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Objectives Autoimmune diseases (AID) follow a complex, probably polygenic, pattern of inheritance and often cluster in families of patients with multiple sclerosis (MS). Our objective was to analyze family patterns and characteristics in families including more than one patient with MS. Materials and Methods We analyzed personal and family history of neurological, systemic, and autoimmune diseases in 84 MS patients from 40 different families. Families were classified in two groups: families with cases of MS in at least two different generations (15 families) and families in which cases of MS belonged to only one generation (25 families). Results The two previously established groups presented different clinical patterns and frequency of association with another AID. In one group, the second generation displayed a higher annual relapse rate than the first generation, higher frequency of progressive forms of MS, and more patients with another AID in addition to MS. Relapsing‐remitting forms of MS (RRMS) were more frequent in the other group. Conclusions Families that include more than one MS patient may show two distinct patterns. This finding seems important for the compression and analysis of genetic information on MS. In families of MS patients, there is a high frequency of other autoimmune diseases. Two main patterns of distribution of MS cases between generations were observed. In these families, more cases with concomitant autoimmune diseases were observed.

Background The Paced Auditory Serial Addition Test (PASAT) is a useful cognitive test in patients with multiple sclerosis (MS), assessing sustained attention and information processing speed. However, the neural underpinnings of performance in the test are controversial. We aimed to study the neural basis of PASAT performance by using structural magnetic resonance imaging (MRI) in a series of 242 patients with MS. Methods PASAT (3-s) was administered together with a comprehensive neuropsychological battery. Global brain volumes and total T2-weighted lesion volumes were estimated. Voxel-based morphometry and lesion symptom mapping analyses were performed. Results Mean PASAT score was 42.98 ± 10.44; results indicated impairment in 75 cases (31.0%). PASAT score was correlated with several clusters involving the following regions: bilateral precuneus and posterior cingulate, bilateral caudate and putamen, and bilateral cerebellum. Voxel-based lesion symptom mapping showed no significant clusters. Region of interest–based analysis restricted to white matter regions revealed a correlation with the left cingulum, corpus callosum, bilateral corticospinal tracts, and right arcuate fasciculus. Correlations between PASAT scores and global volumes were weak. Conclusion PASAT score was associated with regional volumes of the posterior cingulate/precuneus and several subcortical structures, specifically the caudate, putamen, and cerebellum. This emphasises the role of both cortical and subcortical structures in cognitive functioning and information processing speed in patients with MS.

The logopenic variant of primary progressive aphasia (lvPPA) has been associated with Alzheimer disease, although this relationship is still subject to debate. The purpose of this study is to determine the frequency of amyloid biomarkers in patients with lvPPA, and record any potential clinical or topographic differences between patients with and without amyloid deposits. We conducted cognitive examination and positron-emission tomography studies with fluorodeoxyglucose ( 18 F) and florbetapir ( 18 F) in a cohort of 16 patients diagnosed with lvPPA. We evaluated the prevalence of amyloid deposits as well as any clinical and metabolic differences between the groups with and without significant presence of amyloid deposits. Eleven patients (69 %) were considered amyloid-positive. The amyloid-positive group displayed less metabolic activity in the left temporoparietal region than the control group, while the amyloid-negative group showed lower metabolism in the left temporoparietal region extending to the anterior temporal and basal frontal regions. The percentage of change in patients with clinical and FDG-PET follow-up did not differ between the amyloid-positive and amyloid-negative subgroups. The frequency of amyloid-positive cases confirms that lvPPA is frequently associated with Alzheimer disease. Amyloid-negative patients show a different cerebral metabolic pattern. These findings show the relevance of using amyloid PET to study lvPPA, and also suggest that the logopenic variant may not be specific to Alzheimer disease in certain cases.

Primary progressive aphasia (PPA) is a clinical syndrome characterized by the neurodegeneration of language brain systems. Three main clinical forms (non-fluent, semantic, and logopenic PPA) have been recognized, but applicability of the classification and the capacity to predict the underlying pathology is controversial. We aimed to study FDG-PET imaging data in a large consecutive case series of patients with PPA to cluster them into different subtypes according to regional brain metabolism. 122 FDG-PET imaging studies belonging to 91 PPA patients and 28 healthy controls were included. We developed a hierarchical agglomerative cluster analysis with Ward's linkage method, an unsupervised clustering algorithm. We conducted voxel-based brain mapping analysis to evaluate the patterns of hypometabolism of each identified cluster. Cluster analysis confirmed the three current PPA variants, but the optimal number of clusters according to Davies-Bouldin index was 6 subtypes of PPA. This classification resulted from splitting non-fluent variant into three subtypes, while logopenic PPA was split into two subtypes. Voxel-brain mapping analysis displayed different patterns of hypometabolism for each PPA group. New subtypes also showed a different clinical course and were predictive of amyloid imaging results. Our study found that there are more than the three already recognized subtypes of PPA. These new subtypes were more predictive of clinical course and showed different neuroimaging patterns. Our results support the usefulness of FDG-PET in evaluating PPA, and the applicability of computational methods in the analysis of brain metabolism for improving the classification of neurodegenerative disorders.

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is an uncommon neuro-ophthalmologic syndrome consisting of both eyes primary position exotropia and bilateral internuclear ophthalmoplegia. It is thought to be caused by medial midbrain lesions involving both bilateral medial longitudinal fasciculi and medial rectus subnuclei. We report the clinical and neuroimaging findings of a WEBINO syndrome associated to bilateral ptosis, non-reactive mydriasis and complete vertical gaze palsy in a 55-year-old man who suffered a top of the basilar artery stroke causing tegmental midbrain infarction.

ABSTRACTBackgroundAddenbrooke's Cognitive Examination III (ACE-III) is a screening test that was recently validated for diagnosing dementia. Since it assesses attention, language, memory, fluency, and visuospatial function separately, it may also be useful for general neuropsychological assessments. The aim of this study was to analyze the tool's ability to detect early stages of Alzheimer's disease and to examine the correlation between ACE-III scores and scores on standardized neuropsychological tests. MethodsOur study included 200 participants categorized as follows: 25 healthy controls, 48 individuals with subjective memory complaints, 47 patients with amnestic mild cognitive impairment and 47 mild Alzheimer's disease, and 33 patients with other neurodegenerative diseases. ResultsThe ACE-III memory and language domains were highly correlated with the neuropsychological tests specific to those domains (Pearson correlation coefficient of 0.806 for total delayed recall on the Free and Cued Selective Reminding Test vs. 0.744 on the Boston Naming Test). ACE-III scores discriminated between controls and patients with amnestic mild cognitive impairment (AUC: 0.906), and between controls and patients with mild Alzheimer's disease (AUC: 0.978). ConclusionOur results suggest that ACE-III is a useful neuropsychological test for assessing the cognitive domains of attention, language, memory, and visuospatial function. It also enables detection of Alzheimer's disease in early stages.

ABSTRACTBackgroundWe aim to provide a conversion between Addenbrooke's Cognitive Examination III (ACE-III) and Mini-Mental State Examination (MMSE) scores, to predict the MMSE result based on ACE-III, thus avoiding the need for both tests, and improving their comparability. MethodsEquipercentile equating method was used to elaborate a conversion table using a group of 400 participants comprising healthy controls and Alzheimer's disease (AD) patients. Then, reliability was assessed in a group of 100 healthy controls and patients with AD, 52 with primary progressive aphasia and 22 with behavioral variant frontotemporal dementia. ResultsThe conversion table between ACE-III and MMSE denoted a high reliability, with intra-class correlation coefficients of 0.940, 0.922, and 0.902 in the groups of healthy controls and AD, behavioral variant frontotemporal dementia, and primary progressive aphasia, respectively. ConclusionOur conversion table between ACE-III and MMSE suggests that MMSE may be estimated based on the ACE-III score, which could be useful for clinical and research purposes.

Positron emission tomography (PET) images with amyloid tracers show normal uptake in healthy white matter, which suggests that amyloid tracers are potentially useful for studying such white matter diseases as multiple sclerosis (MS). Twelve patients diagnosed with MS (5 with RRMS, 5 with SPMS, and 2 with PPMS) and 3 healthy controls underwent studies with MRI and (18)F-florbetaben-PET imaging. Images were preprocessed using Statistical Parametric Mapping software. We analysed (18)F-florbetaben uptake in demyelinating plaques (appearing as hyperintense lesions in FLAIR sequences), in normal-appearing white matter, and in grey matter. Mean standardized uptake value relative to cerebellum was higher in normally appearing white matter (NAWM) (1.51 ± 0.12) than in damaged white matter (DWM) (1.24 ± 0.12; P = .002). Mean percentage of change between NAWM and DWM was -17.56% ± 6.22%. This percentage of change correlated negatively with EDSS scores (r = -0.61, p < .05) and with age (r = -0.83, p < 0.01). Progressive forms of MS showed a more pronounced reduction of the uptake in DWM in comparison to relapsing-remitting form. Uptake of (18)F-florbetaben in damaged white matter is lower than that occurring in normally-appearing white matter. These findings indicate that amyloid tracers may be useful in studies of MS, although further research is needed to evaluate the utility of amyloid-PET in monitoring MS progression.

Purpose We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). Methods This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with 18 F-fluorodeoxyglucose (FDG), and amyloid-PET with 18 F-florbetaben. Results Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased 18 F-florbetaben uptake compared to controls. Conclusions We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint.

The ability to reject an automatic tendency, i.e. inhibition, has been linked to the prefrontal cortex, but its neural underpinnings are still controversial. Neurodegenerative diseases represent an interesting model to explore this issue, given its frequent impairment in these disorders. We investigated the inhibitory impairment and its neural basis using four different tests, which evaluate the presence of inhibitory dysfunction (Stroop test, Hayling test, and two graphical perseveration tests), and assessed their correlation with brain metabolism using 18F-fluorodeoxyglucose positron emission tomography in a group of 76 participants with behavioral variant frontotemporal dementia (bvFTD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and healthy controls (HC). Inhibition impairment was more frequent in bvFTD and AD, than ALS and HC. AD and bvFTD only differed in the strategy used in Hayling test, and the frequency of impairment in graphical perseveration tests. Correlation between inhibition tests was moderate. The Stroop test correlated with several regions of the frontal and parietal lobes, mainly on the left side. Hayling test correlated with almost all regions of the frontal lobe and, especially, with the orbitofrontal cortex. Some differences in the impaired regions in each disease were found. Inhibition ability was mainly impaired in bvFTD and AD, and it correlated with the bilateral frontal lobe metabolism. There were certain particularities according to the specific task and patients evaluated. These dissimilarities may support the concept of inhibition as a multidimensional construct, with the involvement of common and divergent neural mechanisms.