Obsessive-compulsive disorder associated with brain lesions: clinical phenomenology, cognitive function, and anatomic correlates

We studied the behavioral, cognitive, and neuroimaging characteristics of obsessive-compulsive disorder (OCD) in 13 patients with focal brain lesions (acquired OCD) and compared their clinical features and the severity of obsessive and compulsive (OC) symptoms with patients with idiopathic OCD. Both OCD groups were further compared with matched normal controls on a series of neuropsychological tests. Patients with acquired OCD had a negative familial history and later age at onset of OCD symptoms than patients with idiopathic OCD. The two OCD groups showed relatively similar clinical phenomenology, severity of OC symptoms, and profile of neuropsychological deficits. Compared with normal control subjects, both OCD groups showed cognitive deficits affecting attention, intellectual function, memory, word retrieval, and motor and executive functions. Eight of the 13 patients with acquired OCD had abnormal neurologic examinations, whereas only 3 of the 13 patients with idiopathic OCD had abnormal neurologic examinations. Neuroimaging in the acquired OCD group disclosed a variety of lesions involving exclusively the cerebral cortex (frontal, temporal, or cingulate regions), the basal ganglia, or both. These results suggest that acquired and idiopathic OCDs may share a common pathophysiologic mechanism, and that structural damage to specific frontal-limbic-subcortical circuits plays an important role in the pathogenesis of acquired OCD.     

The hereditary ataxias

Efforts to classify the hereditary ataxias by their clinical and neuropathological phenotypes are troubled by excessive heterogeneity. Linkage analysis opened the door to a new approach with the methods of molecular biology. The classic form of autosomal recessive ataxia, Friedreich's ataxia (FA), is now known to be due to an intronic expansion of a guanine-adenine-adenine (GAA)-trinucleotide repeat. The autosomal dominant ataxias such as olivopontocerebellar atrophy (OPCA), familial cortical cerebellar atrophy (FCCA), and Machado-Joseph disease (MJD) have been renamed the spinocerebellar ataxias (SCA). Specific gene loci are indicated as SCA-1, SCA-2, SCA-3, SCA-4, SCA-5, SCA-6, and SCA-7. In 5 of them (SCA-1, SCA-2, SCA-3, SCA-6, and SCA-7), expanded cytosine-adenine-guanine (CAG)-trinucleotide repeats and their abnormal gene products cause the ataxic condition. The most common underlying loci for olivopontocerebellar atrophy (OPCA) are SCA-1 and SCA-2, although other genotypes may be added in the future. A major recent advance was the identification of the gene for SCA-3 and MJD, and the high prevalence of this form of autosomal dominant ataxia. In FA and the SCA with expanded CAG-trinucleotide repeats, clinical and neuropathological severity are inversely correlated with the lengths of the repeats. Anticipation in the dominant ataxias can now be explained by lengthening of the repeats in successive generations. Progress is being made in the understanding of the pathogenesis of FA and SCA as the absent or mutated gene products are studied by immunocytochemistry in human and transgenic murine brain tissue. In FA, frataxin is diminished or absent, and an excess of mitochondrial iron may cause the illness of the nervous system and the heart. In SCA-3, abnormal ataxin-3 is aggregated in neuronal nuclei, and in SCA-6, a mutated alpha1A-calcium channel protein is the likely cause of abnormal calcium channel function in Purkinje cells and in the death of these neurons.     

Clinical and molecular features of spinocerebellar ataxia type 6

The mutation involved in spinocerebellar ataxia type 6 (SCA6) is a small CAG expansion in the alpha-1A subunit of the voltage-dependent calcium channel gene. We looked for this mutation in 91 families with autosomal-dominant cerebellar ataxias and found that SCA6 is a minor locus in our series (2%) and is rare in France (1%). Furthermore, we did not detect the SCA6 mutation on 146 sporadic cases with isolated cerebellar ataxia or olivopontocerebellar atrophy. The normal and expanded alleles ranged from 4 to 15 and 22 to 28 CAG repeats, respectively, and age at onset was correlated to CAG repeat length (r = -0.87). In contrast with other SCA, the expanded allele was stable during transmission. Clinically, SCA6 patients (n = 12) presented with moderate to severe cerebellar ataxia with a lower frequency of associated signs compared with other SCA and a mean age at onset of 45 +/- 14 years (range, 24 to 67). MRI showed extensive cerebellar atrophy but not of the brainstem or cerebral cortex.     

Donor-specific cytotoxic lymphocyte activity from bronchoalveolar lavage during acute canine lung allograft rejection

OBJECTIVE: We investigated the relationship between acute lung rejection and donor-specific cytotoxic activity (DSCA) in recipient's lymphocytes obtained from bronchoalveolar lavage (BAL). METHODS: A total of 26 mongrel dogs underwent left lung allotransplantation. Dogs received either no immunosuppressive treatment (group I), cyclosporine (group II), or cyclosporine and methylprednisolone for evidence of acute rejection (group III). DSCA was measured by a 51Cr release assay, using lymphocytes from BAL samples as effector cells and 51Cr-labeled donor skin fibroblasts as target cells. The pathologic findings of the transplanted lungs were classified according to the working formulation for classification and grading of pulmonary rejection. In addition, the degree of cellular infiltration in the perivascular, peribronchial, interstitial, and intraalveolar areas was determined based on an infiltration score. RESULTS: DSCA in BAL samples was elevated during mild, moderate and severe acute rejection. The accuracy of the diagnosis of mild or moderate rejection was 92.3% at effector:target (E:T) ratios of 100:1 and 50:1. The DSCA in the BAL fluid and the total infiltration score were correlated closely with correlation coefficients of 0.859 and 0.828 at E:T ratios of 100:1 in group I and group II dogs, respectively. Lung aeration improved and DSCA decreased with methylprednisolone therapy in three of four dogs with grade 2 rejection. CONCLUSION: There is a direct relationship between the DSCA in BAL fluid and the degree of tissue damage caused by acute rejection. The DSCA can be detected by a 51Cr release assay which may hold promise for future clinical applications.     

Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adult-onset hereditary ataxia in Scotland

A systematic search for cases of adult-onset hereditary ataxia was conducted on location in Scotland. The investigation resulted in the discovery of eight pedigrees with 42 patients of whom 16 were alive in 1975. Nine patients were examined by the authors and recent hospital records were available on the remaining seven. The clinical features were quite variable. In declining order of frequency, findings were gait and limb ataxia, dysarthria, hyperreflexia, extrapyramidal motor disturbances, impaired vibratory sense, spasticity, defects of extraocular movements and nystagmus, reflex depression, Babinski signs, impaired joint position sense, muscle weakness, optic atrophy, and mental abnormalities. Foot deformity occurred only once. Inheritance was compatible with autosomal dominant transmission, but complicated by consanguinity in two families. The minimum prevalence was calculated as 0.31/100,000. Autopsy in two members in one family revealed olivopontocerebellar degeneration.     

Functional results and long-term outcome after bilateral lung transplantation for pulmonary hypertension

With the growing popularity of soccer both in the United States and worldwide, reports of adverse effects of 'heading' on brain function are a source of concern. This article reviews the related research literature on neurologic and neuropsychological findings. Neurologic and neuropsychological abnormalities have been reported in a significant minority of older former professional players in Norway. Purportedly unrelated to age, the most prominent findings were cerebral atrophy and impairment on intelligence test abilities that are particularly vulnerable to brain damage. Also noteworthy in these retired players were persistent physical, cognitive, and emotional complaints consistent with a postconcussive syndrome. Younger amateur players appear to be free of major abnormalities, although some report persistent difficulties with memory and concentration. The severity of these complaints may be related to a history of soccer-related head injuries and not necessarily specific to heading. Research findings specific to heading are not more than suggestive at best, and clarification of the risks of heading a soccer ball awaits more definitive studies.     

Ability of counselors to detect cognitive impairment among substance-abusing patients: An examination of diagnostic efficiency.

Counselors (N?=?12) in 1 of 2 substance abuse treatment facilities were asked to identify which of their patients (N ?=?97) had general neurocognitive impairment. Counselors were required to base their judgements on information collected from patients during psychosocial history gathering, clinical interviews, physical examinations, brief cognitive screening tests, and substance abuse severity evaluations, but not on neuropsychological test results. All patients were subsequently administered a neuropsychological test battery. Diagnostic agreement between counselors' impressions of patients' cognitive status and patients' actual neuropsychological test performance was poor. Subsequent analyses revealed counselors' impressions about patients' neuropsychological functioning were based on information that did not reliably discriminate between cognitively impaired and intact patients (e.g., years of education and self-reported symptoms of cognitive dysfunction). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropsychological functioning in older insomniacs with or without obstructive sleep apnea.

The relationships between neuropsychological functioning and sleep loss, sleep apnea, and hypoxemia were examined. Forty-five older insomniacs (M age?=?64.6 yrs) with or without sleep apnea were administered neuropsychological tests after 1 night of nocturnal monitoring in a sleep laboratory. The results showed few differences on cognitive and psychomotor performance between individuals with sleep disruptions alone compared with those whose insomnia was associated with sleep apnea and hypoxemia. There were no significant relationships between nocturnal sleep and respiratory variables and daytime functioning. Furthermore, cognitive and psychomotor performance in older insomniacs with or without sleep apnea revealed minimal impairment compared with age-matched normative data. The results suggest that when the severity of sleep disruptions is controlled, there are minimal differences in neuropsychological functioning of older adults with mild to moderate sleep apnea compared with those without apnea. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitivity to ethanol-induced ataxia in HOT and COLD selected lines of mice

Studies with inbred strains of mice have suggested that there may be a genetic correlation between strain sensitivities to the ataxic and hypothermic responses to ethanol (EtOH), which would suggest that some genes influence both responses. To test this hypothesis, EtOH sensitivity was determined in replicate lines of mice selectively bred for sensitivity (COLD) or resistance (HOT) to acute ethanol hypothermia. Several tests were used to index ataxia, related traits such as muscle strength, and locomotor activity. The screen test yielded a dose-dependent EtOH-induced decrease in performance that did not differ between the selected lines. Based on the dose-response characteristics of this task, 2.5 g/kg of EtOH was used as the test dose for the remaining experiments. Results from the fixed-speed rotarod and the grid test of motor incoordination also indicated no significant differences between HOT and COLD mice in sensitivity to EtOH impairment. When the selected lines were tested on an accelerating rotarod, COLD mice were impaired by the acute EtOH injection, but HOT mice were unaffected. COLD mice were more sensitive to EtOH-induced decrements in grip strength and locomotor activity. Overall, the results indicated that HOT and COLD mice were only differentially sensitive to EtOH in some tasks related to ataxia, suggesting that some genes must be associated uniquely with EtOH-induced hypothermia or ataxia. The mixed results from the various tests indicate that ataxia can best be conceived as a group of related complex behaviors that cannot be assessed adequately by the use of a single task and that ataxia-related behaviors are influenced by different groups of genes.     

Cholinergic neuron-specific ganglioside GQ1b alpha a possible target molecule for serum IgM antibodies in some patients with sensory ataxia

In neurological diseases the presence of certain anti-glycosphingolipid antibody species is associated with the clinical features. We recently isolated the novel cholinergic neuron-specific gangliosides GQ1b alpha and GT1a alpha from bovine brain. A monoclonal antibody specific for GQ1b alpha and GT1a alpha reacted strongly with the dorsal born of human spinal cord but not with human motor neurons. We investigated the serum antibodies to these minor gangliosides in a number of neurologic diseases and found that 4 patients with sensory ataxic neuropathy had a remarkably high IgM anti-GQ1b alpha antibody titer. GQ1b alpha may be a target molecule for serum IgM antibodies in some patients with sensory ataxic neuropathy.     

Sex differences in neuropsychological functioning of first-episode and chronically ill schizophrenic patients

OBJECTIVE: The purpose of this study was to determine whether men and women with schizophrenia demonstrate differences in cognitive abilities. METHOD: Two cohorts of patients with schizophrenia, an acute first-episode and a chronically hospitalized group, were evaluated with a neuropsychological battery and compared with a normal group of subjects. RESULTS: After adjustment for age, age at onset, and premorbid IQ, male chronic patients performed worse than female chronic patients on measures of visual memory. These differences were eliminated after control for symptom severity. No other differences were found in cognitive function between men and women in either cohort. CONCLUSIONS: Sex differences in cognitive function in schizophrenic patients are not robust findings.     

Neuropsychological symptom presentation after electrical injury

OBJECTIVE: This study explored the relationship of neuropsychological complaints to accident- and injury-related characteristics, affective state, and work status in a group of electrical injury (EI) patients. METHODS: Sixty-three EI patients and 22 electricians with no history of electrical shock completed the Neuropsychological Symptom Checklist and the Beck Depression Inventory as part of an extensive neuropsychological evaluation. RESULTS: The EI group endorsed significantly more physical, cognitive, and emotional symptoms than did the controls. Symptom complaints were not related to injury parameters or litigation status. Only the time interval between injury and assessment accounted for differences in symptom presentation, with patients in the postacute stages of recovery showing the most cognitive and emotional complaints. CONCLUSION: The neuropsychological syndrome of electrical injury survival includes physical, cognitive, and emotional complaints. Considering that most electrically injured patients are treated within the acute medical setting, greater attention needs to be directed early in the course of treatment toward addressing neuropsychologic and psychiatric issues.     

Motivational reserve: Lifetime motivational abilities contribute to cognitive and emotional health in old age.

The authors recently developed the concept of motivational reserve, which implies a set of motivational abilities that provide individuals with resilience to neuropathological damage. This study investigated how lifetime motivational abilities are associated with current cognitive status, mild cognitive impairment, and psychological well-being in old age. A community sample of 147 participants without dementia between 60 and 94 years of age, stratified for age group, sex, and education, completed motivation and well-being questionnaires and cognitive tests. A new procedure was used to estimate their midlife motivational and cognitive abilities on the basis of their main occupation using the Occupational Information Network (O*NET) system. O*NET-estimated motivational abilities predicted cognitive status, psychological well-being, and odds of mild cognitive impairment, even when age, sex, education, and cognitive ability were controlled. Although O*NET-estimated cognitive abilities were not significant predictors, scores on a measure of crystallized intelligence were associated with current cognitive status and odds of mild cognitive impairment. Findings suggest that motivational reserve acts as a protective factor against the manifestation of cognitive impairment and emotional problems in later life. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inferior parietal perfusion, lateralization, and neuropsychological dysfunction in Alzheimer's disease

The severity of inferior parietal perfusion deficits in Alzheimer's disease (AD) is strongly associated with global intellectual decline. The relationship to specific losses of neuropsychological functioning, however, is less clear, as is the relative importance of the side (left vs. right) of hemispheric deficit. In this study, 53 patients with probable AD and 35 elderly controls received both a resting 133Xe rCBF measurement and neuropsychological examination. AD patients demonstrated the expected bilateral deficits in inferior parietal perfusion, as well as impairment on measures of mental status, intelligence verbal and visual memory, attention, language, and construction abilities. The severity of this bilateral parietal deficit, in turn, was associated with virtually all of these AD-related neuropsychological impairments, most strongly with declining Performance IQ. Left-sided deficits correlated better with overall declines in IQ, as well as with declining attention and language fluency. Right-sided deficits, on the other hand, correlated best with declines in mental status and--paradoxically--verbal memory and contributed independently to declines in Full Scale and Performance IQ. In terms of the number and strength of their association to neuropsychological measures, left-sided deficits appear much more predicative of cognitive decline in AD. Right-sided deficits, however, may be most important in predicting aspects of performance skill that are only indirectly assessed in standard paper-and-pencil format. Overall, it appears that both sides make significant, but independent contributions to general functional decline in AD, but that left-sided deficits are more closely associated with cognitive decline in measured by most standard neuropsychological measures.     

Characterizing amnesic patients for neurobehavioral study.

One complicating feature of neuropsychological testing with amnesic patients is the fact that amnesic patients differ in terms of the pattern of their lesions and in terms of what damage is present in addition to the lesions that cause amnesia. Accordingly, as the questions asked of amnesic patients have become more sophisticated, it has become increasingly important in every group of study patients to obtain information about both the severity and the selectiveness of memory impairment. The suitability of several memory tests and other cognitive tests for the purpose of characterizing amnesic patients is considered. Data from these tests are presented for 10 amnesic patients (6 with Korsakoff's syndrome, 3 with amnesia owing to anoxia or ischemia, and case N.A.), who constitute our standing population of study patients, and for two control groups. Data from most of the tests are also presented for patients who were amnesic following bilateral electroconvulsive therapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.     

Ataxia and a cerebellar defect in the exencephaly-prone SELH/Bc mouse stock

SELH/Bc inbred mice have an abnormal mechanism of anterior neural tube closure and 10-20% of embryos have a lethal neural tube closure defect, exencephaly. Our previous studies have focused on this multifactorial threshold trait. However, SELH mice are also characterized by another trait that also shows non-Mendelian transmission ratios, an ataxia recognized in juvenile and adult mice. Here we report our first genetic and morphological studies of the ataxia trait. Recent pedigree records for the SELH colony showed that 7% of the 467 weaned progeny from normal breeding pairs were ataxic; 17 of the 20 pairs produced ataxic progeny. This result was statistically consistent with the hypothesis that all SELH mice have the ataxic genotype, which is expressed in only 7% of them. Genetic studies of an outcross to a normal strain and the subsequent F2 and testcross of the F2 were also done. The results were consistent with a one or two gene locus cause of liability to ataxia in SELH mice. The genetic correlation between exencephaly production and ataxia production for a sample of nine F2 males was 0.35, as expected if both traits are caused by the same genes, but was not statistically significant. In another approach, we examined the morphology of brains from normal and ataxic adult SELH mice. All 20 brains from non-ataxic SELH mice were morphologically normal. In all 18 brains from ataxic SELH mice the cerebellum was abnormal, lacking the vermis, and characterized by a midline fissure. This phenotype in mice has previously been known in Mendelian mutants at the Wnt-1 locus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atm-deficient mice: a paradigm of ataxia telangiectasia

A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. The majority of animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulate the ataxia telangiectasia phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder.     

The Relationship Between Neuropsychological Functioning and Driving Ability in Dementia: A Meta-Analysis.

A meta-analysis of 27 primary studies was conducted to examine the relationship between neuropsychological functioning and driving ability for adults with dementia. When studies using a control group were included, the relationship between cognitive measures and on-road or non-road driving measures was significant for all reported domains; mean correlations ranged from .35 to .65. Caregiver reports of driving ability and cognitive variables were correlated significantly only on measures of mental status and visuospatial skills. When studies using a control group were excluded, moderate mean correlations were observed for visuospatial skills and on-road or non-road measures, and for mental status with non-road tests. Other effects were small or nonsignificant. Implications for basing driving recommendations on neuropsychological testing are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)