NEWS FROM BRESCIA- Natural history and predictors of survival in progressive supranuclear palsy.

Abstract

BACKGROUND:

Progressive supranuclear palsy is a neurodegenerative disorder characterized by high functional disability and rapidly progressive dependency. The predictors of survival are still unclear.

METHODS:

The predictors of survival were evaluated in a group of clinically diagnosed PSP patients, focusing primarily on extensive cognitive assessment.

RESULTS:

The mean survival time from symptom onset was 8.25±3.0years. Sex, age at onset, education, occupation and severity of extrapyramidal symptoms did not correlate with survival. The only factor associated with a shorter life expectancy in our cohort was the presence of dementia at diagnosis. Impairment of executive functions was the best predictor of an unfavorable outcome.

CONCLUSIONS:

Our findings suggest that dementia and executive functions need to be evaluated in order to define survival probability in PSP patients.

J. Neurol. Sci 2017

NEWS FROM THE WORLD- Stereoelectroencephalography and surgical outcome in polymicrogyria-related epilepsy: A multicentric study

Objective

We aimed to (1) assess the concordance between various polymicrogyria (PMG) types and the associated epileptogenic zone (EZ), as defined by stereoelectroencephalography (SEEG), and (2) determine the postsurgical seizure outcome in PMG-related drug-resistant epilepsy.MethodsWe retrospectively analyzed 58 cases: 49 had SEEG and 39 corticectomy or hemispherotomy.ResultsMean age at SEEG or surgery was 28.3 years (range, 2–50). PMG was bilateral in 9 (16%) patients and unilateral in 49, including 17 (29%) unilobar, 12 (21%) multilobar, 15 (26%) perisylvian, and only 5 (9%) hemispheric. Twenty-eight (48%) patients additionally had schizencephaly, heterotopia, or focal cortical dysplasia. The SEEG-determined EZ was fully concordant with the PMG in only 8 (16%) cases, partially concordant in 74%, and discordant in 10%. The EZ included remote cortical areas in 21 (43%) cases and was primarily localized in those in 5 (10%), all related to the mesial temporal structures. All but 1 PMG patient with corticectomy or hemispherotomy had a unilateral PMG. At last follow-up (mean, 4.6 years; range, 1–16), 28 (72%) patients remained seizure free. Shorter epilepsy duration to surgery was an independent predictor of seizure freedom.InterpretationPMG-related drug-resistant epilepsy warrants a comprehensive presurgical evaluation, including SEEG investigations in most cases, given that the EZ may only partially overlap with the PMG or include solely remote cortical areas. Seizure freedom is feasible in a large proportion of patients. PMG extent should not deter from exploring the possibility of epilepsy surgery. Our data support the early consideration of epilepsy surgery in this patient group. 

Ann Neurol 2017

NEWS FROM THE WORLD- Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives

Objective

Mutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear.

Methods

We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very-long-chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.

Results

Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis-related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1-deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8-blocking antibody reduces phagocytic activity.

Interpretation

Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. 

Ann Neurol 2017

NEWS FROM THE WORLD- Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives

Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.

Nature Reviews Neurology 2017

NEWS FROM THE WORLD- Amyloid β Deposition and Suspected Non-Alzheimer Pathophysiology and Cognitive Decline Patterns for 12 Years in Oldest Old Participants Without Dementia

Importance  The prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers.

Objective  To compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia.

Design, Setting, and Participants  A longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment.

Main Outcomes and Measures  Biomarker groups included amyloid β negative (Aβ⁻)/neurodegeneration negative (ND⁻), amyloid β positive (Aβ⁺)/ND⁻, Aβ⁻/neurodegeneration positive (ND⁺), and Aβ⁺/ND⁺based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education.

Results  Of the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Aβ⁻/ND⁻, 32 (18.3%) were Aβ⁺/ND⁻, 35 (20.0%) were Aβ⁻/ND⁺, and 66 (37.7%) were Aβ⁺/ND⁺. On all cognitive measures, the Aβ⁺/ND⁺group showed the steepest decline. Compared with the Aβ⁻/ND⁻ group, the amyloid deposition alone (Aβ⁺/ND⁻) group showed faster decline on tests of verbal and visual memory (–0.3513; 95% CI, –0.5269 to –0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (–0.1934; 95% CI, –0.3520 to –0.0348). The Aβ⁻/ND+ group showed faster visual memory decline than the Aβ⁻/ND⁻reference group (–0.3007; 95% CI, –0.4736 to –0.1279).

Conclusions and Relevance  In the oldest old without dementia, presence of either or both Aβ and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Aβ is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Aβ⁺/ND⁻ and Aβ⁻/ND⁺ groups.

JAMA Neurology 2017

NEWS FROM THE WORLD- Association of Cardiac Hemodynamic Factors With Severity of White Matter Hyperintensities in Chronic Valvular Heart Disease

Importance  The cerebral white matter hyperintensity (WMH) is frequently noted in patients with chronic heart disease. Long-term alteration of cardiac hemodynamics might have an influence on the mechanism of cerebral WMH.

Objective  To investigate the association between chronically altered cardiac hemodynamics and severity of cerebral WMH in patients with chronic valvular heart disease.

Design, Setting, and Participants  This cross-sectional analysis identified 303 consecutive patients at a tertiary referral center between 2008 and 2016 who were 50 years or older, and diagnosed with severe chronic valvular heart disease and underwent cardiac catherization, echocardiography, and received brain magnetic resonance imaging. Among these patients, 71 with other demonstrated cardiac disease, central nervous system disease, and/or without sufficient catheterization data were excluded, and the remaining 232 patients were included in further analyses.

Exposures  The site and mechanism of valve diseases, as well as clinical and medication profiles, were reviewed. Cardiac catheterization parameters such as right atrial (RA) mean pressure, right ventricular pressure, and aortic mean pressure were obtained. Comprehensive echocardiographic hemodynamic markers such as left ventricular (LV) ejection fraction, LV mass index, LV end diastolic volume, cardiac index, and E/e′ ratio were also obtained.

Main Outcomes and Measures  White matter hyperintensity volume was quantitatively evaluated using volumetric analysis.

Results  This study included 232 patients (103 men [44.4%] and 129 women [55.6%]; mean [SD] (range) age, 65.6 [8.8] (51-88) years) in the final analysis. The mean (SD) WMH volume was 5.93 (7.14) mL (median [interquartile range], 4.33 [1.33-8.62] mL), and mean (SD) RA pressure was 10.0 (4.7) mm Hg. From the catheterization data, 147 patients (63.4%) were classified as having a disease involving the mitral valve; 93 (40.1%), aortic valve; 37 (15.9%), tricuspid valve; and 4 (1.7%), pulmonary valve. In multivariate linear regression analysis, adjusting the type and mechanism of valve disease and clinical, echocardiographic, and/or other catheterization parameters, WMH volume was linearly associated with mean RA pressure (B coefficient, 0.702; 95% CI, 0.373-1.031; P = .001), along with age (B coefficient, 0.145; 95% CI, 0.029-0.261; P = .01) and mean aortic pressure (B coefficient, 0.112; 95% CI, 0.034-0.190; P = .005).

Conclusions and Relevance  Mean RA pressure was independently associated with the WMH volume in chronic valvular heart disease. Chronically altered RA hemodynamics might have a distinct influence on the pathomechanism underlying the development of WMH.

JAMA Neurology 2017

NEWS FROM THE WORLD- Concordance Between Different Amyloid Immunoassays and Visual Amyloid Positron Emission Tomographic Assessment

Importance  Visual assessment of amyloid positron emission tomographic (PET) images has been approved by regulatory authorities for clinical use. Several immunoassays have been developed to measure β-amyloid (Aβ) 42 in cerebrospinal fluid (CSF). The agreement between CSF Aβ42 measures from different immunoassays and visual PET readings may influence the use of CSF biomarkers and/or amyloid PET assessment in clinical practice and trials.

Objective  To determine the concordance between CSF Aβ42 levels measured using 5 different immunoassays and visual amyloid PET analysis.

Design, Setting, and Participants  The study included 262 patients with mild cognitive impairment or subjective cognitive decline from the Swedish BioFINDER (Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably) cohort (recruited from September 1, 2010, through December 31, 2014) who had undergone flutemetamol F 18 ([¹⁸F]flutemetamol)–labeled PET. Levels of CSF Aβ42 were analyzed using the classic INNOTEST and the newer modified INNOTEST, fully automated Lumipulse (FL), EUROIMMUN (EI), and Meso Scale Discovery (MSD) assays. Concentrations of CSF Aβ were assessed using an antibody-independent mass spectrometry–based reference measurement procedure.

Main Outcomes and Measures  The concordance of CSF Aβ42 levels and Aβ42:Aβ40 and Aβ42:tau ratios with visual [¹⁸F]flutemetamol PET status.

Results  Of 262 participants (mean [SD] age, 70.9 [5.5] years), 108 were women (41.2%) and 154 were men (58.8%). The mass spectrometry–derived Aβ42 values showed higher correlations with the modified Aβ42-INNOTEST (r = 0.97), Aβ42-FL (r = 0.93), Aβ42-EI (r = 0.93), and Aβ42-MSD (r = 0.95) assays compared with the classic Aβ42-INNOTEST assay (r = 0.88; P ≤ .01). The signal in the classic Aβ42-INNOTEST assay was partly quenched by recombinant Aβ1-40 peptide. However, the classic Aβ42-INNOTEST assay showed better concordance with visual [¹⁸F]flutemetamol PET status (area under the receiver operating characteristic curve [AUC], 0.92) compared with the newer assays (AUCs, 0.87-0.89; P ≤ .01). The accuracies of the newer assays improved significantly when Aβ42:Aβ40 (AUCs, 0.93-0.95; P ≤ .01), Aβ42 to total tau (T-tau) (AUCs, 0.94; P ≤ .05), or Aβ42 to phosphorylated tau (P-tau) (AUCs, 0.94-0.95; P ≤ .001) ratios were used. A combination of the Aβ42:Aβ40 ratio and T-tau or P-tau level did not improve the accuracy compared with the ratio alone.

Conclusions and Relevance  Concentrations of CSF Aβ42 derived from the new immunoassays (modified INNOTEST, FL, EI, and MSD) may correlate better with the antibody-independent mass spectrometry–based reference measurement procedure and may show improved agreement with visual [¹⁸F]flutemetamol PET assessment when using the Aβ42:Aβ40 or Aβ42:tau ratios. These findings suggest the benefit of implementing the CSF Aβ42:Aβ40 or Aβ42:tau ratios as a biomarker of amyloid deposition in clinical practice and trials.

JAMA Neurology 2017