Showing papers in "Neurology in 2005"

Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.

Abstract: Background: AN1792 (beta-amyloid [Aβ]1–42) immunization reduces Aβ plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients. Methods: This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 μg plus the adjuvant QS-21 50 μg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale–Cognitive Subscale [ADAS–Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Aβ42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer ≥ 1:2,200). Results: Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS–Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 ± 0.37 vs -0.20 ± 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p Conclusion: Although interrupted, this trial provides an indication that Aβ immunotherapy may be useful in Alzheimer disease.

Midlife cardiovascular risk factors and risk of dementia in late life

Abstract: Objective: To evaluate if midlife cardiovascular risk factors are associated with risk of late-life dementia in a large, diverse cohort. Method: The authors conducted a retrospective cohort study of 8,845 participants of a health maintenance organization who underwent health evaluations from 1964 to 1973 when they were between the ages of 40 and 44. Midlife cardiovascular risk factors included total cholesterol, diabetes, hypertension, and smoking. Diagnoses of dementia were ascertained by medical records from January 1994 to April 2003. Results: The authors identified 721 participants (8.2%) with dementia. Smoking, hypertension, high cholesterol, and diabetes at midlife were each associated with a 20 to 40% increase in risk of dementia (fully adjusted Cox proportional hazards model: HR 1.24, 95% CI 1.04 to 1.48 for hypertension, HR 1.26, 95% CI 1.08 to 1.47 for smoking, HR 1.42, 95% CI 1.22 to 1.66 for high cholesterol, and HR 1.46, 95% CI 1.19 to 1.79 for diabetes). A composite cardiovascular risk score was created using all four risk factors and was associated with dementia in a dose-dependent fashion. Compared with participants having no risk factors, the risk for dementia increased from 1.27 for having one risk factor to 2.37 for having all four risk factors (fully adjusted model: HR 2.37, 95% CI 1.10 to 5.10). Conclusion: The presence of multiple cardiovascular risk factors at midlife substantially increases risk of late-life dementia in a dose dependent manner.

Cognitive profile of patients with newly diagnosed Parkinson disease

Abstract: Objective: To determine the frequency and pattern of cognitive dysfunction in patients with newly diagnosed Parkinson disease (PD) and to identify its demographic and clinical correlates. Methods: A cohort of 115 consecutive patients with newly diagnosed PD and 70 healthy controls underwent a comprehensive neuropsychological assessment including tests of psychomotor speed, attention, language, memory, executive and visuospatial functions, as well as measures of affective status. Patients also received quantitative ratings of motor symptom severity and functional status. Neuropsychological performance of PD patients was compared with that of healthy controls and with available normative data. Independent demographic and clinical predictors of cognitive impairment were identified with multiple logistic regression analysis. Results: Relative to controls, PD patients performed significantly worse on most cognitive measures. However, further analysis revealed that group differences in cognitive performance could mainly be explained by measures of immediate memory and executive function. Comparison with normative data showed that impairments were most frequent on measures of executive function, memory and psychomotor speed. In all, 24% of PD patients (4% of controls) displayed defective performance on at least three neuropsychological tests and were classified as cognitively impaired. Late onset of disease was an independent predictor of cognitive dysfunction in PD. Conclusion: Cognitive impairments are common even in newly diagnosed Parkinson disease patients, with deficits being most prominent in the domains of memory and executive functions. Older age at disease onset is likely to be an important determinant of cognitive dysfunction in Parkinson disease.

Multiple Sclerosis Severity Score: Using disability and disease duration to rate disease severity

Abstract: Background: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. Methods: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. Results: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. Conclusion: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD

Abstract: Objective: To use fMRI to investigate whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (MCI). Methods: Three groups of older individuals were studied: 10 cognitively intact controls, 9 individuals at the mild end of the spectrum of MCI, and 10 patients with probable Alzheimer disease (AD). Subjects performed a face-name associative encoding task during fMRI scanning, and were tested for recognition of stimuli afterward. Data were analyzed using a functional-anatomic method in which medial temporal lobe (MTL) regions of interest were identified from each individual9s structural MRI, and fMRI activation was quantified within each region. Results: Significantly greater hippocampal activation was present in the MCI group compared to controls; there were no differences between these two groups in hippocampal or entorhinal volumes. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The subjects with MCI performed similarly to controls on the fMRI recognition memory task; patients with AD exhibited poorer performance. Across all 29 subjects, greater mean entorhinal activation was found in the subgroup of 13 carriers of the APOE e4 allele than in the 16 noncarriers. Conclusions: The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer disease followed by a subsequent decrease as the disease progresses.

Prevalence and patterns of cognitive impairment in sporadic ALS.

Abstract: Objective: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study. Methods: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes. Results: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance. Conclusions: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Aggregation of vascular risk factors and risk of incident Alzheimer disease.

Abstract: Background: The prevalence of Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk. Objective: To explore the association of the aggregation of vascular risk factors with AD. Methods: The authors followed 1,138 individuals without dementia at baseline (mean age 76.2) for a mean of 5.5 years. The presence of vascular risk factors was related to incident possible and probable AD. Results: Four risk factors (diabetes, hypertension, heart disease, and current smoking) were associated with a higher risk of AD ( p p for trend Conclusions: The risk of Alzheimer disease (AD) increased with the number of vascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of AD. These associations are unlikely to be explained by misclassification of the outcome, given strong associations when only probable AD is considered.

The AD8: A brief informant interview to detect dementia

Abstract: Background: Brief measures that accurately discriminate normal cognitive aging from very mild dementia are lacking. Cognitive tests often are insensitive to very mild dementia. Informant-based measures may be more sensitive in detecting early dementia. Objective: To identify informant-reported clinical variables that differentiate cognitively normal individuals from those with very mild dementia. Methods: A 55-item battery of informant queries regarding an individual9s cognitive status was derived from a semistructured interview and a consensus panel of dementia experts. The battery was evaluated with informants for 189 consecutive participants of a longitudinal study of memory and aging and compared with an independently obtained Clinical Dementia Rating (CDR) score for the participant. Multiple regression and receiver operator characteristic curves assessed subsets of the items to discriminate between CDR 0 (no dementia) and CDR 0.5 (very mild dementia). Results: The final version (AD8) querying memory, orientation, judgment, and function was administered to an additional sample of 112 CDR 0 and 68 CDR 0.5 participants. Using a cut-off of two items endorsed, the area under the curve was 0.834, suggesting good to excellent discrimination, sensitivity was 74%, and specificity was 86% (prevalence of 0.38 for very mild dementia). Inclusion of 56 additional individuals with mild to severe dementia (increasing dementia prevalence to 0.53) increased sensitivity to 85%. Conclusions: The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

A developmental and genetic classification for malformations of cortical development

Abstract: Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

Distal symmetric polyneuropathy: A definition for clinical research Report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

Abstract: The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.

Safety and cognitive effect of frontal DC brain polarization in healthy individuals

Abstract: Background: Data from the human motor cortex suggest that, depending on polarity, direct current (DC) brain polarization can depress or activate cortical neurons. Activating effects on the frontal lobe might be beneficial for patients with frontal lobe disorders. This phase 1 study tested the safety of frontal DC, including its effects on frontal and other brain functions. Methods: The authors applied 20 minutes of anodal, cathodal, or sham DC to the left prefrontal cortex in three groups of right-handed subjects and looked for effects on global measures of processing and psychomotor speed, emotion, and verbal fluency, a measure of local cortical function. In one experiment (n = 30), the authors tested before and after 1 mA DC and monitored EEG in 9 subjects. In two other experiments using 1 mA (n = 43) and 2 mA (n = 30), the authors tested before and then starting 5 minutes after the onset of DC. Results: All subjects tolerated DC well. There were no significant effects on performance with 1 mA DC. At 2 mA, verbal fluency improved significantly with anodal and decreased mildly with cathodal DC. There were no clinically significant effects on the other measures. Conclusions: Limited exposure to direct current polarization of the prefrontal cortex is safe and can enhance verbal fluency selectively in healthy subjects. As such, it deserves consideration as a procedure to improve frontal lobe function in patients.

An open label study of the effects of rituximab in neuromyelitis optica

Abstract: Eight patients with worsening neuromyelitis optica were treated with rituximab to achieve B cell depletion. Treatment was well tolerated. Six of eight patients were relapse free and median attack rate declined from 2.6 attacks/patient/year to 0 attacks/patient/year (p = 0.0078). Seven of eight patients experienced substantial recovery of neurologic function over 1 year of average follow-up. The pretreatment median Expanded Disability Status Scale score was 7.5, and at follow-up examination was 5.5 (p = 0.013).

Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis

Abstract: Background: Central pain in multiple sclerosis (MS) is common and often refractory to treatment. Methods: We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic, seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment. Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours. Results: Sixty-four patients (97%) completed the trial, 34 received CBM. In week 4, the mean number of daily sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1 to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale. CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change −2.7, 95% CI: −3.4 to −2.0, placebo –1.4 95% CI: −2.0 to −0.8, comparison between groups, p = 0.005) and sleep disturbance (CBM mean change –2.5, 95% CI: −3.4 to −1.7, placebo –0.8, 95% CI: −1.5 to −0.1, comparison between groups, p = 0.003). CBM was generally well tolerated, although more patients on CBM than placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-term memory storage. Conclusions: Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.

Insulin therapy protects the central and peripheral nervous system of intensive care patients

Abstract: Objective: To investigate the effectiveness of maintaining blood glucose levels below 6.1 mmol/L with insulin as prevention of secondary injury to the central and peripheral nervous systems of intensive care patients. Methods: The authors studied the effect of intensive insulin therapy on critical illness polyneuropathy (CIPNP), assessed by weekly EMG screening, and its impact on mechanical ventilation dependency, as a prospectively planned subanalysis of a large randomized, controlled trial of 1,548 intensive care patients. In the 63 patients admitted with isolated brain injury, the authors studied the impact of insulin therapy on intracranial pressure, diabetes insipidus, seizures, and long-term rehabilitation at 6 and 12 months follow-up. Results: Intensive insulin therapy reduced ventilation dependency (p 0.0007; Mantel-Cox log rank test) and the risk of CIPNP (p 0.0001). The risk of CIPNP among the 405 long-stay (7 days in intensive care unit) patients was lowered by 49% (p 0.0001). Of all metabolic and clinical effects of insulin therapy, and corrected for known risk factors, the level of glycemic control independently explained this benefit (OR for CIPNP 1.26 (1.09 to 1.46) per mmol blood glucose, p 0.002). In turn, prevention of CIPNP explained the ability of intensive insulin therapy to reduce the risk of prolonged mechanical ventilation (OR 3.75 (1.49 to 9.39), p 0.005). In isolated brain injury patients, intensive insulin therapy reduced mean (p 0.003) and maximal (p 0.0001) intracranial pressure while identical cerebral perfusion pressures were obtained with eightfold less vasopressors (p 0.01). Seizures (p 0.0001) and diabetes insipidus (p 0.06) occurred less frequently. At 12 months follow-up, more brain-injured survivors in the intensive insulin group were able to care for most of their own needs (p 0.05). Conclusions: Preventing even moderate hyperglycemia with insulin during intensive care protected the central and peripheral nervous systems, with clinical consequences such as shortening of intensive care dependency and possibly better long-term rehabilitation. NEUROLOGY 2005;64:1348-1353

A sham stimulation-controlled trial of rTMS of the unaffected hemisphere in stroke patients

Abstract: The authors investigated the use of slow-frequency repetitive transcranial magnetic stimulation (rTMS) to the unaffected hemisphere to decrease interhemispheric inhibition of the lesioned hemisphere and improve motor function in patients within 12 months of a stroke. Patients showed a significant decrease in simple and choice reaction time and improved performance of the Purdue Pegboard test with their affected hand after rTMS of the motor cortex in the intact hemisphere as compared with sham rTMS.

Patients with ALS can use sensorimotor rhythms to operate a brain-computer interface.

Abstract: People with severe motor disabilities can maintain an acceptable quality of life if they can communicate. Brain-computer interfaces (BCIs), which do not depend on muscle control, can provide communication. Four people severely disabled by ALS learned to operate a BCI with EEG rhythms recorded over sensorimotor cortex. These results suggest that a sensorimotor rhythm-based BCI could help maintain quality of life for people with ALS.

Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease.

Abstract: Background: Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients. Objective: To assess cerebral volume changes in patients immunized with AN1792 (β-amyloid [Aβ] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of ≥1:2,200) compared with placebo patients. Methods: This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 μg plus QS-21 50 μg included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs. Results: Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 ± 1.98 vs 2.04 ± 1.74%; p = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 ± 0.75 vs 0.48 ± 0.40%; p p = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite z score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 ± 0.39 vs −0.24 ± 0.45; p = 0.008). Conclusions: A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.

Evidence of increased oxidative damage in subjects with mild cognitive impairment

Abstract: Objective: To determine if increased levels of oxidative damage are present in the brains of persons with mild cognitive impairment (MCI), a condition that often precedes Alzheimer disease (AD). Methods: The authors assessed the amount of protein carbonyls, thiobarbituric acid-reactive substances (TBARS), and malondialdehyde in the superior and middle temporal gyri (SMTG) and cerebellum of short postmortem interval and longitudinally evaluated normal subjects and those with MCI and early AD. Results: Elevated levels of protein carbonyls (∼25%), malondialdehyde (∼60%), and TBARS (∼210%) were observed in the SMTG of individuals with MCI and early AD vs normal control subjects. The elevation in TBARS was associated with the numbers of neuritic but not diffuse plaques. Levels of protein carbonyls increased as delayed verbal memory performance declined. Conclusion: Oxidative damage occurs in the brain of subjects with mild cognitive impairment, suggesting that oxidative damage may be one of the earliest events in the onset and progression of Alzheimer disease.

Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD.

Abstract: Objective: To test the hypotheses 1) that whole-brain volume decline begins in early adulthood, 2) that cross-sectional and longitudinal atrophy estimates agree in older, nondemented individuals, and 3) that longitudinal atrophy accelerates in the earliest stages of Alzheimer disease (AD). Methods: High-resolution, high-contrast structural MRIs were obtained from 370 adults (age 18 to 97). Participants over 65 (n = 192) were characterized using the Clinical Dementia Rating (CDR) as either nondemented (CDR 0, n = 94) or with very mild to mild dementia of the Alzheimer type (DAT, CDR 0.5 and 1, n = 98). Of these older participants, 79 belonged to a longitudinal cohort and were imaged again a mean 1.8 years after baseline. Estimates of gray matter (nGM), white matter (nWM), and whole-brain volume (nWBV) normalized for head sizes were generated based on atlas registration and image segmentation. Results: Hierarchical regression of nWBV estimates from nondemented individuals across the adult lifespan revealed a strong linear, moderate quadratic pattern of decline beginning in early adulthood, with later onset of nWM than nGM loss. Whole-brain volume differences were detected by age 30. The cross-sectional atrophy model overlapped with the rates measured longitudinally in older, nondemented individuals (mean decline of −0.45% per year). In those individuals with very mild DAT, atrophy rate more than doubled (−0.98% per year). Conclusions: Nondemented individuals exhibit a slow rate of whole-brain atrophy from early in adulthood with white-matter loss beginning in middle age; in older adults, the onset of dementia of the Alzheimer type is associated with a markedly accelerated atrophy rate.

Cognitive status correlates with neuropathologic stage in Parkinson disease

Abstract: Objective: To study the association of cognitive status with the stages of a published neuropathologic staging procedure for sporadic Parkinson disease (PD) in a cohort of 88 patients with PD from a single neurologic unit. None had received the clinical diagnosis of dementia with Lewy bodies (DLB). Methods: The authors assessed Lewy neurites/bodies (LNs/LBs) immunoreactive for α-synuclein semiquantitatively in sections from 18 brain regions. In silver-stained sections and sections immunostained for tau and β-amyloid protein, the authors semiquantitatively evaluated comorbidities potentially contributing to cognitive decline, e.g., Alzheimer disease (AD), argyrophilic grain disease (AGD), and cerebral vascular disease. The authors analyzed four Mini-Mental State Examination (MMSE) subgroups ranging from marginally impaired cognition to severe dementia using nonparametric tests. Results: It was possible to assign all patients to one of the PD stages. MMSE scores correlated with neuropathologic stages ( p p p p p p Conclusions: The decrease in median Mini-Mental State Examination scores between PD stages 3 to 6 indicates that the risk of developing dementia increases with disease progression. In some individuals, however, cognitive decline can develop in the presence of mild Parkinson disease–related cortical pathology and, conversely, widespread cortical lesions do not necessarily lead to cognitive decline.

The nature and frequency of cognitive deficits in children with neurofibromatosis type 1

Abstract: Objective: To assess the frequency and severity of specific cognitive deficits in children with neurofibromatosis type 1 (NF1) in a large unbiased cohort. Methods: Extensive cognitive assessments were performed in 81 children with NF1 ages 8 to 16 years and their performance was compared with that of 49 unaffected sibling controls. Results: Eighty-one percent of the children with NF1 had moderate to severe impairment in one or more areas of cognitive functioning. Although 51% of children with NF1 performed poorly on tasks of reading, spelling, and mathematics, specific learning disabilities (as defined by IQ–achievement discrepancies) were present in only 20% of the children. Sustained attention difficulties were present in 63% of children with NF1, with 38% of children with NF1 fulfilling the diagnostic criteria for attention deficit–hyperactivity disorder. The NF1 neuropsychological profile is characterized by deficits in perceptual skills (visuospatial and visuoperceptual), executive functioning (planning and abstract concept formation), and attention (sustained and switching). Interestingly, both verbal and visual memory was unaffected in NF1 children, and their memory skills were in general stronger than their level of general intellectual function. Although both expressive and receptive language skills were significantly impaired in NF1 children, they appeared to be relatively better preserved than visuospatial abilities once IQ is taken into account. Conclusion: There is an extremely high frequency of cognitive problems in children with neurofibromatosis type 1, making cognitive dysfunction the most common complication to affect quality of life in these children.

Epidemiology of vestibular vertigo: a neurotologic survey of the general population.

Abstract: Objective: The purpose of this study was to determine the prevalence and incidence of vestibular vertigo in the general population and to describe its clinical characteristics and associated factors. Methods: The neurotologic survey had a two-stage general population sampling design: nationwide modified random digit dialing sampling for participation in the German National Telephone Health Interview Survey 2003 (response rate 52%) with screening of a random sample of 4,869 participants for moderate or severe dizziness or vertigo, followed by detailed neurotologic interviews developed through piloting and validation (n = 1,003, response rate 87%). Diagnostic criteria for vestibular vertigo were rotational vertigo, positional vertigo, or recurrent dizziness with nausea and oscillopsia or imbalance. Vestibular vertigo was detected by our interview with a specificity of 94% and a sensitivity of 88% in a concurrent validation study using neurotology clinic diagnoses as an accepted standard (n = 61). Results: The lifetime prevalence of vestibular vertigo was 7.8%, the 1-year prevalence was 5.2%, and the incidence was 1.5%. In 80% of affected individuals, vertigo resulted in a medical consultation, interruption of daily activities, or sick leave. Female sex, age, lower educational level, and various comorbid conditions, including tinnitus, depression, and several cardiovascular diseases and risk factors, were associated with vestibular vertigo in the past year in univariate analysis. In multivariable analysis, only female sex, self-reported depression, tinnitus, hypertension, and dyslipidemia had an independent effect on vestibular vertigo. Conclusions: Vestibular vertigo is common in the general population, affecting more than 5% of adults in 1 year. The frequency and health care impact of vestibular symptoms at the population level have been underestimated.

Mild cognitive impairment is related to alzheimer disease pathology and cerebral infarctions

Abstract: Objectives: To examine the extent to which persons with mild cognitive impairment have intermediate levels of Alzheimer disease (AD) pathology, cerebral infarcts, and Lewy body disease. Methods: A total of 180 Catholic clergy participating in the Religious Orders Study underwent annual detailed evaluation and brain autopsy. Blocks of midfrontal, superior temporal, medial temporal lobe, inferior parietal, entorhinal cortex, hippocampus, and substantia nigra were paraffin embedded, and sectioned at 6 μm. Cortical neuritic plaques, diffuse plaques, and neurofibrillary tangles were visualized with Bielschowsky silver stain, and counted and summarized to yield a Braak stage, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) diagnosis, National Institute on Aging (NIA)–Reagan diagnosis, and composite measure of AD pathology. The authors recorded the number and location of all gross chronic cerebral infarctions. Lewy bodies were identified with antibodies to alpha-synuclein. Multiple regression analyses were used to examine the relation of AD pathology and cerebral infarctions to clinical diagnosis proximate to death, controlling for age, sex, and education. Results: A total of 37 had mild cognitive impairment, 60 did not have cognitive impairment, and 83 had dementia proximate to death. Nearly all persons had at least some AD pathology. Cerebral infarctions were present in 35.2%, and 15.6% had Lewy body disease. Persons with mild cognitive impairment were intermediate in terms of Braak stage and CERAD and NIA–Reagan neuropathologic criteria for AD compared to the other two groups. In multiple regression analyses, persons with mild cognitive impairment had intermediate levels of AD pathology from those without cognitive impairment and those with dementia (test for trend, F = 45.2, p p = 0.04). Only 3 (8.1%) persons with mild cognitive impairment had Lewy body disease. Conclusion: These data suggest that mild cognitive impairment may be the earliest clinical manifestation of common age-related neurologic diseases.

Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI

Abstract: Objective: To test the hypothesis that the atrophy rate measured from serial MRI studies is associated with time to subsequent clinical conversion to a more impaired state in both cognitively healthy elderly subjects and in subjects with amnestic mild cognitive impairment (MCI). Methods: Ninety-one healthy elderly patients and 72 patients with amnestic MCI who met inclusion criteria were identified from the Mayo Alzheimer’s Disease Research Center and Alzheimer’s Disease Patient Registry. Atrophy rates of four different brain structures—hippocampus, entorhinal cortex, whole brain, and ventricle—were measured from a pair of MRI studies separated by 1 to 2 years. The time of the second scan marked the beginning of the clinical observation period. Results: During follow-up, 13 healthy patients converted to MCI or Alzheimer disease (AD), whereas 39 MCI subjects converted to AD. Among those healthy at baseline, only larger ventricular annual percent volume change (APC) was associated with a higher risk of conversion (hazard ratio for a 1-SD increase 1.9, p = 0.03). Among MCI subjects, both greater ventricular volume APC (hazard ratio for a 1-SD increase 1.7, p p = 0.007) increased the risk of conversion to AD. Both ventricular APC (hazard ratio for a 1-SD increase 1.59, p = 0.001) and whole brain APC (hazard ratio for a 1-SD increase 1.32, p = 0.009) provided additional predictive information to covariate-adjusted cross-sectional hippocampal volume at baseline about the risk of converting from MCI to AD. Discussion: Higher whole brain and ventricle atrophy rates 1 to 2 years before baseline are associated with an increased hazard of conversion to a more impaired state. Combining a measure of hippocampal volume at baseline with a measure of either whole brain or ventricle atrophy rates from serial MRI scans provides complimentary predictive information about the hazard of subsequent conversion from mild cognitive impairment to Alzheimer disease. However, overlap among those who did vs those who did not convert indicate that these measures are unlikely to provide absolute prognostic information for individual patients.

Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke

Abstract: Repetitive transcranial magnetic stimulation (rTMS) or sham stimulation was given over the motor cortex daily for 10 days to two randomly assigned groups of 26 patients with acute ischemic stroke. Patients otherwise continued their normal treatment. Disability scales measured before rTMS, at the end of the last rTMS session, and 10 days later showed that real rTMS improved patients' scores more than sham.

Carotid endarterectomy—An evidence-based review Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Abstract: Objective: To assess the efficacy of carotid endarterectomy for stroke prevention in asymptomatic and symptomatic patients with internal carotid artery stenosis. Additional clinical scenarios, such as use of endarterectomy combined with cardiac surgery, are also reviewed. Methods: The authors selected nine important clinical questions. A systematic search was performed for articles from 1990 (the year of the last statement) until 2001. Additional articles from 2002 through 2004 were included using prespecified criteria. Two reviewers also screened for other relevant articles from 2002 to 2004. Case reports, review articles, technical studies, and single surgeon case series were excluded. Results: For several questions, high quality randomized clinical trials had been completed. Carotid endarterectomy reduces the stroke risk compared to medical therapy alone for patients with 70 to 99% symptomatic stenosis (16% absolute risk reduction at 5 years). There is a smaller benefit for patients with 50 to 69% symptomatic stenosis (absolute risk reduction 4.6% at 5 years). There is a small benefit for asymptomatic patients with 60 to 99% stenosis if the perioperative complication rate is low. Aspirin in a dose of 81 to 325 mg per day is preferred vs higher doses (650 to 1,300 mg per day) in patients undergoing endarterectomy. Conclusions: Evidence supports carotid endarterectomy for severe (70 to 99%) symptomatic stenosis (Level A). Endarterectomy is moderately useful for symptomatic patients with 50 to 69% stenosis (Level B) and not indicated for symptomatic patients with

New onset geriatric epilepsy: A randomized study of gabapentin, lamotrigine, and carbamazepine

Abstract: Objective: To determine the relative tolerability and efficacy of two newer antiepileptic drugs, lamotrigine (LTG) and gabapentin (GBP), as compared to carbamazepine (CBZ) in older patients with epilepsy. Methods: This was an 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 mg/day. The primary outcome measure was retention in trial for 12 months. Results: Mean age was 72 years. The most common etiology was cerebral infarction. Patients had multiple medical conditions and took an average of seven comedications. Mean plasma levels at 6 weeks were as follows: GBP 8.67 ± 4.83 μg/mL, LTG 2.87 ± 1.60 μg/mL, CBZ 6.79 ± 2.92 μg/mL. They remained stable throughout the trial. Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% ( p = 0.0002). Significant paired comparisons: LTG vs CBZ: p p = 0.008. Terminations for adverse events: LTG 12.1%, GBP 21.6%, CBZ 31% ( p = 0.001). Significant paired comparisons: LTG vs CBZ: p p = 0.015. There were no significant differences in seizure free rate at 12 months. Conclusions: The main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.

Cardiovascular risk factors and migraine The GEM population-based study

Abstract: Background: Migraine, particularly with aura, is a risk factor for early-onset ischemic stroke. The underlying mechanisms are unknown, but may in part be due to migraineurs having an increased risk profile for cardiovascular disease. In this study, the authors compare the cardiovascular risk profile of adult migraineurs to that of nonmigraineurs. Methods: Participants (n = 5,755, 48% men, age 20 to 65 years) are from the Genetic Epidemiology of Migraine (GEM) study, a population-based study in the Netherlands. A total of 620 current migraineurs were identified: 31% with aura (MA), 64% without aura (MO), and 5% unclassified. Controls were 5,135 individuals without lifetime migraine. Measured cardiovascular risk factors included blood pressure (BP), serum total and high-density lipoprotein cholesterol (TC, HDL), smoking, oral contraceptive use, and the Framingham risk score for myocardial infarction or coronary heart disease (CHD) death. Results: Compared to controls, migraineurs were more likely to smoke (OR = 1.43 [1.1 to 1.8]), less likely to consume alcohol (OR = 0.58 [0.5 to 0.7]), and more likely to report a parental history of early myocardial infarction. Migraineurs with aura were more likely to have an unfavorable cholesterol profile (TC ≥ 240 mg/dL [OR = 1.43 (0.97 to 2.1)], TC:HDL ratio > 5.0 [OR = 1.64 (1.1 to 2.4)]), have elevated BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg [OR = 1.76 (1.04 to 3.0)]), and report a history of early onset CHD or stroke (OR = 3.96 [1.1 to 14.3]); female migraineurs with aura were more likely to be using oral contraceptives (OR = 2.06 [1.05 to 4.0]). The odds of having an elevated Framingham risk score for CHD were approximately doubled for the migraineurs with aura. Conclusions: Migraineurs, particularly with aura, have a higher cardiovascular risk profile than individuals without migraine.

Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease.

Abstract: Objectives: To compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced Parkinson disease (P ...