Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition

Abstract

Background: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer’s disease (AD). Objective: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1–42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. Methods: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Results: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p > 0.05). Conclusion: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

Plasma microglial-derived extracellular vesicles are increased in frail patients with Mild Cognitive Impairment and exert a neurotoxic effect

“…After the diagnostic workup, subjects were diagnosed by expert neurologists with MCI or AD, according to the specific criteria of each syndrome [27,28]. Specifically, AD and MCI patients underwent a clinical interview, neurological and neuropsychological examination, routine blood tests, brain MRI and lumbar puncture (LP) for quantification of the cerebrospinal fluid (CSF) biomarkers Aβ-amyloid 42, total tau and tau phosphorylated at position 181 (Ptau181) as previously described [29]. The control group consisted of 20 non-demented volunteers matched for ethnic background and age and without memory and psycho-behavioral dysfunctions (MMSE ≥ 28).…”

Calabria as a Genetic Isolate: A Model for the Study of Neurodegenerative Diseases

“…Thus, heterozygosity can be a risk factor for dementia, and this is also confirmed by the high risk of neurodegenerative diseases, especially AD, in the parents of NCP patients [ 86 ] and by the links between lipid metabolism and Aβ [ 87 ]. Therefore, even the study of very rare forms can help to identify pathogenetic pathways of neurodegeneration that have not yet been fully elucidated.…”

Calabria as a Genetic Isolate, a Model for the Study of Neurodegenerative Diseases

“…Thus, heterozygosity can be a risk factor for dementia, and this is also confirmed by the high risk of neurodegenerative diseases, especially AD, in the parents of NCP patients [86] and by the links between lipid metabolism and A [87]. Therefore, even the study of very rare forms can help to identify pathogenetic pathways of neurodegeneration that have not yet been fully elucidated.…”