RESUMO
PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.
Assuntos
Doença de Alzheimer , Sequenciamento do Exoma , Predisposição Genética para Doença , Testes Genéticos , Glicoproteínas de Membrana , Presenilina-2 , Receptores Imunológicos , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , Testes Genéticos/métodos , Feminino , Masculino , Idoso , Fatores de Risco , Estudos Prospectivos , Pessoa de Meia-Idade , Presenilina-2/genética , Presenilina-1/genética , Linhagem , Idade de Início , Precursor de Proteína beta-Amiloide/genética , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. METHODS: Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. RESULTS: Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aß42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. DISCUSSION: Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.
Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Amiloide/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/complicações , Hemorragia Cerebral/complicações , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Imageamento por Ressonância Magnética , Fenótipo , Estudos RetrospectivosRESUMO
We report here the case of a female patient who developed the following behavioural changes after a brain lesion involving the left posterior insula and SII cortices. She discovered de novo artistic capabilities for painting, with an episodic and compulsive need to paint ("hyperpainting"), but also exhibited changes in her ability to feel emotions. In addition, she had a typical neuropathic pain syndrome, including provoked pain and spontaneous pain, whose intensity was worsened when she painted with cold colours. This case-report suggests some kind of synaesthesiae, which has previously been reported for other sensory modalities. These findings suggest that a cross-talk between emotional, thermosensory, pain, and motivational functions may take place during recovery, at the level of the left insular-SII cortices.