Archives of neurology最新文献

Objective: To describe a patient positive for the anti-aquaporin 4 antibody with hypothalamic lesions showing hypothermia, hypotension, hypersomnia, and obesity.

Design: Case report.

Setting: University hospital.

Patient: We describe a 21-year-old woman who was positive for anti-aquaporin 4 antibody and presented with hypothermia, hypotension, and hypersomnia owing to bilateral hypothalamic lesions as the only abnormal clinical finding.

Results: Immediate steroid administration resulted in significant improvement of the patient's vital signs and imaging findings; however, her cognitive impairment and sleepiness persisted, and she subsequently developed obesity. Decreased cerebrospinal fluid orexin levels and sleep studies confirmed the diagnosis of narcolepsy due to medical condition. Physicians should be aware that neuromyelitis optica spectrum disorders can initially involve the hypothalamus.

Conclusions: We emphasize that measurement of anti-aquaporin 4 antibody is of clinical importance in the differential diagnosis of hypothalamic lesions.

Objective: To evaluate the frequency and clinical spectrum of the recently identified p.D620N mutation in the VPS35 gene in Parkinson disease (PD) in an international sample.

Design: Genetic analysis by DNA sequencing and detailed clinical and neuropsychiatric assessment as well as neuroimaging in mutation carriers.

Setting: Tertiary referral centers in Germany, Serbia, Chile, and the United States.

Patients: One thousand seven hundred seventy-four patients with PD.

Main outcome measure: Frequency of the p.D620N mutation.

Results: A single mutation carrier was identified. The mutation carrier was a 60-year-old German man who had tremor-dominant PD since the age of 45 years. Longitudinal follow-up over 13 years revealed a disease progression from Hoehn and Yahr stage 1 to 3. There was evidence of mild cognitive impairment on the Montreal Cognitive Assessment. No abnormalities were observed by multimodal neuroimaging. He had a family history consistent with autosomal dominant inheritance. An affected paternal aunt and 3 reportedly unaffected siblings were also found to be mutation carriers.

Conclusion: VPS35 mutations are a rare cause of PD in different populations. The clinical phenotype may be indistinguishable from idiopathic PD with the possible exception of an earlier age at onset. Genetic analysis of the extended family revealed incomplete penetrance of the p.D620N mutation.

Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent.

Objective: To determine the relative contributions of individual pathologic protein deposits associated with dementia in patients with Parkinson disease (PD).

Design: Autopsied patients were analyzed from February 24, 2005, through July 25, 2010, to determine the distribution and severity of individual pathologic protein deposits (α-synuclein, Aβ, and tau) using routine protocols for histologic and immunohistochemical analysis and established neuropathologic staging criteria. Clinical data were extracted from an electronic medical record system used for all patients with PD.

Patients: Thirty-two consecutive autopsied patients treated at the Washington University Movement Disorders Center who had neuropathologic confirmation of PD and a history of dementia, regardless of the timing of the onset of dementia with respect to motor symptoms.

Results: Three pathologic subgroups of dementia associated with PD were identified: (1) predominant synucleinopathy (Braak Lewy body stages 5-6) (12 [38%]), (2) predominant synucleinopathy with Aβ deposition (Braak amyloid stages B-C) but minimal or no cortical tau deposition (19 [59%]), and (3) synucleinopathy and Aβ deposition with at least moderate neocortical tauopathy (Braak tau stages 5-6; 1 [3%]). Kaplan-Meier and Cox regression analyses revealed that patients with synucleinopathy plus Aβ deposition had significantly shorter survival (years from PD onset until death and years from dementia onset until death) than patients with synucleinopathy only.

Conclusions: Dementia associated with PD has 2 major pathologic subgroups: neocortical synucleinopathy and neocortical synucleinopathy with Aβ deposition. Alzheimer disease with neocortical Aβ and tau deposition does not commonly cause dementia with PD. Furthermore, accumulation of Aβ is associated with lower survival rates in PD patients with dementia. Additional studies are needed to prospectively determine the association between α-synuclein and Aβ accumulation and the role of Aβ in the development and progression of cognitive impairment in PD.

Background: A blood-based test that could be used as a screen for Alzheimer disease (AD) may enable early intervention and better access to treatment.

Objective: To apply a multiplex immunoassay panel to identify plasma biomarkers of AD using plasma samples from the Alzheimer's Disease Neuroimaging Initiative cohort.

Design: Cohort study.

Setting: The Biomarkers Consortium Alzheimer's Disease Plasma Proteomics Project.

Participants: Plasma samples at baseline and at 1 year were analyzed from 396 (345 at 1 year) patients with mild cognitive impairment, 112 (97 at 1 year) patients with AD, and 58 (54 at 1 year) healthy control subjects.

Main outcome measures: Multivariate and univariate statistical analyses were used to examine differences across diagnostic groups and relative to the apolipoprotein E (ApoE) genotype.

Results: Increased levels of eotaxin 3, pancreatic polypeptide, and N-terminal protein B-type brain natriuretic peptide were observed in patients, confirming similar changes reported in cerebrospinal fluid samples of patients with AD and MCI. Increases in tenascin C levels and decreases in IgM and ApoE levels were also observed. All participants with Apo ε3/ε4 or ε4/ε4 alleles showed a distinct biochemical profile characterized by low C-reactive protein and ApoE levels and by high cortisol, interleukin 13, apolipoprotein B, and gamma interferon levels. The use of plasma biomarkers improved specificity in differentiating patients with AD from controls, and ApoE plasma levels were lowest in patients whose mild cognitive impairment had progressed to dementia.

Conclusions: Plasma biomarker results confirm cerebrospinal fluid studies reporting increased levels of pancreatic polypeptide and N-terminal protein B-type brain natriuretic peptide in patients with AD and mild cognitive impairment. Incorporation of plasma biomarkers yielded high sensitivity with improved specificity, supporting their usefulness as a screening tool. The ApoE genotype was associated with a unique biochemical profile irrespective of diagnosis, highlighting the importance of genotype on blood protein profiles.