Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis, and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 + or - 12.46) and without FXTAS (n = 17, age: 44.94 + or - 11.23), in genetically normal female controls (n = 8, age: 50.63 + or - 11.43), male carriers with FXTAS (n = 34, age: 66.44 + or - 6.77) and without FXTAS (n = 21, age: 52.38 + or - 12.11), and genetically normal male controls (n = 30, age: 57.20 + or - 14.12). We examined the relationship between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the significant negative correlation between right hippocampal volume and anxiety. Other anxiety-related subscales also correlated with the right hippocampus in females. In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a negative association between hippocampal volume and the severity of anxiety-related psychological symptoms. Though the presentation of FXTAS symptoms is less common in females, anxiety-related problems are common both prior to and after the onset of FXTAS, and may be related to hippocampal changes.

Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS).

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. METHODS: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 +/- 10.3 years), 20 unaffected female carriers (43.3 +/- 11.2 years), 11 genetically normal female controls (51.0 +/- 10.3 years), 36 affected male carriers (65.0 +/- 5.6 years), 25 unaffected male carriers (53.5 +/- 12.5 years), and 39 male controls (58.0 +/- 15.0 years). Female and male carriers with FXTAS were matched on duration of disease. RESULTS: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females. CONCLUSIONS: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.

Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.

OBJECTIVES: To assess changes in regional brain volumes associated with the fragile X-associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes. METHODS: We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education. RESULTS: We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity. CONCLUSIONS: The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X-associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.

We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.

Delayed diffusion-weighted MR abnormality in a patient with an extensive acute cerebral hypoxic injury.

Diffusion-weighted (DW) MR imaging usually identifies acute cerebral infarction injury in symptomatic patients. We report a patient with severe hypoxic brain injury following suicide attempt by hanging, but with normal DW MR imaging 5-6 h after the event. Follow-up DW MR imaging 3 days after the event, and subsequent autopsy, revealed extensive cerebral anoxic injury.

Brain structure and cognition in a community sample of elderly Latinos.

BACKGROUND: Previous studies have found that hippocampal atrophy and white matter hyperintensities (WMH) on MRI are linked to cognitive impairment and dementia. The authors measured these variables in a population-based cohort of older Mexican Americans with a wide spectrum of cognitive ability, ranging from normal cognition to dementia. OBJECTIVE: To investigate whether these structural brain changes were seen in individuals prior to the development of dementia and how these changes were related to the presence of dementia. METHODS: A sample of 122 subjects was selected from the Sacramento Area Latino Study on Aging, and subjects were categorized into four groups of increasing levels of cognitive impairment: normal, memory impaired (MI), cognitively impaired but not demented (CIND), and demented. Hippocampal volume was quantified using a region of interest approach. WMH was rated on a semiquantitative scale as the percent of total volume of white matter. RESULTS: Hippocampal volume was significantly reduced in CIND and demented individuals, and WMH were significantly increased in demented subjects. MI subjects did not have any significant changes in hippocampal volume or WMH. The risk for developing dementia was significantly and comparably increased in subjects with either hippocampal atrophy or high WMH. However, the risk for dementia increased dramatically in subjects with both hippocampal atrophy and a high degree of WMH. CONCLUSION: Reductions in hippocampal volume may be present before dementia but not until cognitive impairment is relatively severe. Because there is a synergistic effect between high WMH and hippocampal atrophy, interactions between vascular and degenerative processes may be important determinants of dementia.

Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology.

The hippocampus and amygdala are believed to be involved in the pathology of schizophrenia. In this study, we attempted to replicate the reported bilateral volume reduction of the hippocampus and amygdala and to study the relationship of the volumes of these structures to the symptoms of schizophrenia. The hippocampus-amygdala complex (HAC) was manually traced on 3-mm coronal T(1)-weighted MRIs, resampled into 1-mm coronal slices, from 20 male patients with schizophrenia and 20 age-matched male controls. The complex was divided into three parts: anterior one-third representing the amygdala and middle and posterior thirds representing the anterior and posterior halves of the hippocampus. Positive and negative symptoms and severity of hallucinations and thought disorder (conceptual disorganization) were quantified using the Brief Psychiatric Rating Scale (BPRS). None of the above structures, controlled for brain volume, differed significantly in patients compared with normal controls. When the relationship between volumes and symptoms was examined, the left HAC was found to inversely correlate with thought disorder and negative symptoms. Specifically, significant inverse correlations were found between (i) left amygdala and thought disorder, (ii) left hippocampus and negative symptoms, and (iii) left anterior and posterior hippocampus volumes and positive and negative symptoms, respectively. Our findings further support the role of the HAC in the pathophysiology of schizophrenia and suggest unique associations between individual structures and specific symptoms of the illness.

Prevalence of cavum septum pellucidum in schizophrenia studied with MRI.

OBJECTIVE: To study the prevalence of cavum septum pellucidum (CSP), a midline developmental anomaly, in patients with schizophrenia. METHODS: Three-millimeter coronal T1 weighted MRI images of 43 normal controls and 73 patients with schizophrenia were examined. The images were resampled into 1-mm slices and CSP was measured by the number of slices in which it appeared. RESULTS: Patients had significantly higher incidence of CSP (Fisher's exact test 0.042; one-sided). Eighteen (41.9%) of the controls and 44 (60.3%) of patients had a CSP, and one of 46 controls and three of 73 patients had a large CSP of six slices or more. There was no relationship between the presence or size of CSP and regional brain volumes or volumes of hippocampus-amygdala complex, caudate, superior temporal gyrus or ventricular CSF. CONCLUSION: Higher incidence of CSP may reflect a neurodevelopmental disturbance in schizophrenia.

Neurodevelopmental outcome of patients after the fontan operation: A comparison between children with hypoplastic left heart syndrome and other functional single ventricle lesions.

OBJECTIVE: To compare neurodevelopmental outcome (NDO) in patients with hypoplastic left heart syndrome (HLHS), other functional single ventricle lesions, and the standard population and to investigate predictors of NDO in the population of children with functional single ventricle (FSV). STUDY DESIGN: A time- and age-defined cohort of patients with the Fontan circulation was recruited to participate in neurodevelopmental testing, behavioral evaluation, and imaging of the central nervous system. The Wechsler Intelligence test was the primary measure of NDO. Analysis included comparison of patients with HLHS with other patients with functional single ventricles. Other potential clinical predictors of NDO were investigated. RESULTS: The mean Full Scale Wechsler Intelligence score was 101.4+/-5.4. For the HLHS subgroup the mean Full Scale Wechsler score was 93.8+/-7.3, and for the non-HLHS subgroup it was 107.0+/-7.0. Although the HLHS group had significantly lower scores than the non-HLHS subgroup, neither subgroup scored significantly different from the standard population on the Wechsler Scales. Socioeconomic status, circulatory arrest, and perioperative seizures also were predictive of neurodevelopmental outcome. CONCLUSION: Neurodevelopmental and behavioral outcome in patients who have undergone the Fontan procedure including patients with HLHS is good in the preschool and early school years, with Wechsler Intelligence scores generally in the normal range.

Magnetic resonance imaging in patients with central nervous system pathology: a comparison of OptiMARK (Gd-DTPA-BMEA) and Magnevist (Gd-DTPA).

RATIONALE AND OBJECTIVES: The objective of the two pivotal phase 3 studies was to evaluate the safety and efficacy of OptiMARK (Gd-DTPA-bis(methoxyethylamide) [Gd-DTPA-BMEA]) compared with Magnevist (Gd-DTPA) in magnetic resonance imaging of the central nervous system. METHODS: Two multicenter, randomized, double-blind, parallel group studies were conducted in 395 patients with known or suspected central nervous system pathology. Subjects were randomized to receive a single 0.1 mmol/kg intravenous injection of either Gd-DTPA-BMEA or Gd-DTPA. The safety of Gd-DTPA-BMEA and Gd-DTPA was monitored for up to 72 hours after study drug administration. Precontrast and postcontrast administration magnetic resonance scans were acquired using identical imaging planes and techniques. RESULTS: No deaths or unexpected adverse events were reported in either group. A comparison of adverse events by intensity and relation demonstrated no statistically significant differences between the two groups. Gd-DTPA-BMEA and Gd-DTPA were equivalent with respect to confidence in diagnosis, conspicuity, and border delineation. CONCLUSIONS: Gd-DTPA-BMEA and Gd-DTPA demonstrated comparable efficacy profiles, and the safety profiles were considered similar.

Imaging of spinal intradural arachnoid cysts: MRI, myelography and CT.

Imaging studies in eight patients with surgically-confirmed spinal arachnoid cysts were analyzed retrospectively. All patients had preoperative MRI of the spine and seven preoperative myelography with postmyelographic CT. In all cases the correct diagnosis could be made preoperatively on the basis solely of MRI. The diagnosis could also be established from myelography and postmyelographic CT in six of the seven cases. In one case myelography and CT simply demonstrated an intradural extramedullary mass.

Treatment of Wilson's disease with zinc: XV long-term follow-up studies.

Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilson's disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilson's disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilson's disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.

Spinal cord infection: myelitis and abscess formation.

PURPOSE: Our purpose was to describe the MR findings and evolution of spinal cord abscess and to define those MR features that allow differentiation of cord infection from other intramedullary abnormalities. METHODS: We retrospectively reviewed the MR studies of all patients in whom intramedullary spinal cord abscess was proved either by blood or cerebrospinal fluid culture or by serologic examination at our institution between January 1988 and January 1996. The study group included four adults and two children, 7 to 74 years old (mean age, 38 years). RESULTS: Initial MR studies showed intramedullary high signal on T2-weighted sequences with poorly defined marginal enhancement on T1-weighted images. On follow-up contrast-enhanced T1-weighted studies, the lesions had well-defined enhancing margins with central low signal intensity. After the initiation of therapy, T2 signal abnormalities decreased markedly and contrast-enhanced studies showed ring enhancement. These T1 findings resolved with treatment over serial studies in four patients. The organisms identified were Streptococcus milleria, S pyogenes, atypical mycobacteria, Mycobacterium tuberculosis, and Schistosoma mansoni (both children). CONCLUSION: A characteristic sequence of imaging findings aids in the differentiation of cord infection from other intramedullary lesions.

Magnetic resonance evaluation of ventrolateral medullary compression in essential hypertension.

OBJECT: The authors designed a blinded prospective study comparing patients with essential hypertension to patients without hypertension in which magnetic resonance (MR) imaging was used to evaluate the role of lateral medullary compression by adjacent vascular structures as a cause of neurogenic hypertension. METHODS: Patients with documented essential hypertension were recruited to undergo thin-slice axial brainstem MR imaging evaluation. Nonhypertensive (control) patients scheduled to undergo MR imaging for other reasons also underwent thin-slice MR imaging to form a basis for comparison. Magnetic resonance images obtained in patients from the hypertensive (30 patients) and the control (45 patients) groups were then compared by four independent reviewers (two neuroradiologists and two neurosurgeons) who were blinded to the patients' diagnosis and hypertensive status. Images were reviewed with regard to left versus right vertebral artery (VA) dominance, compression of the medulla on the left and/or right side, and brainstem rotation. Medullary compression was graded as either vessel contact without associated brainstem deformity or vessel contact with associated brainstem deformity. CONCLUSIONS: There was a tendency toward left VA dominance in the hypertensive group compared with the control group, although a significant difference was shown by only one of the four reviewers. There were no differences in brainstem compression or rotation between the hypertensive and nonhypertensive groups. These results are contrary to those of recently published studies in which MR imaging and/or MR angiography revealed lateral brainstem vascular compression in hypertensive patients but not in nonhypertensive (control) patients. Reasons for this discrepancy are discussed. On the basis of their own experience and that of others, the authors believe that neurogenic hypertension does exist. However, thin-slice MR imaging may not be a reliable method for detecting neurovascularly induced essential hypertension and the prevalence of neurovascular compression as the source of hypertension may be overestimated when using current imaging techniques.

Correlation of Continuous EEG Monitoring with [O-l5]H2O Positron Emission Tomography Determination of Cerebral Blood Flow during Balloon Test Occlusion of the Internal Carotid Artery. Experience in 34 cases.

SUMMARY: The purpose of this paper was to evaluate the utility of continuous electroencephalography (EEG) during balloon test occlusion (BTO) of the internal carotid artery (ICA). Continuous EEG monitoring and [O-15] H2O PET cerebral blood flow (CBF) studies were completed in 34 patients undergoing BTO of the ICA. CBF determinations were obtained as a baseline without carotid occlusion, and following balloon occlusion, with continuous EEG monitoring. Patients were divided into three groups based on clinical and CBF response to BTO. Group I had no clinical signs or symptoms and had a CBF decrease less than 10 ml/l00 g/min ipsilateral to the occlusion. Group II had no symptoms but CBF fell to 35 to 25 ml/l00 g/min on the occluded side. Group III were clinically unable to tolerate occlusion or CBF fell to less than 25 ml/l00 g/min on the occluded side. The results of continuous 21 channel EEG monitoring were assessed at the time of the examination and retrospectively reviewed for changes in the EEG pattern indicative of ischaemia. On the basis of PET CBF, eighteen patients were classified as Group I, four as Group II, and twelve as Group III. EEG evidence of ischaemia was seen in three patients, all members of Group III. Of the three patients, only one patient had clinical signs or symptoms of ischaemia. All four patients in Group II had PET quantitated CBF levels indicating carotid sacrifice should be done with caution or following a presacrifice by-pass procedure, and nine patients in Group III with PET quantitated CBFs below eligibility for carotid sacrifice, were not identified by EEG monitoring. Even when CBF falls below 25 ml/100 g/minute continuous EEG monitoring is insensitive to reduction in perfusion. Reliance upon EEG for detection of cerebral hypoperfusion in interventionl neuroradiological procedures will significantly underestimate ischaemic risk.