APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid ß (Aß)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Executive and Attentional Disorders, Epilepsy and Porencephalic Cyst in Autosomal Recessive Cerebellar Ataxia Type 3 Due to ANO10 Mutation.

BACKGROUND: ANO10 mutations have recently been reported in autosomal recessive cerebellar ataxia type 3 (ARCA3). The objective of this study was to describe the phenotype of 2 siblings with compound heterozygous ANO10 mutations and progressive cerebellar ataxia, epilepsy, and cognitive impairment. A porencephalic cyst was also described in one of them and a coenzyme Q10 deficiency in the other one. METHODS: We performed neurological, neuropsychological, electromyographic, electroencephalic and MRI examinations in 2 siblings with compound heterozygous ANO10 mutations. RESULTS: We reported for the first time the neuropsychological profile of 2 ARCA3 patients showing an adult-onset executive and attentional syndrome. Both presented epilepsy. One of them presented a porencephalic cyst. CONCLUSION: These results suggest that executive and attentional disorders are impaired in ANO10 mutation. In addition, epilepsy and porencephalic cysts were also described in our ARCA3 patients, the cyst thus expanding the clinical phenotype of ARCA3 patients due to ANO10 mutation.

Verbal Fluencies and Fampridine Treatment in Multiple Sclerosis.

BACKGROUND/AIMS: Fampridine is sometimes reported to improve cognition and especially the information-processing speed. Motor improvement might be a confounding factor. The aim of this study was to evaluate the effects of fampridine on verbal fluencies in patients with multiple sclerosis (MS). METHODS: Fifty MS patients were included in a prospective monocentric open label trial with a mean Expanded Disability Status Scale of 5.3 ± 1.1. Assessments of verbal phonological and semantic fluencies were repeated twice (within 1 week) before fampridine treatment and twice after fampridine treatment in order to have the maximal practice effect. Gait velocity and fatigue (visual analogical scale) were also assessed. Distribution into gait responders, gait non-responders, fluency responders and fluency non-responders, was described. RESULTS: Verbal fluencies were significantly higher after fampridine treatment. No correlation was observed between phonological fluency improvement and semantic fluency improvement. Gait responders and gait non-responders did not present significant differences in verbal fluency performance and fatigue score. No correlation between gait velocity improvement and fatigue improvement compared with verbal fluency improvement was observed. CONCLUSION: Our results suggest that fampridine could have a selective procognitive effect on phonological fluency in MS, even in the gait non-responder patients.

Cognitive Impairment Involving Social Cognition in SPG4 Hereditary Spastic Paraplegia.

Objectives. To describe cognitive assessment including social cognition in SPG4 patients. Methods. We reported a series of nine patients with SPG4 mutation with an extensive neuropsychological examination including social cognition assessment. Results. None of our patients presented with mental retardation or dementia. All presented with mild cognitive impairment with a high frequency of attention deficit (100%), executive disorders (89%), and social cognition impairment (78%). An asymptomatic patient for motor skills presented with the same cognitive profile. No correlation was found in this small sample between cognitive impairment and motor impairment, age at disease onset, or disease duration. Conclusions. SPG4 phenotypes share some cognitive features of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Cognitive disorders including executive disorders and social cognition impairment are frequent in SPG4 patients and might sometimes occur before motor disorders. Therefore, cognitive functions including social cognition should be systematically assessed in order to improve the clinical management of this population.

Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.

Seizures in dominantly inherited Alzheimer disease.

OBJECTIVE: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. METHODS: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. RESULTS: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005). CONCLUSIONS: Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures.

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons.

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

Increased cerebrospinal fluid tau levels in logopenic variant of Alzheimer's disease.

BACKGROUND: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer's disease (AD). OBJECTIVE: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). METHODS: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). RESULTS: p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. CONCLUSIONS: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD.

Can Chronic Remote Cortical Hypoperfusion Induced by Thalamic Infarction Cause Damage of Tracts Passing through Those Hypoperfused Regions?

We report the case of a woman presenting with changes on cerebral imaging a year and a half after a bi-thalamic (predominantly left-sided) infarction including lateral and medial thalamic nuclei. Lateral geniculate body and pulvinar were not damaged. Hypoperfusion was observed in left cortical and basal structures. White matter FLAIR hyperintense lesions occurred in the left hemisphere and the occipital region 1 year and half after stroke. Medial and lateral thalamic nuclei are not highly connected to the occipital cortex. Therefore, in addition to Wallerian degeneration after thalamic stroke, we hypothesize that the chronic left temporal hypoperfusion induced by diaschisis can lead to a lateralized chronic hypoxic damage of the occipital fiber tract (optic radiation) that passes through the temporal lobe.

Amyloid-related imaging abnormalities in AßPP duplication carriers.

Immune response to vascular amyloid-ß deposits leads to cerebral amyloid angiopathy related-inflammation (CAA-ri). Amyloid-related imaging abnormalities (ARIA) were initially reported during anti-amyloid trials and are associated with the APOE 4/4 genotype. We report the evolution of an AßPP duplication carrier with an APOE 3/3 genotype presenting ARIA-Effusion and then ARIA-Hemosiderin deposit, without anti-amyloid therapy, suggestive of a possible spontaneously resolutive CAA-ri (not neuropathologically proven). It suggests common mechanisms between ARIA and CAA-ri and raises questions about mechanisms of this acute episode without APOE risk factor. The high vascular amyloid burden, induced by AßPP duplication, might increase amyloid epitope presentation and lead to inflammatory process.

Logopenic syndrome in posterior cortical atrophy.

Few language disorders have been reported in posterior cortical atrophy (PCA). Furthermore, no study has focused on screening for them and described these language deficits. The goal of this work was to describe linguistic examination of PCA patients and the impact of language disorders on neuropsychological performances compared to patients with other neurodegenerative syndromes and control groups. Linguistic examination of 9 PCA patients was carried out. The neuropsychological performance of the PCA group (16 patients) in the RAPID battery tests was compared with performances of patients with a logopenic variant of primary progressive aphasia (LPPA), patients with Alzheimer's disease and patients with amnestic mild cognitive impairment, as well as the control group. A "logopenic syndrome" with anomia, fluency impairment, and length-dependent deficit was found in 8/9 PCA patients. A comparison with other neurodegenerative syndromes showed that not only visual disorders but also language and verbal short-term memory disorders, such as those found in LPPA, can explain neuropsychological performances. A "logopenic syndrome" is frequently found in PCA and may be associated with poor performance on other verbally mediated neuropsychological tasks (e.g., verbal memory). Specific logopedic rehabilitation should be offered to these patients.