cerebral white matter lesions and spinal cord atrophy have been frequently reported in patients with HTLV-I associated myelopathy (HAM). The exact frequency and the clinical relevance of these findings still remain to be elucidated. Twenty-nine patients with HAM were studied by magnetic resonance imaging of the brain and spine. Cerebral white matter lesions equal or over 3 mm in diameter were considered abnormal. The spinal cord size was evaluated using an index we have called "spinal cord index". The radiological findings were correlated to the clinical features of the myelopathy. Cerebral white matter lesions occurred in 52% of the patients, and spinal cord atrophy in 74%. There was no significant correlation between these abnormalities and the clinical features studied. These findings suggest that the resonance imaging is a useful method for detection of cerebral and spinal cord abnormalities in HAM patients. The absence of correlation between cerebral white matter lesions and either patient age or risk factors for cardiovascular disease suggests a possible association between the leukoencephalopathy and the infection.     

Relationship of education and IQ in the WAIS—R standardization sample.

Analyzed years of schooling as compared to WAIS—R scores in each of the 1,880 Ss used to standardize the test. Results show a progressive increase in mean Full Scale IQ (FSIQ) from individuals who completed 8 or fewer years of education (FSIQ?=?86.4) to individuals who completed 9–21 yrs (FSIQ?=?96.4), 12 yrs (FSIQ?=?100.1), 13–25 yrs (FSIQ?=?107.4) and 16 or more years of education (FSIQ?=?115.3). In a further analysis, 600 16–24 yr old Ss included in the sample were excluded because they had not yet completed their education. Results show that the correlation between education and FSIQ was .63 for 500 24–44 yr old Ss and .62 for 730 45–74 yr old Ss. It is suggested that when other information is available, years of schooling may be used in clinical neuropsychological practice as a rough estimate of premorbid WAIS—R IQ. (5 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Validation of the Child Premorbid Intelligence Estimate method to predict premorbid Wechsler Intelligence Scale for Children-Fourth Edition Full Scale IQ among children with brain injury.

Determination of neuropsychological impairment involves contrasting obtained performances with a comparison standard, which is often an estimate of premorbid IQ. M. R. Schoenberg, R. T. Lange, T. A. Brickell, and D. H. Saklofske (2007) proposed the Child Premorbid Intelligence Estimate (CPIE) to predict premorbid Full Scale IQ (FSIQ) using the Wechsler Intelligence Scale for Children-4th Edition (WISC-IV; Wechsler, 2003). The CPIE includes 12 algorithms to predict FSIQ, 1 using demographic variables and 11 algorithms combining WISC-IV subtest raw scores with demographic variables. The CPIE was applied to a sample of children with acquired traumatic brain injury (TBI sample; n = 40) and a healthy demographically matched sample (n = 40). Paired-samples t tests found estimated premorbid FSIQ differed from obtained FSIQ when applied to the TBI sample (ps ≤ .01). When applied to healthy peers, estimated and obtained FSIQ did not differ (ps > .02). The demographic only algorithm performed well at a group level, but estimates were restricted in range. Algorithms combining single subtest scores with demographics performed adequately. Results support the clinical application of the CPIE algorithms. However, limitations to estimating individual premorbid ability, including statistical and developmental factors, must be considered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cautions in interpretation of comparisons between the WAIS—R and the Wechsler Memory Scale.

Investigated the relation of the Wechsler Adult Intelligence Scale—Revised (WAIS—R) Full Scale IQ (FSIQ) to the Wechsler Memory Scale Memory Quotient (MQ) when the WAIS—R rather than the WAIS is used, noting that G. P. Prigatano (1978) found that a MQ at least 12 points below the WAIS FSIQ may be an indication of memory impairment. 120 psychiatric inpatients (mean age 39.95 yrs) completed the MQ and either the WAIS or WAIS—R. Mean WAIS—R FSIQ and MQ were not equivalent, and a 12-point discrepancy between FSIQ and MQ occurred less often with the WAIS—R than with the WAIS. (6 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term MR follow-up of cerebral lesions in neuro-Beh?et's disease

To study the long-term evolution of cerebral lesions in neuro-Beh?et's disease, MRI was carried out on 12 patients, with follow-up from 1.5 to 6 years (mean 3.5 years). On the first MRI, 66 lesions in all were found; each patient had 1-10 lesions (mean 5.5). There were 30 (46%) lesions in the brain stem, 18 (27%) in the basal ganglia region and 18 (27%) in the periventricular white matter. Of these 22 (33%) were small, 31 (47%) medium-size and 13 (20%) large lesions. On the last MRI, 60 lesions were found: each patient had 1-10 lesions (mean 5). At this time 31 lesions (52%) were in the brain stem, 13 (22%) in the basal ganglia region and 16 (26%) in the periventricular white matter. There were 41 (68%) small, 13 (22%) medium-size and 6 (10%) large lesions. About 40% of the lesions disappeared, 35% reduced in size and 25% remained unchanged. No lesion had enlarged. Of the 60 final lesions 20 (34%) were not observed on the first study. Small new lesions were found in 5 of 12 patients (42%), and were asymptomatic. Medium-size or large new lesions were found in 2 patients (17%) who had stopped steroid treatment and had a neurological relapse. Enlargement of the ventricular system or worsening of initial cerebral atrophy was observed in 9 of 12 patients. Appearance of small lesions and worsening of cerebral atrophy on long-term follow-up suggest the possibility of subclinical progression of cerebral vasculitis and should be considered in the prognosis of neuro-Beh?et's disease.     

Hippocampal volume is associated with memory but not monmemory cognitive performance in patients with mild cognitive impairment

Mild cognitive impairment (MCI) appears to be a transitional stage in the development of Alzheimer's disease (AD). Patients with MCI show impaired memory performance and hippocampal atrophy relative to normal elderly controls. Prior studies indicate that the degree of hippocampal atrophy in MCI patients predicts conversion to AD. In contrast to patients with MCI who have deficits primarily in memory, AD patients have clinically evident impairments in both memory and nonmemory cognitive domains. One explanation for the observation that a smaller hippocampal volume predicts conversion to AD might be that hippocampal atrophy is associated with early impairment in nonmemory cognitive areas as well as memory. A link between hippocampal volume and nonmemory function could occur if hippocampal atrophy was correlated with AD pathology in other brain regions. We therefore sought to determine the relationship of hippocampal volume with performance on memory and nonmemory tasks in patients with MCI. Although we found a significant correlation between hippocampal volume and memory performance, we did not find a significant correlation between hippocampal volume and nonmemory performance. We conclude that the relationship between hippocampal volume and risk of AD is likely tied to reduced memory performance and not associated with impairment in nonmemory cognitive domains.     

Myotonic dystrophy phenotype without expansion of (CTG)n repeat: an entity distinct from proximal myotonic myopathy (PROMM)?

Myotonic dystrophy (DM) is associated with an expansion of an unstable (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene on chromosome 19q13.3. We studied six patients from two families who showed no expansions of the repeat, in spite of their clinical diagnosis of DM. These patients had multi-systemic manifestations that were distinguishable from those seen in other myotonic disorders, including proximal myotonic myopathy (PROMM). In one additional family, two symptomatic members showed no expanded (CTG)n repeats, while their affected relatives had the expanded repeats. DM haplotype analysis failed to exclude the DMPK locus as a possible site of mutation in each family; however, DMPK mRNA levels were normal. We conclude that a mutation(s) other than the expanded (CTG)n repeat can cause the DM phenotype. The mutation(s) in these families remain(s) to be mapped and characterized.     

Amygdala atrophy and seizure outcome after temporal lobe epilepsy surgery

Surgical outcome in hippocampal atrophy (n = 44) and amygdalohippocampal atrophy (n = 14) were compared. Hippocampal atrophy had better seizure-free outcome than amygdalohippocampal atrophy (80% versus 50%, p = 0.043). Severity of hippocampal atrophy correlated with duration of epilepsy in patients with hippocampal atrophy (r = 0.4, p = 0.007), but not in those with amygdalohippocampal atrophy, suggesting that these two groups may have a different pathogenesis.     

Visuo-perceptual impairment and cerebral lesions in spastic diplegia with preterm birth

Eighteen cases of spastic diplegia (SD) ranging in age from 5 year 4 month to 9 year 5 month with preterm birth were studied to clarify the relationship between visuo-perceptual impairment and their cerebral lesions. All underwent neuropsychological examinations including the Frostig developmental test of visual perception, Tanaka-Binet or Suzuki-Binet intelligence test, and MRI examination. Cerebral lesions were detected in all subjects, and the volume of the peritrigonal white matter of the parietal and occipital lobes was significantly correlated with the visuo-perceptual impairment (r = 0.74, in the axial plane; r = 0.64, in the coronal plane). We propose that visuo-perceptual impairment is caused by cerebral lesions and that the measurement of peritrigonal white matter by MRI is useful for detecting potential visuo-perceptual impairment at an early age.     

Magnetic resonance in AIDS-related encephalopathy

Fifty-eight patients with AIDS disease were studied with MR imaging in the aim of detecting the grade of brain involvement. The examinations were performed with a 1.5 Tesla magnet. Thirty-seven showed white matter lesion (63.5%), twenty-five patients showed cerebral atrophy (43%), in eight patients the MR appearance was consistent with toxoplasmosis infection (13.5%), two patients showed a linfoma (3.4%) and two patients micrococcosis (3.4%). Seventeen out of the thirty-seven patients with white matter disease showed focal well circumscribed lesion (46%), while twenty showed diffuse involvement. Between the twenty-five patients with cerebral atrophy, twelve showed a prevalence of the cortical involvement and eight a subcortical atrophy. In five patients a concomitant, cortical and subcortical atrophy was found. Between the eight patients with neurotoxolesion and two of them a widespread encephalitis picture. The MR appearance of the two limphomas was that of periventricular, space occupying, masses. In two patients with micrococcis a nodular aspect of leptomeningeal lesions was found.