Longitudinal evaluation of diffusion tensor imaging and cognition in systemic lupus erythematosus.

Objective This pilot study aimed to examine longitudinal changes in brain structure and function in patients with systemic lupus erythematosus (SLE) using diffusion tensor imaging (DTI) and neuropsychological testing. Methods Fifteen female SLE patients with no history of major neuropsychiatric (NP) manifestations had brain magnetic resonance imaging (MRI) with DTI at baseline and approximately 1.5 years later. At the same time points, a standardized battery of cognitive tests yielding a global cognitive impairment index (CII) was administered. At baseline, the SLE patients had mean age of 34.0 years (SD = 11.4), mean education of 14.9 years (SD = 2.1), and mean disease duration of 121.5 months (SD = 106.5). The MRI images were acquired with a 3T GE MRI scanner. A DTI sequence with 33 diffusion directions and b-value of 800 s/mm2 was used. Image acquisition time was about 10 minutes. Results No significant change in cognitive dysfunction (from the CII) was detected. Clinically evaluated MRI scans remained essentially unchanged, with 62% considered normal at both times, and the remainder showing white matter (WM) hyperintensities that remained stable or resolved. DTI showed decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in bilateral cerebral WM and gray matter (GM) with no major change in NP status, medical symptoms, or medications over time. Lower FA was found in the following regions: left and right cerebral WM, and in GM areas including the parahippocampal gyrus, thalamus, precentral gyrus, postcentral gyrus, angular gyrus, parietal lobe, and cerebellum. Greater MD was found in the following regions: left and right cerebral WM, frontal cortex, left cerebral cortex, and the putamen. Conclusions This is the first longitudinal study of DTI and cognition in SLE, and results disclosed changes in both WM and GM without cognitive decline over an 18-month period. DTI abnormalities in our participants were not associated with emergent NP activity, medical decline, or medication changes, and the microstructural changes developed in the absence of macrostructural abnormalities on standard MRI. Microstructural changes may relate to ongoing inflammation, and the stability of cognitive function may be explained by medical treatment, the variability of NP progression in SLE, or the impact of cognitive reserve.

Functional Magnetic Resonance Imaging of Working Memory and Executive Dysfunction in Systemic Lupus Erythematosus and Antiphospholipid Antibody-Positive Patients.

OBJECTIVE: Standardized cognitive tests and functional magnetic resonance imaging (fMRI) studies of systemic lupus erythematosus (SLE) patients demonstrate deficits in working memory and executive function. These neurobehavioral abnormalities are not well studied in antiphospholipid syndrome, which may occur independently of or together with SLE. This study compares an fMRI paradigm involving motor skills, working memory, and executive function in SLE patients without antiphospholipid antibody (aPL) (the SLE group), aPL-positive non-SLE patients (the aPL-positive group), and controls. METHODS: Brain MRI, fMRI, and standardized cognitive assessment results were obtained from 20 SLE, 20 aPL-positive, and 10 healthy female subjects with no history of neuropsychiatric abnormality. RESULTS: Analysis of fMRI data showed no differences in performance across groups on bilateral motor tasks. When analysis of variance was used, significant group differences were found in 2 executive function tasks (word generation and word rhyming) and in a working memory task (N-Back). Patients positive for aPL demonstrated higher activation in bilateral frontal, temporal, and parietal cortices compared to controls during working memory and executive function tasks. SLE patients also demonstrated bilateral frontal and temporal activation during working memory and executive function tasks. CONCLUSION: Compared to controls, both aPL-positive and SLE patients had elevated cortical activation, primarily in the frontal lobes, during tasks involving working memory and executive function. These findings are consistent with cortical overactivation as a compensatory mechanism for early white matter neuropathology in these disorders.

Site differences in mild cognitive dysfunction (MCD) among patients with systemic lupus erythematosus (SLE).

BACKGROUND: Mild cognitive dysfunction (MCD) is common in patients with systemic lupus erythematosus (MCD-SLE) but few studies have investigated potential site differences. METHODS: SLE patients from Denver, CO, and New York, NY, were enrolled in two different cognition studies employing similar screening methods. Using the resulting neuropsychological scores, cognitive impairment was calculated using a cognitive impairment index (CII). RESULTS: The rate of MCD-SLE was 24% at the Denver, CO, site and 60% at the New York, NY, site. The mean CII was 2.6 ± 2.3 versus 4.4 ± 2.7, respectively (p = 0.005). The NY participants had a significantly longer disease duration (p = 0.13) and higher American College of Rheumatology SLE criteria scores (p > 0.001). NY participants had a higher frequency of impairment in semantic verbal fluency (p = 0.005), visuomotor speed (p = 0.013), and motor sequencing (p = 0.001). A correlation was found between cognitive impairment and SLE disease duration (p = 0.03). CONCLUSIONS: The rate of MCD-SLE was greater in SLE patients from New York, NY, compared to patients in the Denver, CO, area. The greater duration of disease and higher prevalence of medical complications in the NY group might contribute to this difference. Findings suggest that MCD-SLE may differ by site, but future studies that better evaluate site or selection bias are recommended.

Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations.

OBJECTIVE: This study examined the relationship between immune, cognitive and neuroimaging assessments in subjects with systemic lupus erythematosus (SLE) without histories of overt neuropsychiatric (NP) disorders. METHODS: In total, 84 subjects with nonNPSLE and 37 healthy controls completed neuropsychological testing from the American College of Rheumatology SLE battery. Serum autoantibody and cytokine measures, volumetric magnetic resonance imaging, and magnetic resonance spectroscopy data were collected on a subset of subjects. RESULTS: NonNPSLE subjects had lower scores on measures of visual/complex attention, visuomotor speed and verbal memory compared with controls. No clinically significant differences between nonNPSLE patients and controls were found on serum measures of lupus anticoagulant, anticardiolipin antibodies, beta 2-glycoproteins, or pro-inflammatory cytokines (interleukin (IL)-1, IL-6, interferon alpha (IFN-alpha), and interferon gamma (IFN-gamma)). Higher scores on a global cognitive impairment index and a memory impairment index were correlated with lower IFN-alpha. Few associations between immune functions and neuroimaging parameters were found. CONCLUSIONS: Results indicated that nonNPSLE patients demonstrated cognitive impairment but not immune differences compared with controls. In these subjects, who were relatively young and with mild disease, no relationship between cognitive dysfunction, immune parameters, or previously documented neuroimaging abnormalities were noted. Immune measures acquired from cerebrospinal fluid instead of serum may yield stronger associations.

Memory impairment associated with neurometabolic abnormalities of the hippocampus in patients with non-neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Memory impairment is common in patients with systemic lupus erythematosus (SLE). This study examined hippocampal volumes and neurometabolic alterations in relation to memory function in SLE patients without a history of neuropsychiatric syndromes (nonNPSLE). METHODS: Subjects included 81 nonNPSLE patients and 34 healthy controls. Volumetric magnetic resonance imaging and magnetic resonance spectroscopy of the right and left hippocampal areas (RH, LH) were performed. Verbal and visual memory tests were administered and a memory impairment index (MII) was derived from standardized tests. RESULTS: Higher memory impairment (MII) was correlated with lower RH glutamate + glutamine/creatine (p = 0.009) and lower RH N-acetylaspartic acid/creatine (p = 0.012) in nonNPSLE patients. A trend for a negative correlation between RH and LH volumes and MII was evident for absolute hippocampal volumes. Lower RH glutamate + glutamine/creatine was also correlated with worse performance in a mean visual memory index (p = 0.017). CONCLUSIONS: An association between reduced memory and lower N-acetylaspartic acid/creatine in the RH suggests neuronal damage in nonNPSLE patients with very mild and early disease. Alterations in glutamate + glutamine/creatine further indicate early metabolic changes in nonNPSLE are related to memory impairment, a finding that might suggest that memory impairment relates to presynaptic glutamatergic dysfunction in the hippocampus.

PRNP H187R mutation associated with neuropsychiatric disorders in childhood and dementia.

Described is a large family with an autosomal dominant dementia associated with an H187R mutation in the prion protein gene (PRNP). Clinical features include neuropsychiatric disturbances in childhood and adolescence, dementia in young adulthood with frontotemporal manifestations, and long disease duration. Neuropathology revealed atrophy and mild gliosis, whereas prion protein analysis revealed an abnormal conformer with unusual sensitivity to protease digestion. Mutations in PRNP may cause neuropsychiatric disorders that predate dementia by many years.

Fulminant ascending paralysis as a delayed sequela of diethylene glycol (Sterno) ingestion.

The authors report a 57-year-old man who survived 18 days after swallowing an 8-oz. can of Sterno in a suicide attempt. Two days after ingestion, he developed confusion and acute renal failure requiring hemodialysis, followed on day 8 by a delayed but rapidly evolving ascending paralysis. Pathologic examination showed severe demyelination, with lesser axonal damage, of virtually all cranial and peripheral nerves sampled and sparing of central myelin. The diethylene glycol in the Sterno was considered responsible for this intoxication.

CADASIL: neuropsychological findings in three generations of an affected family.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary brain disease with a variety of neurologic and psychiatric manifestations. We studied 3 members of a family who each had leukoencephalopathy on neuroimaging studies and a characteristic mutation for CADASIL in the notch 3 region of chromosome 19q12. In all 3 cases, neurobehavioral impairment dominated the clinical picture, and a pattern of psychiatric dysfunction heralding cognitive decline emerged. Neuropsychological evaluation revealed diverse deficits, but a profile of frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, and relatively preserved language was evident. These cases provide a cross-sectional study of the evolution of CADASIL, and suggest that, as in other diseases characterized by white matter dementia, psychiatric dysfunction may occur initially, followed by pervasive cognitive dysfunction later in the course of the disease. CADASIL should be considered in young adults with unexplained leukoencephalopathy on neuroimaging studies, and in those with neurobehavioral dysfunction and a suggestive family history.

Toward an understanding of violence: neurobehavioral aspects of unwarranted physical aggression: Aspen Neurobehavioral Conference consensus statement.

OBJECTIVE: Violence is a global problem that poses a major challenge to individuals and society. This document is a consensus statement on neurobehavioral aspects of violence as one approach to its understanding and control. BACKGROUND: This consensus group was convened under the auspices of the Aspen Neurobehavioral Conference, an annual consensus conference devoted to the understanding of issues related to mind and brain. The conference is supported by the Brain Injury Association and by individual philanthropic contributions. Participants were selected by conference organizers to represent leading opinion in neurology, neuropsychology, psychiatry, trauma surgery, nursing, evolutionary psychology, medical ethics, and law. METHODS: A literature review of the role of the brain in violent behavior was conducted and combined with expert opinion from the group. The major goal was to survey this field so as to identify major areas of interest that could be targeted for further research. Additional review was secured from the other attendees at the Aspen Neurobehavioral Conference. RESULTS: The group met in the spring of 1998 and 1999 for two 5-day sessions, between which individual assignments were carried out. The consensus statement was prepared after the second meeting, and agreement on the statement was reached by participants after final review of the document. CONCLUSIONS: Violence can result from brain dysfunction, although social and evolutionary factors also contribute. Study of the neurobehavioral aspects of violence, particularly frontal lobe dysfunction, altered serotonin metabolism, and the influence of heredity, promises to lead to a deeper understanding of the causes and solution of this urgent problem.

N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer's disease.

The N-methyl-D-aspartate (NMDA) receptor is a subtype of the ionotropic glutamate receptor that plays a pivotal role in synaptic mechanisms of learning and memory. We tested the hypothesis that NMDA receptor protein levels are abnormal in Alzheimer's disease (AD). By immunoblotting, we assessed levels of both non-phosphorylated and phosphorylated receptor subunit proteins from four separate regions of 16 post-mortem brains. Three patient groups with thorough pre-mortem neuropsychological testing were evaluated, including AD, early AD (p-AD), and control patients. Protein levels and phosphorylation status of NMDA receptor subunits NR1, NR2A and NR2B were correlated with measurements of cognitive performance. Selective regional reductions in NMDA receptor subunit protein levels were found in AD compared to controls, but protein levels in the p-AD group were similar to controls. Reductions of NR1 (53%, P<0.05) and NR2B (40%, P<0.05) were identified in hippocampus. Reductions of NR2A (39%, P<0.05) and NR2B (31%, P<0.01) were found in entorhinal cortex. No reductions were noted in occipital cortex and caudate. Phosphorylated NR2A (30%, P<0.05) and NR2B (56%, P<0.01) were selectively reduced in entorhinal cortex in AD when compared to controls. Both phosphorylated and non-phosphorylated NMDA receptor protein levels in entorhinal cortex correlated with Mini-Mental Status Examination (MMSE) and Blessed (BIMC) scores. The losses of phosphorylated and non-phosphorylated NMDA receptor subunit proteins correlated with changes in synaptobrevin levels (a presynaptic protein), but not with age or post-mortem interval. Our results demonstrate that NMDA receptor subunits are selectively and differentially reduced in areas of AD brain, and these abnormalities correlate with presynaptic alterations and cognitive deficits in AD.

Clinical neurology and executive dysfunction.

Executive function is a uniquely human ability that permits an individual to plan, carry out, and monitor a sequence of actions that is intended to accomplish a goal. This crucial neurobehavioral capacity depends on the integrity of the frontal lobes, most importantly the dorsolateral prefrontal cortices and their connections. Executive dysfunction is associated with a wide range of neurologic disorders that affect these regions. In this paper, executive dysfunction is considered from the perspective of behavioral neurology, and the lesion method is employed to illustrate this impairment in a diverse group of disorders. Frontal system damage leading to disturbed executive function is common and clinically significant. Recognition of this syndrome is critical for ensuring the correct diagnosis, accurate prognosis, and appropriate treatment of affected patients. Executive dysfunction also represents an intriguing aspect of brain-behavior relationships and offers important insights into one of the highest cerebral functions.

Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains.

We tested whether regional or selective alterations in presynaptic proteins occur in Alzheimer's disease (AD) and correlate with tests of cognitive function. We measured the levels of seven presynaptic proteins (synaptobrevin, synaptotagmin, SNAP-25, syntaxin, SV2, Rab3a, and synapsin I) by immunoblotting in postmortem tissue from four brain regions (hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex). Three subject groups were studied: AD, possible/early AD (p-AD), and age-matched controls. Synaptobrevin and synaptotagmin were significantly reduced (29%, P<0.08; 38%, P<0. 07) in hippocampus in p-AD compared to controls. In definite AD compared to controls, selective regional reductions in vesicle proteins were found: synaptobrevin (46%, P<0.05), synaptotagmin (52%, P<0.01), and Rab3a (30%, P<0.05) in hippocampus; synaptobrevin (31%, P<0.01), synaptotagmin (15%, P<0.05), and Rab3a (44%, P<0.05) in entorhinal cortex. In contrast, the levels of two vesicle proteins (synapsin I and SV2) and two presynaptic membrane proteins (syntaxin and SNAP-25) were similar to controls. Synaptobrevin was the only vesicle protein reduced in AD in all four brain regions (occipital cortex 37%, P<0.05; caudate nucleus 31%, P<0.05). By univariate analysis of all cases, Mini-Mental State Examination, Blessed (BIMC) and Free Recall scores were strongly correlated with reduced levels of synaptic vesicle proteins synaptobrevin, synaptotagmin, and Rab3a in hippocampus and entorhinal cortex. These results suggest that there are selective and early defects in presynaptic vesicle proteins, but not synaptic plasma membrane proteins in AD and that defects correlate with cognitive dysfunction in this disease.

A twin MRI study of size variations in human brain.

Although it is well known that there is considerable variation among individuals in the size of the human brain, the etiology of less extreme individual differences in brain size is largely unknown. We present here data from the first large twin sample (N=132 individuals) in which the size of brain structures has been measured. As part of an ongoing project examining the brain correlates of reading disability (RD), whole brain morphometric analyses of structural magnetic response image (MRI) scans were performed on a sample of adolescent twins. Specifically, there were 25 monozygotic (MZ) and 23 dizygotic (DZ) pairs in which at least one member of each pair had RD and 9 MZ and 9 DZ pairs in which neither member had RD. We first factor-analyzed volume data for 13 individual brain structures, comprising all of the neocortex and most of the subcortex. This analysis yielded two factors ("cortical" and "subcortical") that accounted for 64% of the variance. We next tested whether genetic and environmental influences on brain size variations varied for these two factors or by hemisphere. We computed intraclass correlations within MZ and DZ pairs in each sample for the cortical and subcortical factor scores, for left and right neocortex, and for the total cerebral volume. All five MZ correlations were substantial (r's=.78 to.98) and significant in both samples, as well as being larger than the corresponding DZ correlations, (r's=0.32 to 0.65) in both samples. The MZ-DZ difference was significant for 3 variables in the RD sample and for one variable in the smaller control sample. These results indicate significant genetic influences on these variables. The magnitude of genetic influence did not vary markedly either for the 2 factors or the 2 hemispheres. There was also a positive correlation between brain size and full-scale IQ, consistent with the results of earlier studies. The total cerebral volume was moderately correlated (r=.42, p<.01, two-tailed) with full-scale IQ in the RD sample; there was a similar trend in the smaller control sample (r=.31, p<.07, two-tailed). Corrections of similar magnitude were found between the subcortical factor and full-scale IQ, whereas the results for the cortical factor (r=.16 and.13) were smaller and not significant. In sum, these results provide evidence for the heritability of individual differences in brain size which do not vary markedly by hemisphere or for neocortex relative to subcortex. Since there are also correlations between brain size and full-scale IQ in this sample, it is possible that genetic influences on brain size partly contribute to individual differences in IQ.

Impaired auditory gating and P50 nonsuppression following traumatic brain injury.

Traumatic brain injury (TBI) can produce persistent attention and memory impairment that may in part be produced by impaired auditory sensory gating. The P50 evoked waveform response to paired auditory stimuli appears to be a useful measure of auditory gating. The first controlled measurement of the P50 ratio in TBI patients is described: when 20 patients with persistently symptomatic TBI were compared with 20 control subjects, the P50 ratio was significantly greater in the TBI group. The potential neurophysiologic and therapeutic implications of this finding in TBI patients who report symptoms consistent with impaired auditory gating are discussed.

Dementia DDx. Office diagnosis of the four major types of dementia.

The prevalence of dementia increases with age from 1% at age 60 to about 40% at age 85. Four types of dementia--Alzheimer's disease, diffuse Lewy body dementia, frontotemporal dementia, and vascular dementia--account for 90% of all cases. The office-based physician can recognize these dementing illnesses in older patients by using existing consensus criteria. Differential diagnosis has an important bearing on patient management and prognosis, due to the potential value of treatment with some medications, possible drug toxicities in certain circumstances, and the complex care needs of patients and their families.

One and one-half syndrome with supranuclear facial weakness: magnetic resonance imaging localization.

OBJECTIVE: To provide clinicoanatomical correlation for a small pontine tegmental ischemic stroke producing the one and one-half syndrome associated with supranuclear facial weakness. DESIGN: Case report. SETTING: Tertiary care center. PATIENT: A 70-year-old man developed left-sided facial weakness sparing the forehead, a left internuclear ophthalmoplegia, and a complete left horizontal gaze palsy immediately after percutaneous transluminal coronary angioplasty. Magnetic resonance imaging demonstrated a small lesion in the left paramedian aspect of the dorsal pontine tegmentum. MAIN OUTCOME AND RESULTS: Electromyographic findings were consistent with supranuclear facial involvement. The patient had nearly complete recovery after 1 year. CONCLUSIONS: To our knowledge, this is the first report of supranuclear facial weakness in association with the one and one-half syndrome. The location of the lesion provides evidence of the existence of corticofugal fibers that extend to the facial nucleus in the dorsal paramedian pontine tegmentum.

Brief recall tasks and memory assessment in Alzheimer's disease.

Memory measures that permit pattern and error analysis are useful in the differential diagnosis of dementia. However, little is known about the relative utility or relations among verbal memory tests of different lengths. A 6-item verbal learning test (6-VLT) that assesses qualitative performance features was developed and compared to 3-word recall and the California Verbal Learning Test (CVLT) in patients with Alzheimer's disease. Stronger correlations were observed between the 6-VLT and the CVLT. Significant relations were found between 6-VLT and CVLT indexes of learning, recall, and recognition (hits and false positive errors), although free recall errors were unrelated. Brief tasks such as the 6-VLT may provide more useful information regarding gross memory capacity than 3-word recall, although more challenging tasks may be required to elicit characteristic error patterns in Alzheimer's disease.

Toxic leukoencephalopathy.

The white matter of the brain is vulnerable to a wide variety of toxins. Leukoencephalopathy is being increasingly recognized in a number of different patient populations. The detection of early and subtle toxin effects has been facilitated by the advent of magnetic resonance imaging, which offers better resolution of white matter than other neuroimaging methods. Neuropathologic features of leukoencephalopathy are also becoming more completely elucidated. Injury to white matter has been described from cranial irradiation and cancer chemotherapeutic drugs, and from a number of other therapeutic agents, drugs of abuse, and environmental toxins. Many patients have reversible leukoencephalopathy, whereas others experience a progressive and irreversible course. Leukoencephalopathy is associated with neurobehavioral manifestations that may be subtle or devastating, and the syndrome of white matter dementia may result. The pathogenesis of toxic leukoencephalopathy remains largely unknown, and treatment is limited in most cases to prevention by avoidance or minimization of the toxin exposure. However, the prognosis for this syndrome may be relatively favorable because of the frequent sparing of axons even when myelin is affected. Toxic leukoencephalopathy is an emerging clinical disorder that presents the opportunity for improving clinical outcomes in a number of patient groups and for achieving a deeper understanding of the role of white matter in cognitive and emotional function.