Background and purpose

Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between infectious burden (IB) and Alzheimer's disease (AD) was examined.

Methods

Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV‐1), , and were measured by enzyme‐linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens.

Results

Seropositivities toward zero−two, three and four−five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini‐Mental State Examination scores were negatively correlated with IB in all cases. Serum beta‐amyloid protein (Aβ) levels (i.e. Aβ40, Aβ42 and total Aβ) and inflammatory cytokines (i.e. interferon‐γ, tumor necrosis factor α, interleukin‐1β and interleukin‐6) in individuals exposed to four−five infectious pathogens were significantly higher than those exposed to zero−two or three pathogens.

Conclusions

IB consisting of CMV, HSV‐1, , and is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.

Abstract

Click to view the accompanying paper in this issue.

Abstract

Neuromyelitis optica (NMO) is a rare inflammatory disorder of the central nervous system. The hallmark of NMO is the presence of specific autoantibodies directed against aquaporin 4 (AQP4‐IgG). AQP4‐IgG, included in diagnostic criteria, has enlarged the clinical spectrum of NMO and serves to predict relapses. Moreover AQP4‐IgG has provided unprecedented insight in the immunopathology of NMO, representing a rationale for therapeutic intervention with relevant novel treatment strategies specific for NMO. However, some patients remain seronegative for AQP4‐IgG despite a definite diagnosis of NMO and the use of the finest methods for antibody detection. Interestingly, seronegative NMO (NMO) patients exhibit different demographic and disease‐related characteristics in comparison to seropositive patients. The recent association with autoantibodies specific for myelin oligodendrocyte glycoprotein (MOG) is the main indication that disease mechanisms might differ in NMO and NMO, challenging the position of NMO patients in the spectrum of demyelinating diseases and therapeutic strategies to be adopted. Thus, a reappraisal of the NMO population is needed to improve NMO care. Here the current knowledge regarding NMO is reviewed and hypotheses on its pathogenesis are made including a comprehensive description of detection methods and the prevalence of AQP4‐IgG and a review of the epidemiological, clinical and paraclinical characteristics of NMO; finally an integrated view of the general pathophysiological mechanisms underlying NMO is provided.

Background and purpose

This double‐blind, randomized, placebo‐controlled study investigated the beneficial effects of repetitive transcranial magnetic stimulation (rTMS) to patients with motor paresis in acute subcortical stroke on functional recovery and electrophysiological measures.

Methods

Twenty patients with acute stroke were randomized into real rTMS ( = 10) or sham ( = 10) groups. Patients received five daily sessions of rTMS with 1200 pulses at 1 Hz for 20 min or sham stimulation over the contralesional motor cortex. Movement‐related cortical potential MRCP, consisting of the Bereitschaftpotential, negative slope (NS′) and motor potential (MP), was recorded during self‐paced wrist extension of the affected limb associated with assessment of the Fugl−Meyer assessment (FMA) of the upper extremity, the pegboard test and the grip strength before and after the rTMS session.

Results

Real rTMS improved the FMA and pegboard test scores compared to the sham group in the affected hand. This improvement was associated with increases in the MP and NS′ over the front‐central sites in the ipsilesional hemisphere, whereas the sham group did not show significant changes in MRCP components by rTMS.

Conclusions

Our findings suggest that low‐frequency rTMS to the contralesional motor cortex facilitates functional recovery of paretic limbs in acute stroke patients through enhancing the the neuronal activity of ipsilesional motor and pre‐motor areas.

Background and purpose

Patients with idiopathic normal pressure hydrocephalus (iNPH) present cognitive deficits that overlap with other neurological conditions such as Parkinson's disease or vascular dementia, therefore mimicking iNPH. This prospective study aimed to compare cognitive performances between iNPH and iNPH mimics before and after cerebrospinal fluid (CSF) tapping.

Methods

A total of 57 patients with suspicion of iNPH (75.84 ± 6.42 years; 39% female) were included in this study (37 iNPH and 20 iNPH mimics). Neuropsychological assessments were performed before and 24 h after CSF tapping of 40 ml. Multivariate logistic regressions were used to examine the association between iNPH and cognitive functions, adjusted for age, education, baseline cognitive assessment and disease duration.

Results

Both groups presented the same baseline cognitive performances. After CSF tapping, iNPH patients improved their semantic ( = 0.001) and phonemic verbal fluencies ( = 0.001), whereas iNPH mimics presented similar performances to before CSF tapping. The phonemic verbal fluency (odds ratio 1.43, 95% confidence interval 1.05; 1.96) and the Color Trails Test (odds ratio 0.10, 95% confidence interval 0.01; 0.76) improvements were the two discriminative cognitive tests that identified iNPH from iNPH mimics.

Conclusion

Improvement in executive subfunctions after CSF tapping identified iNPH patients from other neurological conditions that mimic iNPH. These findings respond to clinical issues encountered on a daily basis and would improve the diagnostic process of iNPH.

Background and purpose

Secondary cortical thinning and volumetric atrophy in the motor‐related cortex can inhibit early functional recovery after subcortical infarction. However, the relationship between the spontaneous neuronal activity in these cortices and motor recovery in patients with focal cerebral infarct remains unknown.

Methods

Structural magnetic resonance imaging (MRI) and resting‐state functional MRI were conducted 1, 4 and 12 weeks after onset in 22 patients with an acute subcortical infarct and in 22 normal subjects. Group differences in cortical thickness and in the amplitude of low‐frequency fluctuation (ALFF) in motor‐related areas were evaluated, and the relationships between ALFF, cortical thickness changes and changes in the Fugl−Meyer scores of physical performance were further analyzed.

Results

In patients with subcortical infarction, progressively decreasing cortical thickness was found over the observation period ipsilesionally in the primary motor cortex (PMC), supplementary motor cortex (SMC) and precuneus (all < 0.05). Contralesionally, progressive increases in cortical thickness were detected in SMC and insula (all < 0.05). Increases in ALFF were observed only in PMC (bilaterally) and only at 12 weeks after stroke (all < 0.05). The cortical thickness changes in the contralesional SMC ( = 0.483, = 0.023) and the ALFF changes in bilateral PMC (ipsilesional, = 0.51, = 0.015; contralesional, = 0.463, = 0.03) were positively correlated with changes in the Fugl−Meyer scores.

Conclusions

These results suggest that increased spontaneous neuronal activity of the PMC, a region structurally damaged secondarily to ischaemic lesion, may contribute to early motor recovery in patients with subcortical infarction.

Background and purpose

A three‐generation family affected by axonal Charcot−Marie−Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.

Methods

The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, analysis and luciferase reporter assays.

Results

A novel c.1226G>A change (p.R409Q) in the gene was identified. Patients presented with a typical, late‐onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.

Conclusions

This is the first report of an mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the ‐related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the gene.

Background and purpose

Charcot−Marie−Tooth disease (CMT) is a very slowly progressive neuropathy which makes it difficult to detect disease progression over time and to assess intervention efficacy. Experience from completed clinical trials with ascorbic acid and natural history studies confirm difficulties in detecting such changes. Consequently, sensitive‐to‐change outcome measures (OMs) are urgently needed.

Methods

The relative responsiveness of clinical scales of the Italian−UK ascorbic acid trial (placebo arm) were assessed by using the standardized response mean (SRM), which is the ratio of the paired scores mean change over time to the standard deviation of the score change (0 is worst responsiveness).

Results

Little worsening of OM scores was found over 2 years. In detail, the primary OM of the trial, the CMT Neuropathy Score version 1 (CMTNSv1), showed low responsiveness (SRM 0.13). Some CMTNS items showed slightly greater responsiveness (CMT Examination Score 0.17; CMTNS Signs 0.19). Myometric assessments of handgrip and foot dorsiflexion strength were the most responsive (SRM −0.31 and −0.38, respectively). Amongst the other measures, the nine‐hole peg test, which assesses upper limb functioning, showed the best sensitivity to change (SRM 0.28).

Conclusions

Overall these OMs showed low or negligible responsiveness, confirming the need to improve current OMs and to develop novel ones for prognostic and interventional studies. However, handgrip and foot dorsiflexion myometry are worth retaining for future trials as they were the most responsive and are likely to be clinically relevant for patients.

Background and purpose

Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non‐motor symptoms, including cognitive deficits. Several magnetic resonance imaging approaches have been applied to investigate brain atrophy in PD. The aim of this study was to detect early structural cortical and subcortical changes in PD whilst distinguishing cognitive status, clinical phenotype and motor laterality.

Methods

Eighteen PD with mild cognitive impairment (PD‐MCI), 18 PD without MCI (PD‐NC) and 18 healthy control subjects were evaluated. In the PD‐MCI group, nine were tremor dominant and nine were postural instability gait disorder (PIGD) phenotype; 11 had right‐sided symptom dominance and seven had left‐sided symptom dominance. FreeSurfer was used to measure cortical thickness/folding, subcortical structures and to study group differences as well as the association with clinical and neuropsychological data.

Results

Parkinson's disease with MCI showed regional thinning in the right frontal, right middle temporal areas and left insula compared to PD‐NC. A reduction of the volume of the left and right thalamus and left hippocampus was found in PD‐MCI compared to PD‐NC. PD‐MCI PIGD showed regional thinning in the right inferior parietal area compared to healthy controls. A decreased volume of the left thalamus was reported in PD‐MCI with right‐sided symptom dominance compared to PD‐NC and PD‐MCI with left‐sided symptom dominance.

Conclusions

When MCI was present, PD patients showed a fronto‐temporo‐parietal pattern of cortical thinning. This cortical pattern does not appear to be influenced by motor laterality, although one‐sided symptom dominance may contribute to volumetric reduction of specific subcortical structures.

The European Academy of Neurology (EAN), founded in 2014 after the merging of the two previously active European Neurological Societies, considers the production of neurological guidelines a major obligation, as this is a major tool to improve clinical practice in neurology. This paper updates practical suggestions to develop guidelines about the treatment and diagnosis of neurological diseases within the framework of the EAN. Its aim is to make uniform, traceable and explicit the path from the decision to write an EAN guideline to its publication. We explain the protocol structure, handling of conflicts of interest, format, timeline and process of revision and acceptance.