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Effects of Intensive Medical Therapy on Microemboli and Cardiovascular Risk in Asymptomatic Carotid Stenosis [Original Contribution]

Objective To assess the effect of more intensive medical therapy on the rate of transcranial Doppler (TCD) microemboli and cardiovascular events in patients with asymptomatic carotid stenosis (ACS).Design A prospective study.Setting A teaching hospital.Patients Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity.Main Outcome Measures We compared (1) the proportion of ACS patients who had microemboli on TCD, (2) cardiovascular events, (3) rate of carotid plaque progression, and (4) baseline medical therapy, before and since 2003.Results Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 (P < .001). The decline in microemboli coincided with better control of plasma lipids and slower progression of carotid total plaque area. Since 2003, there have been significantly fewer cardiovascular events among patients with ACS: 17.6% had stroke, death, myocardial infarction, or carotid endarterectomy for symptoms before 2003, vs 5.6% since 2003 (P < .001). The rate of carotid plaque progression in the first year of follow-up has declined from 69 mm2 (SD, 96 mm2) to 23 mm2 (SD, 86 mm2) (P < .001).Conclusions Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy. Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD.Published online December 14, 2009 (doi:10.1001/archneurol.2009.289).

Infectious Burden and Risk of Stroke: The Northern Manhattan Study [Original Contribution]

Objective To determine the association between a composite measure of serological test results for common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 1 and 2) and stroke risk in a prospective cohort study.Design Prospective cohort followed up longitudinally for median 8 years.Setting Northern Manhattan Study.Patients Randomly selected stroke-free participants from a multiethnic urban community.Main Outcome Measure Incident stroke and other vascular events.Results All 5 infectious serological results were available from baseline samples in 1625 participants (mean [SD] age, 68.4 [10.1] years; 64.9% women). Cox proportional hazards models were used to estimate associations of each positive serological test result with stroke. Individual parameter estimates were then combined into a weighted index of infectious burden and used to calculate hazard ratios and confidence intervals for association with risk of stroke and other outcomes, adjusted for risk factors. Each individual infection was positively, though not significantly, associated with stroke risk after adjusting for other risk factors. The infectious burden index was associated with an increased risk of all strokes (adjusted hazard ratio per standard deviation, 1.39; 95% confidence interval, 1.02-1.90) after adjusting for demographics and risk factors. Results were similar after excluding those with coronary disease (adjusted hazard ratio, 1.50; 95% confidence interval, 1.05-2.13) and adjusting for inflammatory biomarkers.Conclusions A quantitative weighted index of infectious burden was associated with risk of first stroke in this cohort. Future studies are needed to confirm these findings and to further define optimal measures of infectious burden as a stroke risk factor.Published online November 9, 2009 (doi:10.1001/archneurol.2009.271).

About This Journal [About This Journal]

This Month in Archives of Neurology [This Month in Archives of Neurology]

Natural Oxidant Balance in Parkinson Disease [Editorial]

Mild Cognitive Impairment: Ten Years Later [Neurological Review]

In the past 10 years, there has been a virtual explosion in the literature concerning the construct of mild cognitive impairment. The interest in this topic demonstrates the increasing emphasis on the identification of the earliest features of cognitive disorders such as Alzheimer disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiologic, neuroimaging, biomarker, neuropathological, disease mechanism, and clinical trials research. This review summarizes the progress that has been made while also recognizing the challenges that remain.

Cellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies [Neurological Review]

Natural autoreactive monoclonal IgM antibodies have demonstrated potential as therapeutic agents for central nervous system (CNS) disease. These antibodies bind surface antigens on specific CNS cells, activating intracellular repair-promoting signals. IgM antibodies that bind to surface antigens on oligodendrocytes enhanced remyelination in animal models of multiple sclerosis. IgM antibodies that bind to neurons stimulate neurite outgrowth and prevent neuron apoptosis. The neuron-binding IgM antibodies may have utility in CNS axon- or neuron-damaging diseases, such as amyotrophic lateral sclerosis, stroke, spinal cord injury, or secondary progressive multiple sclerosis. Recombinant remyelination-promoting IgM antibodies have been generated for formal toxicology studies and, after Food and Drug Administration approval, a phase 1 clinical trial. Natural autoreactive monoclonal antibodies directed against CNS cells represent novel therapeutic molecules to induce repair of the nervous system.

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease [Original Contribution]

Background The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. Objective To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. Design, Setting, and Participants Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. Main Outcome Measures Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. Results The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by -tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with -tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with -tocopherol. Conclusions Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression. Published online October 12, 2009 (doi:10.1001/archneurol.2009.247).

Pittsburgh Compound B Imaging and Prediction of Progression From Cognitive Normality to Symptomatic Alzheimer Disease [Original Contribution]

Objective To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD. Design A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT). Setting The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri. Participants One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline. Main Outcome Measure Progression from CDR 0 to CDR 0.5 status (very mild dementia). Results Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0. Conclusion Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.

Cognitive Decline and Brain Volume Loss as Signatures of Cerebral Amyloid-{beta} Peptide Deposition Identified With Pittsburgh Compound B: Cognitive Decline Associated With A{beta} Deposition [Original Contribution]

Objective To examine the relation of amyloid-β peptide (Aβ) levels in the cerebral cortex with structural brain integrity and cognitive performance in cognitively healthy older people. Design Longitudinal study from May 22, 1985, through October 15, 2008. Setting Washington University Alzheimer Disease Research Center. Participants A total of 135 individuals aged 65 to 88 years with a Clinical Dementia Rating of 0. Main Outcome Measures The relations between mean cortical carbon 11 (11C)–labeled Pittsburgh compound B (PiB) binding potential values, proportional to the density of fibrillar Aβ binding sites in the brain, concurrent regional brain volumes as assessed by magnetic resonance imaging, and both concurrent and longitudinal cognitive performance in multiple domains. Results Elevated cerebral Aβ levels, in some cases comparable to those seen in individuals with Alzheimer disease, were observed in 29 participants, who also had smaller regional volumes in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate. Concurrent cognitive performance was unrelated to Aβ levels but was related to regional brain volumes with the exception of the caudate. Longitudinal cognitive decline in episodic and working memory and visuospatial ability was associated with elevated Aβ levels and decreased hippocampal volume. Conclusion The in vivo measure of cerebral amyloidosis known as [11C]PiB is associated with cross-sectional regionally specific brain atrophy and longitudinal cognitive decline in multiple cognitive domains that occur before the clinical diagnosis of Alzheimer disease. These findings contribute to the understanding of the cognitive and structural consequences of Aβ levels in cognitively healthy older adults.

Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down Syndrome [Original Contribution]

Objective To assess the transactive response DNA-binding protein 43 (TDP-43) burden in familial forms of Alzheimer disease (FAD) and Down syndrome (DS) to determine whether TDP-43 inclusions are also present. Design Using standard immunohistochemical techniques, we examined brain tissue samples from 42 subjects with FAD and 14 with DS. Results We found pathological TDP-43 aggregates in 14.0% of participants (6 of 42 and 2 of 14 participants with FAD and DS, respectively). In both FAD and DS, TDP-43 immunoreactivity did not colocalize with neurofibrillary tangles. Occasionally participants with FAD or DS had TDP-43–positive neuropil threads or dots. Overall, the amygdala was most commonly affected, followed by the hippocampus, with no TDP-43 pathology in neocortical regions. A similar distribution of TDP-43 inclusions is seen in sporadic Alzheimer disease, but it differs from that seen in amyotrophic lateral sclerosis and frontotemporal dementia. Conclusions Transactive response DNA-binding protein 43 pathology occurs in FAD and DS, similar to that observed in sporadic Alzheimer disease. Thus, pathological TDP-43 may contribute the cognitive impairments in familial and sporadic forms of Alzheimer disease.

Characteristics and Surgical Outcomes of Patients With Refractory Magnetic Resonance Imaging-Negative Epilepsies [Original Contribution]

Objective To explore several characteristics of patients with pharmacoresistant epilepsy without distinct lesions on magnetic resonance images (MRI–), who account for a relevant proportion of presurgical patient cohorts. Design Retrospective case series. Setting University epilepsy center. Patients A cohort of 1200 patients who had comprehensive presurgical assessment from January 1, 2000, through December 31, 2006. Main Outcome Measures Frequency of MRI– patients in the total presurgical cohort, seizure-free outcome rates in patients who had surgery and those who did not, outcome predictors, and spatial properties of epileptogenic areas in MRI– patients with epilepsy. All MRI– patients were retrospectively analyzed. Presurgical MRIs were reevaluated for subtle cortical dysplasias by postprocessing and visual reassessment. Results One-hundred ninety MRI– patients were identified (16% of all presurgical candidates); 29 (15%) had surgery. Eleven (38%) became seizure free (including those with auras only; 45%). Surgical therapy was more frequently offered to MRI+ patients (76%; P < .001), and their outcome was also superior (66% seizure-free; P = .001). The seizure-free rate of 16% in MRI– patients who did not have surgery was, however, inferior to that of the MRI– patients who did (P = .008). Nine MRI– patients who had surgery had distinct histopathological lesions, 8 of which turned out to be retrospectively detectable on presurgical MRI. Seven of the MRI– but histopathologically lesional patients became seizure free compared with only 4 of 20 patients without histopathological lesions (P = .003). Three-fifths of the histopathologically nonlesional patients had multifocal or extensive epileptogenic areas. Conclusions Patients with epilepsy who are MRI– can be successfully treated with surgery. Improved sensitivity of MRI will improve the outcomes of presurgically studied patients. Surgical failures in patients without histopathological lesions mostly result from extensive epileptogenic areas.

Status Epilepticus Associated With Subtentorial Posterior Fossa Lesions [Original Contribution]

Background Nonconvulsive status epilepticus (SE) is a frequent complication in critically ill patients in the intensive care unit. While seizures have been reported in association with subtentorial posterior fossa lesions, the frequency of occurrence of SE among these patients is not known. Objectives To examine prevalence, clinical features, potential risk factors, and outcome of SE among patients presenting with subtentorial posterior fossa lesions. Design Retrospective review of our hospital database was conducted to identify patients with posterior fossa lesions complicated by SE over 1 year between April 1, 2007, and May 1, 2008. Setting Tertiary care setting. Patients Patients with subtentorial posterior fossa lesions admitted to the hospital for neurological or neurosurgical care. Main Outcome Measures Prevalence of SE, potential risk factors, and eventual neurological outcome. Results Over 1 year, 13 of 501 patients (2.6%) admitted to the hospital with posterior fossa lesions had SE. Some patients had risk factors for SE such as sepsis, use of particular drugs, or intracranial bleeding, while others had no other clear identifiable cause. Conclusions Status epilepticus can be a potential complication in patients with posterior fossa cranial lesions and can be seen in up to 2.6% of such patients. Most have unfavorable outcome.

Functional and Cognitive Outcome in Prolonged Refractory Status Epilepticus [Original Contribution]

Objective To determine the functional and cognitive outcomes of patients with prolonged refractory status epilepticus (PRSE) lasting 7 or more days despite the use of anesthetic agents for seizure suppression. Design Retrospective analysis. Setting St Mary's Hospital, Mayo Clinic, Rochester, Minnesota. Participants Fourteen patients with PRSE. Intervention Hospital follow-up interview. Main Outcome Measures Survival rate of PRSE and functional and cognitive outcome of surviving patients based on the modified Rankin Scale (mRS) and Telephone Interview for Cognitive Status (TICS). Results Forty-three percent of patients (6 of 14) died during hospitalization for PRSE, and 57% (8 of 14) had died by the last follow-up. Of the 6 surviving patients, 4 showed improvement and 2 showed no change in mRS score (median mRS change, –1; range, 0 to –3). Owing to preexisting cognitive deficits, 1 patient could not complete the TICS. The 5 remaining patients scored a median of 34 on the TICS (range, 30-37; reference TICS score, ≥31; maximum TICS score, 41). Age, sex, PRSE duration, and etiology were not associated with chance of survival. Conclusions Despite the high mortality rate, survival with meaningful functional and cognitive recovery is possible after PRSE. Prolonged duration of status epilepticus alone should not be considered a reason to discontinue treatment.

Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Type 2 Caused by Mitofusin 2 Mutations [Original Contribution]

Background Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. Objective To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Design Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations. Setting Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies. Patients One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Main Outcome Measures Results of genetic analyses and phenotypic observations. Results Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. Conclusions MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.

Motor Phenotype of LRRK2 G2019S Carriers in Early-Onset Parkinson Disease [Original Contribution]

Objective To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. Design Cross-sectional observational study. Setting Thirteen movement disorders centers. Participants Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. Main Outcome Measures LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. Results Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001). Conclusion Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.

Heterogeneity in Infarct Patterns and Clinical Outcomes Following Internal Carotid Artery Occlusion [Original Contribution]

Objective To investigate whether the extent of infarction and clinical outcomes after internal carotid artery (ICA) occlusion depends on the additional occlusion of the middle cerebral artery (MCA). Design Using statistical parametric mapping, we compared infarct patterns in stroke patients. Setting A tertiary care hospital. Patients Patients with coexistent ICA and MCA occlusion (n = 25), isolated ICA occlusion (n = 20), and isolated MCA occlusion (n = 40). Main Outcome Measure Modified Rankin scale score. The independent effect of infarct type on clinical outcome was estimated using logistic regression, adjusting for age and sex. Results The mean age was 62.6 years (standard deviation [SD], 15.5 years) in patients with ICA and MCA occlusion, 64.3 years (SD, 12.9 years) in patients with isolated ICA occlusion, and 67.4 years (SD, 14.2 years) in patients with isolated MCA occlusion. Infarct patterns, volume (P = .13), and the proportion of patients with poor outcomes (P = .5) were similar between those with ICA and MCA occlusions and those with isolated MCA occlusion. Compared with the other 2 groups, those with isolated ICA occlusion were less likely to have infarction of the insula (P < .001) and superior temporal lobe (P < .001) and had smaller infarct volume and lower modified Rankin scale scores (all P < .05). Compared with those with isolated ICA occlusion, the risk of poor clinical outcome was greater in those with coexistent ICA and MCA occlusion (P = .02) and those with isolated MCA occlusion (P = .06) independent of age and sex. Comments Patients with ICA occlusion but without coexistent MCA occlusion have different infarct patterns, less extensive infarcts, and better clinical outcomes than those with coexistent MCA occlusion or MCA occlusion alone. It may not be warranted to exclude such patients from acute stroke trials.

HLA-DRB1*1501 and Spinal Cord Magnetic Resonance Imaging Lesions in Multiple Sclerosis [Original Contribution]

Background Multiple sclerosis (MS) is a heterogeneous neurologic disease with extensive variation with respect to the most affected central nervous system region (brain vs spinal cord). Objective To test the hypothesis that this variation in lesion location (brain vs spinal cord) might be (partially) genetically determined. Design Candidate gene study. Setting Academic research. Patients Patients were selected for the availability of DNA material, clinical variables, and brain and spinal cord magnetic resonance images (evaluating T2-weighted lesion load in the brain and the number of spinal cord lesions). Main Outcome Measures For genotyping, we used a DNA chip containing a set of genes mentioned in previous publications noting their relation to different phenotypes of MS. We assessed the association between brain and spinal cord abnormalities and the genotypes of the patients. Results One hundred fifty patients were included in the analysis. Five single-nucleotide polymorphisms within the major histocompatibility complex region were associated with the number of focal abnormalities in the spinal cord. The most significant was rs3135388 (surrogate marker for the HLA-DRB1*1501 allele). Carriers of HLA-DRB1*1501 had a median of 4 spinal cord lesions compared with 2 lesions for noncarriers (P < .001). No significant association was noted between the single-nucleotide polymorphisms and T2-weighted lesion load in the brain. Conclusions Carriership of HLA-DRB1*1501 (via rs3135388) was associated with the extent of focal abnormalities in the spinal cord. Spinal cord lesions might be an explanation for increased MS disease severity in patients carrying HLA-DRB1*1501.

High Striatal Amyloid {beta}-Peptide Deposition Across Different Autosomal Alzheimer Disease Mutation Types [Original Contribution]

Background Supported by compelling genetic data regarding early-onset familial Alzheimer disease (AD), the amyloid β-peptide (Aβ)–centric theory holds that Aβ is involved in the pathogenesis of sporadic AD. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes lead to increased Aβ levels before symptoms arise. Objectives To evaluate the pattern of Pittsburgh Compound B (PiB) retention in subjects with different autosomal dominant mutations associated with familial AD vs that in healthy age-matched control subjects and subjects with probable sporadic AD, to correlate Aβ burden as measured by PiB with available clinical and cognitive data, and to compare the regional brain patterns of PiB retention and fluorodeoxyglucose F 18 (FDG) uptake. Design Correlation analysis of positron emission tomography (PET) imaging studies. Setting Academic research. Participants Seven PSEN1 mutation carriers and 1 APP mutation carrier underwent PiB and FDG PET imaging. Amyloid β-peptide burden and FDG uptake were established using standardized uptake values normalized to pons. Main Outcome Measure Primary outcomes were PET results, which were compared with those of a well-characterized cohort of 30 healthy control subjects and 30 subjects with probable sporadic AD. Results All mutation carriers had high PiB retention in the striatum, with some also having cortical PiB retention in ventrofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Aβ burden was related to cognitive status. Conclusions Consistent with previous studies, the pattern of Aβ deposition in familial AD differs from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in familial AD. The pattern and degree of Aβ deposition were not associated with mutation type nor cognitive status.

Quantitative Template for Subtyping Primary Progressive Aphasia [Original Contribution]

Background The syndrome of primary progressive aphasia (PPA) is diagnosed when a gradual failure of word usage or comprehension emerges as the principal feature of a neurodegenerative disease. Objective To provide a quantitative algorithm for classifying PPA into agrammatic (PPA-G), semantic (PPA-S), and logopenic (PPA-L) variants, each of which is known to have a different probability of association with Alzheimer disease vs frontotemporal lobar degeneration. Design Prospective study. Setting University medical center. Patients Sixteen consecutively enrolled patients with PPA who underwent neuropsychological testing and magnetic resonance imaging recruited nationally in the United States as part of a longitudinal study. Results A 2-dimensional template that reflects performance on tests of syntax (Northwestern Anagram Test) and lexical semantics (Peabody Picture Vocabulary Test—Fourth Edition) classified all 16 patients in concordance with a clinical diagnosis that had been made before the administration of quantitative tests. All 3 PPA subtypes had distinctly asymmetrical atrophy of the left perisylvian language network. Each subtype also had distinctive peak atrophy sites: PPA-G in the inferior frontal gyrus (Broca area), PPA-S in the anterior temporal lobe, and PPA-L in Brodmann area 37. Conclusions Once an accurate root diagnosis of PPA is made, subtyping can be quantitatively guided using a 2-dimensional template based on orthogonal tasks of grammatical competence and word comprehension. Although the choice of tasks and the precise cutoff levels may need to be adjusted to fit linguistic and educational backgrounds, these 16 patients demonstrate the feasibility of using a simple algorithm for clinicoanatomical classification in PPA. Prospective studies will show whether this subtyping can improve clinical prediction of the underlying neuropathologic condition.

Cerebrospinal Fluid {beta}-Amyloid 42, Tau, and P-tau: Confirmation Now Realization [From JAMA]

Surgery Is the Best Option for Intractable Unilateral Mesial Temporal Epilepsy [From JAMA]

Absence of Pittsburgh Compound B Detection of Cerebral Amyloid {beta} in a Patient With Clinical, Cognitive, and Cerebrospinal Fluid Markers of Alzheimer Disease: A Case Report [Observation]

Background To date, there have been no reports of individuals who have been characterized longitudinally using clinical and cognitive measures and who transitioned from cognitive normality to early symptomatic Alzheimer disease (AD) during a period when both cerebrospinal fluid (CSF) markers and Pittsburgh Compound B (PiB) amyloid imaging were obtained. Objective To determine the temporal relationships of clinical, cognitive, CSF, and PiB amyloid imaging markers of AD. Design Case report. Setting Alzheimer disease research center. Participant Longitudinally assessed 85-year-old man in a memory and aging study who was cognitively normal at his initial and next 3 annual assessments. Main Outcome Measures Serial clinical and psychometric assessments over 6 years in addition to PiB imaging with positron emission tomography (PET) and CSF biomarker assays before autopsy. Results Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB PET amyloid imaging was negative at age 881/2 years, but at age 891/2 years there was reduced amyloid β 42 and elevated levels of tau in the CSF. Beginning at age 89 years, very mild cognitive and functional decline reported by his collateral source resulted in a diagnosis of very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse amyloid β plaques sufficient to fulfill Khachaturian neuropathologic criteria for definite AD, but other neuropathologic criteria for AD were not met because only sparse neuritic plaques and neurofibrillary tangles were present. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB PET binding was below the level needed for in vivo detection. Conclusion Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral amyloid β using amyloid imaging agents such as PiB that primarily label fibrillar amyloid β plaques.

Symptomatic Narcolepsy in Patients With Neuromyelitis Optica and Multiple Sclerosis: New Neurochemical and Immunological Implications [Observation]

Objective To characterize factors that contribute to symptomatic narcolepsy and excessive daytime sleepiness in neuromyelitis optica and multiple sclerosis. Setting Japanese university hospitals. Design Case study. Patients Seven Japanese patients whose initial diagnoses were multiple sclerosis and who were exhibiting excessive daytime sleepiness. Main Outcome Measures Lesions on magnetic resonance imaging, cerebrospinal fluid hypocretin-1 levels, and serum anti–aquaporin 4 (AQP4) antibody titer. Results Bilateral and symmetrical hypothalamic lesions associated with marked or moderate hypocretin deficiency were found in all 7 cases. Four of these patients met the International Classification of Sleep Disorders 2 narcolepsy criteria. Three patients, including 2 patients with narcolepsy, were seropositive for anti-AQP4 antibody and diagnosed as having neuromyelitis optica–related disorder. Conclusion Since AQP4 is highly expressed in the hypothalamic periventricular regions, an immune attack on AQP4 may be partially responsible for the bilateral and hypothalamic lesions and hypocretin deficiency in narcolepsy/excessive daytime sleepiness associated with autoimmune demyelinating diseases.

Subdural Fluid Collections in Patients With Infantile Neuronal Ceroid Lipofuscinosis [Observation]

Objective To describe subdural fluid collections on magnetic resonance imaging as part of the natural history of infantile neuronal ceroid lipofuscinosis. Design Case series. Setting Program on Developmental Endocrinology and Genetics, The Clinical Center, National Institutes of Health, Bethesda, Maryland. Patients Patients with infantile neuronal ceroid lipofuscinosis with subdural fluid collections. Main Outcome Measure Neurodegeneration on magnetic resonance imaging. Results During an ongoing bench-to-bedside clinical investigation, magnetic resonance imaging examinations led to the incidental discovery of subdural fluid collections in 4 of 9 patients with infantile neuronal ceroid lipofuscinosis. No particular event (such as trauma) or change in symptoms was linked to this finding, which was already in the chronic phase when discovered. Of the 4 patients, 1 was followed up for 7 years, 2 for 4 years, and 1 for 2.5 years. Over time, these collections remained stable or decreased in size. Conclusion Recognition that subdural fluid collections are part of the infantile neuronal ceroid lipofuscinosis disease process may obviate the necessity of additional workup as well as therapeutic interventions in these chronically sick children.

Shivering in Coma [Images in Neurology]

Lateral Medullary Syndrome and Ipsilateral Hemiplegia (Opalski Syndrome) Due to Left Vertebral Artery Dissection [Images in Neurology]

Progressive Myopathy With Multiple Symmetric Lipomatosis [Images in Neurology]

HIV and the Brain: New Challenges in the Modern Era [Book Reviews]

Adams and Victor's Principles of Neurology, 9th ed [Book Reviews]

Breastfeeding and Multiple Sclerosis [Correspondence]

Protective Effect of Breastfeeding in Postpartum Relapse Rate of Mothers With Multiple Sclerosis [Correspondence]

Protective Effect of Breastfeeding in Postpartum Relapse Rate of Mothers With Multiple Sclerosis--Reply [Correspondence]