Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases

Forloni, Gianluigi; Tettamanti, Mauro; Lucca, Ugo; Albanese, Yasmin; Quaglio, Elena; Chiesa, Roberto; Erbetta, Alessandra; Villani, Flavio; Redaelli, Veronica; Tagliavini, Fabrizio; Artuso, Vladimiro; Roiter, Ignazio

doi:10.1080/19336896.2015.1027857

Cited by 54 publications

(26 citation statements)

References 16 publications

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“…In conclusion, our results add evidences that genes other than PRNP modulate the pathogenesis of prion diseases and influence disease onset in patients with CJD16 29 and might therefore be useful in a future preventive clinical trial in E200K carriers, similarly to that ongoing in D178N/M129 carriers of a large Italian family with Fatal Familial Insomnia,30 for a more homogenous stratification of participants.…”

Section: Discussionsupporting

confidence: 59%

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Poleggi

Lee

Capellari

et al. 2018

J Neurol Neurosurg Psychiatry

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We identified two single nucleotide polymorphisms on the gene locus as candidate disease modifiers in patients with E200K CJD of the cluster area and confirmed this finding in 32 patients with E200K CJD from non-cluster areas and 259 patients with sporadic CJD. Our results indicate that the gene modulates the onset of disease in patients with E200K genetic and sporadic CJD. This finding improves our understanding on the pathogenesis of CJD, suggests new targets for developing novel therapeutic strategies and might be useful for the stratification of patients in future preventive treatment trials.

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Section: Discussionsupporting

confidence: 59%

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Poleggi

Lee

Capellari

et al. 2018

J Neurol Neurosurg Psychiatry

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“…However, it is established that the clinical onset of AD and PD occurred when the pathological process had been triggered for a long time, thus it is possible that the oligomers become an obsolete target. The antioligomer treatment required an early and possible preclinical intervention when it is reasonable in patients at risk to develop the disease . Furthermore, the lack of acceptable surrogate markers in the neurodegenerative disorders compels the clinical studies, also in an exploratory phase, to evaluate the efficacy of a treatment by measuring clinical outcomes.…”

Section: Conclusion and Therapeutic Perspectivesmentioning

confidence: 99%

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

et al. 2016

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The term oligomeropathies defines the neurodegenerative disorders associated with protein misfolding, where small soluble aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathology. The ability of these soluble β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides. Together with the neuronal death, synaptic dysfunction, loss of spines, and LTP impairment were seen with the direct application of β amyloid oligomers. Similar results have been described with proteins associated with other neurodegenerative disorders. The biological activities of oligomeric forms of α synuclein have been described in Parkinson's disease and Lewy body dementia. Detrimental effects have been associated with the oligomeric forms of prion, tau, and huntingtin, the key proteins in prion diseases, frontotemporal dementia, and Huntington's disease, respectively. The molecular mechanisms of the oligomer-related toxic effects can be summarized under three headings: nonspecific perturbance of cellular and intracellular membranes, specific interaction with various cellular entities, and amyloid pore channel formation. To characterize and distinguish oligomer actions better, we compared the ability of β amyloid and α synuclein oligomers to induce cognitive impairment when applied directly into the brain in the same acute mouse model. We also investigated the role of inflammatory components. © 2016 International Parkinson and Movement Disorder Society.

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“…The here included presymptomatic carriers were on average about 44 years old and were still asymptomatic (June 2017), after an average 10 years of follow‐up after PET scan. Considering that FFI has been shown to harbor almost complete penetrance,7 with risk of clinical onset peaking around 50–55 years of age,41 our cohort was studied about 6–11 years before the expected clinical onset. These negative 11 C‐(R)‐PK11195‐PET findings are in accordance with a previous 18 F‐FDG‐PET study in FFI presymptomatic mutation carriers, showing the only dysfunctional marker being significant thalamic hypometabolism 42.…”

Section: Discussionmentioning

confidence: 99%

An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia

Iaccarino

Presotto

Bettinardi

et al. 2017

Ann Clin Transl Neurol

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ObjectivePostmortem studies reported significant microglia activation in association with neuronal apoptosis in Fatal Familial Insomnia (FFI), indicating a specific glial response, but negative evidence also exists. An in vivo study of local immune responses over FFI natural course may contribute to the understanding of the underlying pathogenesis.MethodsWe included eight presymptomatic subjects (mean ± SD age:44.13 ± 3.83 years) carrying the pathogenic D178N‐129met FFI mutation, one symptomatic patient (male, 45 yrs. old), and nine healthy controls (HC) (mean ± SD age: 44.00 ± 11.10 years.) for comparisons. 11C‐(R)‐PK11195 PET allowed the measurement of Translocator Protein (TSPO) overexpression, indexing microglia activation. A clustering algorithm was adopted to define subject‐specific reference regions. Voxel‐wise statistical analyses were performed on 11C‐(R)‐PK11195 binding potential (BP) images both at the group and individual level.ResultsThe D178N‐129met/val FFI patient showed significant 11C‐(R)‐PK11195 BP increases in the midbrain, cerebellum, anterior thalamus, anterior cingulate cortex, orbitofrontal cortex, and anterior insula, bilaterally. Similar TSPO increases, but limited to limbic structures, were observed in four out of eight presymptomatic carriers. The only carrier with the codon 129met/val polymorphism was the only one showing an additional TSPO increase in the anterior thalamus.InterpretationIn comparison to nonprion neurodegenerative diseases, the observed lack of a diffuse brain TSPO overexpression in preclinical and the clinical FFI cases suggests the presence of a different microglia response. The involvement of limbic structures might indicate a role for microglia activation in these key pathologic regions, known to show the most significant neuronal loss and functional deafferentation in FFI.

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Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases

Cited by 54 publications

References 16 publications

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia

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Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases

Cited by 54 publications

References 16 publications

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia

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An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia