Diffusion tensor imaging of normal-appearing white matter in mild cognitive impairment and early Alzheimer disease: preliminary evidence of axonal degeneration in the temporal lobe.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) is a sensitive technique for studying cerebral white matter. We used DTI to characterize microstructural white matter changes and their associations with cognitive dysfunction in Alzheimer disease (AD) and mild cognitive impairment (MCI). MATERIALS AND METHODS: We studied elderly subjects with mild AD (n = 6), MCI (n = 11), or normal cognition (n = 8). A standardized clinical and neuropsychological evaluation was conducted on each subject. DTI images were acquired, and fractional anisotropy (FA), axial diffusivity (DA), and radial diffusivity (DR) of normal-appearing white matter (NAWM) in frontal, temporal, parietal, and occipital lobes were determined. These diffusion measurements were compared across the 3 groups, and significant differences were further examined for correlations with tests of cognitive function. RESULTS: Compared with normal controls, AD subjects demonstrated decreased FA and increased DR in the temporal, parietal, and frontal NAWM and decreased DA in temporal NAWM. MCI subjects also showed decreased FA and decreased DA in temporal NAWM, with decreased FA and increased DR in parietal NAWM. Diffusion measurements showed no differences in occipital NAWM. Across all subjects, temporal lobe FA and DR correlated with episodic memory, frontal FA and DR correlated with executive function, and parietal DR significantly correlated with visuospatial ability. CONCLUSIONS: We found evidence for functionally relevant microstructural changes in the NAWM of patients with AD and MCI. These changes were present in brain regions serving higher cortical functions, but not in regions serving primary functions, and are consistent with a hypothesized loss of axonal processes in the temporal lobe.

The relationship between homocysteine, cognition and stroke subtypes in acute stroke.

BACKGROUND: Elevations in plasma homocysteine (Hcy) have been associated with an increased risk of stroke and dementia. The mechanisms underlying these associations remain poorly understood. OBJECTIVES: This study examines the relationships between Hcy, cognition, and stroke subtype. We hypothesize that: 1) Hcy levels are inversely related to cognition, 2) Hcy levels are unrelated to stroke subtype, and 3) stroke subtype affects cognition. METHODS: We studied 169 consenting patients admitted for acute stroke during a 4 month period. Blood was drawn for Hcy levels and the Mini-Mental State Examination (MMSE) was administered within 9 days of admission. The Oxfordshire Community Stroke Project Classification was used to characterize stroke subtypes. Correlation between Hcy and MMSE scores was examined as was the relationships between Hcy and stroke subtype, and between stroke subtypes and MMSE scores. RESULTS: A significant inverse correlation between Hcy levels and MMSE scores was demonstrated (r=-0.243, p=0.001). MMSE scores also differed according to the type of stroke, with Total or Partial Anterior Circulation Infarcts (TACI/PACI) scoring lowest (F=8.77, df=2, p<0.001). Hcy levels did not differ between the various stroke subtypes (F=0.21, df=2, p=0.81). Multivariate linear regression analysis showed that age, education, and stroke subtype, but not Hcy, were independent predictors of acute MMSE scores. CONCLUSIONS: In this study sample, there was an inverse relationship between Hcy and cognition in acute stroke patients. However, Hcy was not an independent predictor for cognition in acute stroke after other factors such as stroke subtype and patient age were taken into account. These results suggest that during the acute stage of stroke, stroke subtype is a more important factor in determining cognition than Hcy levels.

Hemidystonia precipitated by acute pontine infarct.

Hemidystonia is frequently due to an underlying structural lesion in the basal ganglia and thalamus. It has been suggested that a preserved corticospinal tract may be required for hemidystonia to manifest. We provide the first report of a patient who presented with rapid-onset hemidystonia precipitated by an acute pontine infarct demonstrated on diffusion-weighted magnetic resonance imaging. Acute dysregulation of pallidal efferents to the pedunculopontine and/or pontine afferents to the thalamus may precipitate hemidystonia.

Correction of positron emission tomography data for cerebral atrophy.

Because positron emission tomography (PET) provides measurements per unit volume of intracranial contents, these measurements may be affected by the inclusion of metabolically inactive CSF spaces in the volume in which they are made. Thus, PET measurements of CBF and metabolism may be artifactually lowered in normal aging and dementia, which are both associated with significant brain atrophy. We describe a method to correct global PET data, averaged over several tomographic slices, for cerebral atrophy by using measurements of CSF space volume obtained with quantitative x-ray computed tomography. The importance of making such a correction is demonstrated using PET measurements of CBF and oxygen metabolism obtained in normal young, normal elderly, and demented subjects.

Cortical and subcortical neuropeptides in Alzheimer's disease.

Given the clinical features of AD, the severe atrophy of cerebral cortex that accompanies the disease, and the predominant cortical location of plaques and tangles, it is not surprising to find the most consistent changes in neuropeptides in this disease occurring in the cerebral cortex. The neuropeptide changes that have been reproducibly demonstrated in AD are reduced hippocampal and neocortical SS and CRF concentrations and a reduced CSF level of SS. In cerebral cortex, SS and CRF are found in GABAergic local circuit neurons in layers II, III, and VI. The function of these neurons is not well established, although these cells may act to integrate the flow of incoming and outgoing information in cerebral cortex. If this is true, then dysfunction of this integration could produce widespread failure of cerebrocortical function, resulting in the various neurobehavioral deficits seen in AD. The interpretation of neuropeptide changes in subcortical brain regions, either those that project to cortex, or those that are the efferent targets of cortical projections, is also uncertain. The observed neuropeptide abnormalities in these brain regions in AD are less consistent than are those seen in cerebral cortex. Perhaps the most intriguing result in these regions is the increases in galanin-immunoreactive terminals seen in the nucleus basalis of AD brains. Galanin has been shown to inhibit acetylcholine release and to impair memory function in rats (46,113).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment trial of oxiracetam in Alzheimer's disease.

Twenty-four carefully assessed patients with probable Alzheimer's disease were enrolled in a double-blind, placebo-controlled treatment study of oxiracetam, a nootropic agent reported to improve memory performance in patients with dementia. A broad battery of neuropsychological tests failed to reveal any improvement in the treated group or in any treated patient when individual test scores were analyzed. These findings indicate that oxiracetam is ineffective in reducing cognitive impairment due to Alzheimer's disease.

Neuropeptide changes in cortical and deep gray structures in Alzheimer's disease.

The alteration of certain neuropeptide levels is a dramatic and consistent finding in the brains of AD patients. Levels of SS, which is normally present in high concentrations in cerebral cortex /75/, are consistently decreased in the neocortex, hippocampus and CSF of AD patients. In addition, decreased levels of SS correlate regionally with the distribution of neurofibrillary tangles in AD /47/. Most available evidence suggests that the subset of SS-containing neurons which lack NADPH diaphorase may be relatively vulnerable to degeneration in AD. CRF is another neuropeptide with frequently observed changes in AD. Levels of CRF, which is normally present in low concentrations in cortical structures /75/, are decreased in the neocortex and hippocampus of AD patients. However, levels of CRF in the CSF of AD patients are not consistently reduced, but this is likely a reflection of the relatively low levels of CRF normally present in cerebral cortex. Studies of deep gray structures in AD brains reveal elevated levels of GAL in the nucleus basalis. The ability of GAL to inhibit cholinergic neurotransmission has generated considerable interest, since degeneration of cholinergic neurons in the basal forebrain consistently occurs in AD. In addition, the presence of NADPH diaphorase in GAL-containing neurons may underlie the relative resistance of these neurons to degeneration. From the aforementioned studies, it appears that the neurons which are relatively resistant to neurodegeneration in AD contain NADPH diaphorase. It is hypothesized that the presence of NADPH diaphorase protects these neurons from neurotoxicity mediated by glutamate or nitric oxide. Although one recent study /147/ has reported an elevation of the microtubule-associated protein tau in the CSF of AD patients (and this could become a useful antemortem diagnostic tool for AD), no similar CSF abnormality has been found for any of the neuropeptides. Thus, the measurement of CSF neuropeptide levels presently remains unhelpful in the diagnosis and treatment of AD. Future research on neuropeptides and their potential roles in the pathogenesis, diagnosis, and treatment of AD will likely involve further development of pharmacological modulators of neuropeptide systems, together with the further study of brain neuropeptidases.

Treatment of agitation in AD: a randomized, placebo-controlled clinical trial.

BACKGROUND: Treatment of agitation is a crucial problem in the care of patients with AD. Although antipsychotic and antidepressant medications and behavior management techniques (BMT) have each been used to treat agitation, clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment designs. OBJECTIVE: To compare haloperidol, trazodone, and BMT with placebo in the treatment of agitation in AD outpatients. METHODS: A total of 149 patients with AD and their caregivers participated in a randomized, placebo-controlled, multicenter trial. Blind assessment was conducted at baseline and after 16 weeks of treatment. The three active treatments were haloperidol, trazodone, and BMT. The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure. Secondary outcomes included patient agitation, cognition, and function, and caregiver burden. RESULTS: Thirty-four percent of subjects improved relative to baseline. No significant differences on outcome were obtained between haloperidol (mean dose, 1.8 mg/d), trazodone (mean dose, 200 mg/d), BMT, or placebo. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm. No other significant difference in adverse events was seen. Symptoms did not respond differentially to the different treatments. CONCLUSIONS: Comparable modest reductions in agitation occurred in patients receiving haloperidol, trazodone, BMT, and placebo. More effective pharmacologic, nonpharmacologic, and combination treatments are needed.

Recurrent jaw dislocation after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis.

Botulinum toxin (BTX) has been used successfully to treat various movement disorders, and is increasingly used for many other medical conditions. Sialorrhoea is a disabling symptom in many neurological patients including those with Parkinson's disease, stroke and amyotrophic lateral sclerosis (ALS). BTX has recently been shown to be effective for treating sialorrhoea. We report an ALS patient who developed recurrent jaw dislocation following BTX treatment for sialorrhoea to highlight the observation that intraparotid BTX may be complicated by jaw dislocations in some at-risk ALS patients. Clinicians using BTX to treat sialorrhoea in ALS need to be aware of this potentially serious complication.

Reversible parkinsonism in systemic lupus erythematosus.

Parkinsonism as a manifestation of central nervous system (CNS) lupus is extremely rare. We report the first patient with systemic lupus erythematosus (SLE) who developed a reversible parkinsonian syndrome associated with enhancing subcortical lesions on magnetic resonance imaging (MRI). Following treatment with prednisolone and cyclophosphamide, her bradyphrenia, bradykinesia, hypophonia, rigidity, and abnormal gait progressively improved. Three months after she commenced treatment, repeat MRI scanning demonstrated resolution of the abnormal subcortical white matter enhancement. Our case illustrates unusual clinico-radiologic correlates of reversible parkinsonism in a SLE patient; these findings suggest that disruption of the subcortical frontal pathways may be a possible pathophysiologic mechanism for parkinsonism in cerebral lupus.

Autonomic dysfunction in Parkinson's disease: a comprehensive symptom survey.

BACKGROUND: Autonomic dysfunction occurs in Parkinson's disease (PD), but few studies have addressed it in a comprehensive manner. METHODS: Autonomic symptoms were evaluated by a questionnaire in sixty-eight subjects (44 patients and 24 controls). RESULTS: PD patients experienced higher frequency and severity of autonomic dysfunction. When all autonomic symptoms were pooled into an aggregate score, differences between patients and controls were highly statistically significant (p<0.0001). 'Increased salivation', 'frequency of dysphagia', decreased 'BM (bowel movement) frequency', i.e. constipation, and 'orthostatic dizziness' were more frequent in PD patients (p<0.05). A prediction model to determine the predictors of autonomic dysfunction was unsuccessful. CONCLUSION: Differences in the prevalence of autonomic symptoms in PD and non-parkinsonian controls are apparent from this study.

Dementia in urban black outpatients: initial experience at the Emory satellite clinics.

The purpose of this study is to describe demographic features and clinical diagnoses in a sample of demented urban black outpatients and to report the frequency of different causes of dementia in this patient sample. Retrospective chart review was used to identify demented black outpatients who had completed a full neurodiagnostic evaluation and had received clinical diagnoses using standardized research diagnostic criteria. Probable Alzheimer's disease was the most common cause of dementia in this sample (43% of cases). Probable vascular dementia was uncommon (7%). A multiple etiology dementia was identified in more than one third of the patients.

An analysis of test bias and differential item functioning due to race on the Mattis Dementia Rating Scale.

The Mattis Dementia Rating Scale (MDRS) is a commonly used cognitive measure designed to assess the course of decline in progressive dementias. However, little information is available about possible systematic racial bias on the items presented in this test. We investigated race as a potential source of test bias and differential item functioning in 40 pairs of African American and Caucasian dementia patients (N = 80), matched on age, education, and gender. Principal component analysis revealed similar patterns and magnitudes across component loadings for each racial group, indicating no clear evidence of test bias on account of race. Results of an item analysis of the MDRS revealed differential item functioning across groups on only 4 of 36 items, which may potentially be dropped to produce a modified MDRS that may be less sensitive to cultural factors. Given the absence of test bias because of race, the observed racial differences on the total MDRS score are most likely associated with group differences in dementia severity. We conclude that the MDRS shows no appreciable evidence of test bias and minimal differential item functioning (item bias) because of race, suggesting that the MDRS may be used in both African American and Caucasian dementia patients to assess dementia severity.

Effects of Stereo and Screen Size on the Legibility of Three-Dimensional Streamtube Visualization.

We report the impact of display characteristics (stereo and size) on task performance in diffusion magnetic resonance imaging (DMRI) in a user study with 12 participants. The hypotheses were that (1) adding stereo and increasing display size would improve task accuracy and reduce completion time, and (2) the greater the complexity of a spatial task, the greater the benefits of an improved display. Thus we expected to see greater performance gains when detailed visual reasoning was required. Participants used dense streamtube visualizations to perform five representative tasks: (1) determine the higher average fractional anisotropy (FA) values between two regions, (2) find the endpoints of fiber tracts, (3) name a bundle, (4) mark a brain lesion, and (5) judge if tracts belong to the same bundle. Contrary to our hypotheses, we found the task completion time was not improved by the use of the larger display and that performance accuracy was hurt rather than helped by the introduction of stereo in our study with dense DMRI data. Bigger was not always better. Thus cautious should be taken when selecting displays for scientific visualization applications. We explored the results further using the body-scale unit and subjective size and stereo experiences.

Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort.

BACKGROUND: The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population. METHODS: A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia. RESULTS: A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7. CONCLUSION: Stroke patients with cognitive impairment no dementia (CIND) moderate are at higher risk of developing dementia, while CIND mild patients are not at increased risk of developing dementia.

Galantamine treatment of vascular dementia: a randomized trial.

BACKGROUND: To evaluate efficacy and safety of galantamine for patients with vascular dementia (VaD). METHODS: In this multinational, randomized, double-blind, placebo-controlled, parallel-group clinical trial, 788 patients with probable VaD who also satisfied strict centrally read MRI criteria were randomized to receive galantamine or placebo. Efficacy was evaluated using measures of cognition, daily function, and behavior. The primary efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog/11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) total score. Secondary outcomes included the Clinician's Interview Based on Impression of Change-Plus Caregiver Input (CIBIC-plus), Neuropsychiatric Inventory, and EXIT-25 for assessment of executive functioning. Safety and tolerability were also monitored. RESULTS: Patients treated with galantamine had a greater improvement in ADAS-cog/11 after 26 weeks compared with placebo (-1.8 vs -0.3; p < 0.001). There was no difference between galantamine and placebo at week 26 on the ADCS-ADL score (0.7 vs 1.3; p = 0.783). Improvement in global functioning measured by the CIBIC-plus associated with galantamine approached significance (p = 0.069). A difference between treatment groups for EXIT-25 favoring galantamine was detected (p = 0.041). Safety data revealed that 13% of galantamine and 6% of placebo patients discontinued treatment because of adverse events. CONCLUSIONS: Significance was not reached for both co-primary endpoints. Galantamine was effective for improving cognition, including executive function, in patients with vascular dementia, with good safety and tolerability. However, improvement in activities of daily living with galantamine was similar to that observed with placebo.

Demographic and clinical features of Alzheimer disease in black Americans: preliminary observations on an outpatient sample in Atlanta, Georgia.

This exploratory study describes the frequency, demographic features, and clinical manifestations of Alzheimer disease (AD) in a sample of demented black outpatients evaluated at the Emory University Alzheimer's Disease Center. The study reviews prospectively collected research data from 88 demented black outpatients who completed a standardized diagnostic evaluation. Forty-seven percent of these patients met NINCDS-ADRDA criteria for probable AD, and 29% met NINCDS-ADRDA criteria for possible AD. The majority of the probable AD patients were women, and many were suffering from comorbid medical illnesses. In the probable AD patients, there was an association between higher levels of education and a higher frequency of affective symptoms, and an association between longer duration of cognitive symptoms and the presence of parkinsonism. Possible AD was also common in this sample of demented black outpatients and was often encountered mixed with vascular dementia.

Quantitative light microscopic demonstration of increased pallidal and striatal met5-enkephalin-like immunoreactivity in rats following chronic treatment with haloperidol but not with clozapine: implications for the pathogenesis of neuroleptic-induced movement disorders.

Acute and late onset movement disorders frequently complicate the treatment of psychosis with typical neuroleptic drugs like haloperidol, but not with atypical neuroleptic drugs like clozapine. Although the neural mechanisms underlying neuroleptic-induced movement disorders remain unknown, alterations in basal ganglia function are likely involved. A potential role for the endogenous opiate peptides in neuroleptic-induced movement disorders is suggested by the immunocytochemical localization of met5-enkephalin (ME) in the striatopallidal projection pathway, and by the increased levels of ME measured by radioimmunoassay in the rat caudate-putamen nuclei (CPN) following haloperidol treatment. We sought to determine whether met5-enkephalin-like immunoreactivity (MELI) in terminal fields within globus pallidus and in perikarya in CPN was differentially altered in rats chronically treated with haloperidol or clozapine. Acrolein-fixed forebrain sections were collected from cohorts of adult rats receiving 21-day oral administration of haloperidol, clozapine, or water. Sections from the three treatment groups were collectively processed for immunocytochemical labeling using varying dilutions of ME antiserum and the avidin-biotin peroxidase method. In globus pallidus, densitometry measures revealed significantly increased levels of immunoperoxidase labeling for ME in haloperidol-treated, but not in clozapine-treated animals. In CPN, optical densitometry as well as cell counting measurements also showed a significant increase in MELI only in the haloperidol-treated group. These results support the concept that alterations in endogenous opiate peptides in basal ganglia may contribute to movement disorders seen in patients receiving typical neuroleptic drugs.(ABSTRACT TRUNCATED AT 250 WORDS)