Genome-wide estimate of the heritability of Multiple System Atrophy.

INTRODUCTION: Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis. METHODS: We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform. RESULTS: We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis. DISCUSSION: MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants.

Comparison of patients with and without poststroke major depression matched for size and location of lesion.

Patients who developed major depression within two years following stroke (n = 13) were compared with patients who did not become depressed in the same period (n = 13) but who did have a similar size and location of lesion as in the depressed group. Although the depressed patients were not significantly different from the nondepressed patients in background characteristics, history of depressive disorder, neurological impairment, or social functioning, the depressed group had greater cognitive impairment as measured by Mini-Mental State score. In addition, the depressed group had significantly larger lateral and third ventricular to brain ratios than nondepressed patients on computed tomographic scan analysis. The results suggest that poststroke depression itself may produce an intellectual impairment; subcortical atrophy, which likely preceded the stroke lesion, may produce a vulnerability for depression following stroke.

The dose-response ratio in electroconvulsive therapy a preliminary study.

To investigate pretreatment patient variables that might correlate with dose-response characteristics of electroconvulsive therapy (ECT) and treatment outcomes, 14 patients were assessed on a daily basis, before and during treatment, using self-report affective scales, three simple paper-and-pencil tests of cognitive function,and finger-tapping speed. From these data, dose-response ratios and treatment outcome measures were derived. The dose-response ratio of ECT was found to correlate with age--the younger the patient, the more favorable the ratio. This finding is discussed in terms of the known relationships between brain monoamine oxidase levels and age, and the established relationship between seizure duration and treatment efficacy. The dose-response ratio over the first two electroconvulsive treatments as well as lesser degrees of initial congnitive and greater degrees of initial affective impairment correlated strongly with greater overall affective improvement. Some clinical and research implications of these findings are discussed.

Relationship between anxiety disorders and depressive disorders in patients with cerebrovascular injury.

The interaction between anxiety disorder and major depressive disorder in patients with cerebrovascular lesions was examined in a controlled, 2 x 2 study design. A consecutive series of 24 patients who met criteria for major depression only were compared with 6 patients who met criteria for both major depression and generalized anxiety disorder, and 45 patients who did not meet criteria for either major depression of generalized anxiety. Among patients with positive computed tomographic scans, the anxious-depressed group (n = 19) showed a significantly higher frequency of cortical lesions, while patients with major depression only (n = 15) had a significantly higher frequency of subcortical (basal ganglia) strokes. No significant between-group differences were found in other variables, such as demographic variables, familial and personal history of psychiatric disorders, and neurologic deficits. These findings suggest that, in this mostly black, low-socioeconomic-status population, cortical vs subcortical lesion location may play an important role in determining whether severe anxiety occurs in patients with post-stroke major depression.

Alcohol intake, type of beverage, and the risk of cerebral infarction in young women.

BACKGROUND AND PURPOSE: The relationship between alcohol consumption and cerebral infarction remains uncertain, and few studies have investigated whether the relationship varies by alcohol type or is present in young adults. We examined the relationship between alcohol consumption, beverage type, and ischemic stroke in the Stroke Prevention in Young Women Study. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. Case patients (n=224) were aged 15 to 44 years with a first cerebral infarction, and control subjects (n=392), identified by random-digit dialing, were frequency matched by age and region of residence. The interview assessed lifetime alcohol consumption and consumption and beverage type in the previous year, week, and day. ORs were obtained from logistic regression models controlling for age, race, education, and smoking status, with never drinkers as the referent. RESULTS: Alcohol consumption, up to 24 g/d, in the past year was associated with fewer ischemic strokes (<12 g/d: OR 0.57, 95% CI 0. 38 to 0.86; 12 to 24 g/d: OR 0.38, 95% CI 0.17 to 0.86; >24 g/d: OR 0.95, 95% CI 0.43 to 2.10) in comparison to never drinking. Analyses of beverage type (beer, wine, liquor) indicated a protective effect for wine consumption in the previous year (<12 g/wk: OR 0.58, 95% CI 0.35 to 0.97; 12 g/wk to <12 g/d: OR 0.55, 95% CI 0.28 to 1.10; >/=12 g/d: OR 0.92, 95% CI 0.23 to 3.64). CONCLUSIONS: Light to moderate alcohol consumption appears to be associated with a reduced risk of ischemic stroke in young women.

Severe depressive pseudodementia with and without dementia.

Recent work has documented the existence of the syndrome of pseudodementia. The authors present four cases of depressive pseudodementia, two without associated dementing illnesses and two that occurred in the context of dementing illnesses. These cases emphasize the difficult nature of differential diagnosis and the profound cognitive impairment that can occur in depressive illness. They also document the coexistence of pseudodementia with "true" dementia. The authors discuss diagnostic and management issues for clinicians treating patients with pseudodementia and depressive illness.

Two-year longitudinal study of post-stroke mood disorders: comparison of acute-onset with delayed-onset depression.

Patients who developed post-stroke depression 3 to 24 months after hospital discharge (N = 21) were compared with patients who developed depression during hospitalization (N = 26) and patients who never developed depression over 24 months of follow-up (N = 15). During the acute hospitalization and at follow-up, the three groups were not significantly different in their demographic characteristics, neurological impairment, intellectual impairment, or quality of social support. The acute depression group, however, showed an increased correlation between impairment and depression from hospitalization to follow-up. Findings suggest that impairment does not produce depression, but, once depression occurs, it may interact with impairment to influence post-stroke recovery.

Comparison of mania and depression after brain injury: causal factors.

Patients who developed secondary mania after brain injury (N = 17) had a significantly greater frequency of injury to right hemisphere areas connected with the limbic system than poststroke patients with major depression (N = 31), who had injury primarily in the left frontal cortex and basal ganglia. For patients without mood disturbance after brain injury (N = 28), the location of the lesion was not significant. Secondary mania patients also had a significantly greater frequency of family history of affective disorder than did the other two groups. These results suggest that an interaction between injury to certain areas of the right hemisphere and genetic factors or other neuropathological conditions produces secondary mania.

The dexamethasone suppression test and mood following stroke.

Dexamethasone suppression tests (DSTs) were given to 65 acute and chronic stroke patients. For patients who had had a stroke less than 1 year earlier, nonsuppression on the DST was significantly associated with the presence of poststroke depression. The authors, who used the DSM-III symptom criteria for major depression, found that DST sensitivity was 67% but specificity was only 70%. False positive tests in the stroke patients seemed related to large lesion volume. The DST, although of limited clinical utility in this population because of false positive tests, may help define more homogeneous subtypes of poststroke depression for research.

Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study.

OBJECTIVE: This study was undertaken to test the reliability and validity of the Pathological Laughter and Crying Scale and the effectiveness of nortriptyline treatment for patients with emotional lability following stroke. METHOD: Eighty-two patients with ischemic brain injury-54 who had been hospitalized with acute stroke and 28 others who requested treatment for pathological laughing and crying--were given standardized psychiatric and neurological assessments and then administered the Pathological Laughter and Crying Scale. The 54 acute stroke patients were used to evaluate the Pathological Laughter and Crying Scale, and the 28 patients with pathological emotional display were randomly assigned to nortriptyline treatment or placebo in a 6-week double-blind trial to assess the efficacy of a tricyclic antidepressant in treatment of this disorder. RESULTS: The interrater reliability on the Pathological Laughter and Crying Scale for a subgroup of 15 patients was 0.93, and the test-retest reliability of the scale was excellent. After 4 and 6 weeks of treatment, scores on the Pathological Laughter and Crying Scale showed significantly greater improvement in the 14 patients given nortriptyline than in the 14 given placebo. Although almost one-half of these patients also had major depression, the improvement in emotional lability was independent of depression status. In addition, response to treatment was not significantly affected by lesion location or time since stroke. CONCLUSIONS: The severity of symptoms in pathological emotional display can be reliably quantified with the Pathological Laughter and Crying Scale, and treatment with nortriptyline can effectively ameliorate this emotional disorder.

Lateralization of dementia of depression in stroke patients.

In a group of stroke patients with left-hemisphere lesions, those with major depression performed significantly below nondepressed patients on four of nine cognitive domains examined with a neuropsychological test battery. Among patients with right-hemisphere stroke, those with major depression did not perform below nondepressed patients on any of the nine cognitive domains. The differential effect of depression on cognitive performance between left- and right-hemisphere lesion groups could not be accounted for by demographic variables, neurological symptoms, lesion location, or lesion size. Poststroke major depression appeared to produce a decline in cognitive performance or dementia of depression that depended on the laterality of the lesion.

Are depressive symptoms nonspecific in patients with acute stroke?

OBJECTIVE: Some investigators have suggested that major depression might be overdiagnosed in stroke patients because of changes in appetite, sleep, or sexual interest caused by their medical illness; others have suggested that depression may be underdiagnosed in stroke patients who deny symptoms of depression because of anosognosia, neglect, or aprosody. The authors' goal was to determine how frequently depressive symptoms occur in acute stroke patients with and without depressed mood to estimate how often diagnostic errors of inclusion or exclusion may be made. METHOD: They examined the rate of autonomic and psychological symptoms of depression in 205 patients who were consecutively hospitalized for acute stroke. Eighty-five (41%) of these patients had depressed mood, and 120 (59%) had no mood disturbance. Forty-six (54%) of the 85 patients with depressed mood (22% of all patients) were assigned the DSM-III diagnosis of major depression. RESULTS: The 120 patients without mood disturbance had a mean of one autonomic symptom, but the 85 patients with depressed mood had a mean of almost four. Tightening the diagnostic criteria to account for one more nonspecific autonomic symptom decreased the number of patients with major depression by only three; adding two more criteria decreased the number by only five. Thus, the rate of DSM-III major depression was 1% higher than the rate with one extra nonspecific autonomic symptom and 2% higher than the rate with two extra criteria. Conversely, loosening diagnostic criteria to account for denial of depressive illness increased the rate of major depression by only 5%. CONCLUSIONS: Both autonomic and psychological depressive symptoms are strongly associated with depressed mood in acute stroke patients.

Association of depression with 10-year poststroke mortality.

OBJECTIVE: Depression has been linked to higher than expected mortality from natural causes, particularly among elderly patients with physical illness. The authors examined the effect of depression on mortality among a group of stroke patients followed up for 10 years. METHOD: A consecutive series of 103 patients was assessed for major or dysthymic (minor) depression approximately 2 weeks after stroke with the use of a structured mental status examination and DSM-III diagnostic criteria. Vital status was determined for 91 of these patients 10 years later. RESULTS: Forty-eight (53%) of the 91 patients had died. Patients with diagnoses of either major or minor depression were 3.4 times more likely to have died during the follow-up period than were nondepressed patients, and this relationship was independent of other measured risk factors such as age, sex, social class, type of stroke, lesion location, and level of social functioning. The mortality rate among depressed patients with few social contacts was especially high: over 90% had died. CONCLUSIONS: These results indicate that depressed mood following stroke is associated with an increased risk of subsequent mortality. Patients who are depressed and socially isolated seem to be particularly vulnerable.

Mood disorders in left-handed stroke patients.

Thirty left-handed patients hospitalized for stroke were examined for mood disorders. Patients with left hemisphere lesions and nondominant hand impairments had significantly higher depression scores and more depressive diagnoses than patients with right hemisphere lesions and dominant hand impairments. Major depression was strongly associated with left anterior brain injury, and depression severity was significantly correlated with proximity of the lesion on CAT scan to the left frontal pole. These findings are almost identical to previously reported results from right-handed patients and suggest that cerebral lateralization of poststroke mood disorders may be independent of cerebral motor dominance and language dominance.

Angioimmunoblastic lymphadenopathy. Its occurrence with meningeal involvement.

A case of angioimmunoblastic lymphadenopathy with involvement of the leptomeninges and the lumbosacral nerve roots was studied. This condition seems related to malignant lymphoma, and clinical improvement occurred with administration of systemic corticosteroids.

Differential mood changes following basal ganglia vs thalamic lesions.

Patients with computed tomographic scan-verified unilateral lesions in the basal ganglia or thalamus were examined for the presence of poststroke mood disorders. Patients with left-sided basal ganglia lesions (mainly in the head of the caudate nucleus) showed a significantly higher frequency and severity of depression, as compared with patients with right-sided basal ganglia or thalamic (left- or right-sided) lesions. Results suggest that damage to biogenic amine pathways and/or frontocaudate projections may play an important role in the modulation of mood.

Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study.

OBJECTIVE: To identify risk factors for and functional consequences of lacunar infarct in elderly people. METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years or older, in which 3660 participants underwent cranial magnetic resonance imaging (MRI). Neuroradiologists read scans in a standard fashion without any clinical information. Lacunes were defined as subcortical areas consistent with infarcts measuring 3 to 20 mm. In cross-sectional analyses, clinical correlates were contrasted among groups defined by MRI findings. RESULTS: Of the 3660 subjects who underwent MRI, 2529 (69%) were free of infarcts of any kind and 841 (23%) had 1 or more lacunes without other types present, totaling 1270 lacunes. For most of these 841 subjects, their lacunes were single (66%) and silent (89%), namely without a history of transient ischemic attack or stroke. In multivariate analyses, factors independently associated with lacunes were increased age, diastolic blood pressure, creatinine, and pack-years of smoking (listed in descending order of strength of association; for all, P < .005), as well as maximum internal carotid artery stenosis of more than 50% (odds ratio [OR], 1.81; P < .005), male sex (OR, 0.74; P < .005), and history of diabetes at entrance into the study (OR, 1.33; P < .05). Models for subgroups of single, multiple, silent, and symptomatic lacunes differed only minimally. Those with silent lacunes had more cognitive, upper extremity, and lower extremity dysfunction not recognized as stroke than those whose MRIs were free of infarcts. CONCLUSIONS: In this group of older adults, lacunes defined by MRI are common and associated with factors that likely promote or reflect small-vessel disease. Silent lacunes are also associated with neurologic dysfunction.

Computer-aided assessment of transient ischemic attacks. A clinical evaluation.

We developed and evaluated a computer-based system to assist with the difficult problem of assessing the conditions of patients with transient ischemic attacks (TIAs). The program used criteria to classify a patient's illness localize the neurologic deficit, screen for 46 causative or mimicking disorders, recommend additional tests, and suggest management steps. We evaluated this program in 103 patients with TIAs. The TIA program's localization and classification of patients generally agreed with those made by stroke specialists at our institution, demonstrating that computer programs can reproduce the decision criteria of stroke specialists. With revisions, the TIA program or similar systems could be useful for objective disease classification in clinical trials or epidemiologic studies. In contrast, the TIA program's treatment recommendations were often found to differ significantly from the actual treatments administered by non-stroke specialists.

The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up.

The impact of clinically diagnosed depression on recovery in activities of daily living over a 2-year follow-up was examined in a prospective study of 63 stroke patients. Although impairment in activities of daily living, neurologic diagnoses and findings, lesion location and volume as measured on computed tomographic scan, demographic variables, cognitive impairment, and social functioning were comparable between depressed (n = 25) and nondepressed (n = 38) patients during their acute hospitalization, the two groups had different patterns of recovery in activities of daily living. At 2 years after suffering a stroke, patients with an in-hospital diagnosis of depression (either major or minor depression) were significantly more impaired in both physical activities and language functioning than were non-depressed patients. Among patients with major depression, this disparity in the recovery profile was present even after the depression had remitted. This study emphasizes the need for early recognition and treatment of poststroke depression.

Thalamic stroke. Presentation and prognosis of infarcts and hemorrhages.

Thalamic strokes in 62 patients selected from the Stroke Data Bank were studied to determine differences among 18 infarctions (INF), 23 localized hemorrhages (ICH), and 21 hematomas with ventricular extension (IVH). Stupor or coma at onset occurred more frequently in the IVH (62%) than in the INF (6%) or ICH (13%) groups and was reflected in significantly lower median Glasgow Coma Scores in the IVH group (7) than in the INF (15) and ICH (14) groups. Although ocular movements were more frequently abnormal in the IVH group compared with the ICH and INF groups, no significant differences were found in the frequency of motor or sensory deficits. Among the 62 strokes, 32 had restricted lesions of the posterolateral (n = 9), anterior (n = 3), paramedian (n = 7), and dorsal (n = 13) portions of the thalamus. Differences in consciousness and in motor, sensory, and oculomotor deficits were found among the topographic subgroups. Stroke-related deaths occurred in 52% of IVH cases, 13% of ICH cases, and no cases of INF. Median lesion volume as detected with computed tomography was greater in hemorrhages (INF, 2 cm3; ICH, 10 cm3; IVH, 16 cm3), with mortality related to increasing hematoma size. Coma, Glasgow Coma Score lower than 9, weakness score greater than 15 of a possible 30, abnormal ocular movements, and fixed pupils were also associated with stroke-related mortality. We conclude that the initial neurologic syndrome does not discriminate infarcts from intrathalamic hemorrhages. Ventricular extension, however, causes significantly more severe deficits and higher mortality.