Maite Formaglio

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 β (Aβ)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.

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.

Pseudotumoral presentation of cerebral amyloid angiopathy–related inflammation

Objective: To identify the clinical and radiologic features that should raise suspicion for the pseudotumoral presentation of cerebral amyloid angiopathy–related inflammation (CAA-I). Methods: We retrospectively reviewed the characteristics of 5 newly diagnosed and 23 previously reported patients in whom the CAA-I imaging findings were initially interpreted as CNS neoplasms. Results: Most cases (85%) occurred in patients >60 years old. The clinical characteristics at presentation included subacute cognitive decline (50%), confusion (32%), focal deficits (32%), seizures (25%), and headaches (21%). Brain MRI demonstrated infiltrative white matter lesions that exhibited a loco-regional mass effect without parenchymal enhancement (93%). In general, these findings were interpreted as low-grade glioma or lymphoma. Eighteen patients (64%) underwent a biopsy, which was nondiagnostic in 4 patients (14%), and 6 patients (21%) underwent a surgical resection. The primary reason for the misinterpretation of the imaging findings was the absence of T2*-weighted gradient recalled echo (T2*-GRE) sequences on initial imaging (89%). When subsequently performed (39%), the T2*-GRE sequences demonstrated multiple characteristic cortical and subcortical microhemorrhages in all cases. Perfusion MRI and magnetic resonance spectroscopy (MRS), which were performed on a subset of patients, indicated markedly reduced relative cerebral blood flow and a normal metabolic ratio. Conclusion: The identification of one or several nonenhancing space-occupying lesions, especially in elderly patients presenting with cognitive impairment, should raise suspicion for the pseudotumoral presentation of CAA-I and lead to T2*-GRE sequences. Perfusion MRI and MRS appear to be useful techniques for the differential diagnosis of this entity.

Characteristics in limbic encephalitis with anti–adenylate kinase 5 autoantibodies

Objective: To report 10 patients with limbic encephalitis (LE) and adenylate kinase 5 autoantibodies (AK5-Abs). Methods: We conducted a retrospective study in a cohort of 50 patients with LE with uncharacterized autoantibodies and identified a specific target using immunohistochemistry, Western blotting, immunoprecipitation, mass spectrometry, and cell-based assay. Results: AK5 (a known autoantigen of LE) was identified as the target of antibodies in the CSFs and sera of 10 patients with LE (median age 64 years; range 57–80), which was characterized by subacute anterograde amnesia without seizure and sometimes preceded by a prodromal phase of asthenia or mood disturbances. Anterograde amnesia can be isolated, but some patients also complained of prosopagnosia, paroxysmal anxiety, or abnormal behavior. No associated cancer was observed. All 10 patients had bilateral hippocampal hypersignal on a brain MRI. CSF analysis generally showed a mild pleiocytosis with elevated immunoglobulin G index and oligoclonal bands, as well as high levels of tau protein with normal concentration of Aβ42 and phospho-tau, suggesting a process of neuronal death. Except for one patient, clinical response to immunotherapy was unfavorable, with persistence of severe anterograde amnesia. Two patients evolved to severe cognitive decline. Hippocampal atrophy was observed on control brain MRI. Using in vitro tests on hippocampal neurons, we did not identify clues suggesting a direct pathogenic role of AK5-Abs. Conclusions: AK5-Abs should be systematically considered in aged patients with subacute anterograde amnesia. Recognition of this disorder is important to develop new treatment strategies to prevent irreversible limbic damage.

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 Alzheimers 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.

Prodromal Alzheimer’s Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task

Saccade alterations are potential early signs of Alzheimers disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimers disease (n = 29), as compared to both aged-matched mild Alzheimers disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimers disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimers disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimers disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimers disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

C9orf72 Protein Plasmatic Concentrations Are Similar between C9ORF72 Expansion Carriers and Noncarriers in Frontotemporal Dementia

Background/Aims: The aim of the study was to assess the theory of haploinsufficiency in C9ORF72 expansion carriers, the most frequent causative gene of frontotemporal dementia. Methods: Plasmatic concentrations of C9orf72 protein were measured in 33 patients suspected of familial frontotemporal dementia using an enzyme-linked immunosorbent assay. Results: No difference was observed between C9ORF72 expansion carriers (21.2% of patients) and noncarriers (78.8% of patients). C9orf72 protein determination is not a suitable biomarker for screening C9ORF72 expansion carriers. Conclusion: Our results provide new evidence against the hypothesis of haploinsufficiency leading to frontotemporal dementia in C9ORF72 expansion carriers.

P2a-6 Atrophie corticale postérieure, LCR et imagerie amyloïde : A propos de 2 cas

Introduction L’atrophie corticale posterieure (ACP) est un syndrome clinico-radiologique caracterise par un deficit progressif des fonctions visuelles et gestuelles superieures en lien avec un dysfonctionnement cortical de la partie posterieure des hemispheres. Elle est dans certains cas consideree comme la variante visuelle de la maladie d’Alzheimer (MA), les depots amyloides et les degenerescences neurofibrillaires ayant alors une predilection pour les regions posterieures. Le dosage des biomarqueurs du LCR et l’imagerie amyloide avec le Pittsburgh compound B (PIB) en tomographie par emission de positons (TEP) permettent d’etudier ces processus neuropathologiques du vivant des patients. Materiel Nous rapportons l’observation de deux patients ayant consulte pour une gene visuelle ou une maladresse gestuelle ayant conduit au diagnostic d’ACP. Une evaluation neuropsychologique, un bilan ophtalmologique furent realises ainsi qu’une imagerie anatomique et/ou metabolique, un dosage des proteines amyloides et tau du LCR par ponction lombaire et une mesure de la charge amyloide cerebrale en TEP au 11C-PIB. Resultats Le premier patient presentait des difficultes de lecture secondaires a une alexie et une simultagnosie, le deuxieme, une gene visuelle et une maladresse gestuelle du membre superieur gauche revelatrices d’un syndrome parkinsonien akineto-hypertonique et d’une apraxie ideo-motrice asymetriques associes a des troubles visuo-spatiaux. Le bilan neuropsychologique confirmait les troubles visuo-spatiaux et/ou praxiques et la relative preservation des fonctions mnesiques et executives. Des anomalies campimetriques etaient observees au champ visuel. L’IRM cerebrale retrouvait une atrophie corticale parieto-occipitale ou plus diffuse. L’analyse du LCR a mis en evidence une diminution du peptide Aβ et une augmentation des proteines Tau et Phospho-Tau compatible avec le diagnostic de MA. La TEP au PIB a retrouve une augmentation de la charge amyloide corticale par rapport aux sujets temoins, comparable a celle des sujets MA remplissant les criteres diagnostiques cliniques de MA. Conclusion Ces ACP revelees par des troubles visuo-spatiaux ou praxiques ont des capacites mnesiques preservees et ne remplissent pas les criteres NINCDS-ADRDA pour le diagnostic de MA probable. L’analyse du LCR et l’imagerie amyloide suggerent cependant l’implication des pathologies amyloide et neurofibrillaire caracteristiques de la MA dans ce tableau, soulignant ainsi l’interet de ces biomarqueurs dans le bilan etiologique des atrophies corticales focales.