Preliminary Results on Long-Term Potentiation-Like Cortical Plasticity and Cholinergic Dysfunction After Miglustat Treatment in Niemann-Pick Disease Type C

Benussi, Alberto; Cotelli, Maria Sofia; Cosseddu, Maura; Bertasi, Valeria; Turla, Marinella; Salsano, Ettore; Dardis, Andrea; Padovani, Alessandro; Borroni, Barbara

doi:10.1007/8904_2016_33

Cited by 17 publications

(22 citation statements)

References 36 publications

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“…The involvement of deep gray nuclei has also been confirmed by 123 I-FP-CIT (ioflupane I 123 DaTSCAN) single-photon emission computed tomography (SPECT) imaging in a case of NPC, showing a marked, symmetrical loss of dopamine transporter binding, especially in the putamen 57 . This pattern has also been observed in a heterozygote patient with a “variant phenotype” in filipin staining and with high levels of plasma oxysterols 60 .…”

Section: Neuroimagingsupporting

confidence: 59%

“…In this context, an impairment in short-latency afferent inhibition (SAI), a measurement of sensorimotor integration, has been observed in NPC. SAI is thought to be mediated largely by central cholinergic transmission and has been shown to be impaired in patients with AD 91 , 92 , further supporting the link between NPC and AD 60 , 93 , 94 . Moreover, long-term potentiation (LTP)-like cortical plasticity, evaluated with a paired associative stimulation protocol, has been shown to be impaired in patients with NPC and in a symptomatic heterozygous carrier, confirming previous reports of impaired hippocampal synaptic plasticity in Npc1 -mutant mice 95 .…”

Section: Neurophysiologymentioning

confidence: 95%

“…The impairment in LTP-like cortical plasticity has also been observed in patients with AD and FTD, further highlighting the possible parallelism between these disorders 96 , 97 . Interestingly, after 12 months of treatment with miglustat, a considerable improvement in SAI and LTP-like plasticity was observed in patients with NPC 60 .…”

Section: Neurophysiologymentioning

confidence: 98%

“…Only a limited decrease in short-interval intracortical inhibition, a marker of GABAAergic transmission, and intracortical facilitation, a marker of glutamatergic transmission, has been observed. Long-interval intracortical inhibition, reflecting GABABergic transmission, was reported to be within normal range 60 .…”

Section: Neurophysiologymentioning

confidence: 99%

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Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

Benussi

Cotelli²,

Padovani

et al. 2018

F1000Res

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Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer’s disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults. A number of ongoing clinical trials might hold promise for the development of new treatments for NPC. The objective of the present work is to review and evaluate recent literature data in order to highlight the latest neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC pathophysiology. Furthermore, ongoing developments in disease-modifying treatments will be briefly discussed.

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Section: Neuroimagingsupporting

confidence: 59%

Section: Neurophysiologymentioning

confidence: 95%

Section: Neurophysiologymentioning

confidence: 98%

Section: Neurophysiologymentioning

confidence: 99%

See 2 more Smart Citations

Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

Benussi

Cotelli²,

Padovani

et al. 2018

F1000Res

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“…TMS protocols were carried out as previously published [ 46 ]. TMS was performed with a figure-of-eight coil (each loop diameter 70 mm) connected to a Magstim Bistim 2 system (Magstim Company, Oxford, UK).…”

Section: Methodsmentioning

confidence: 99%

The impact of transcranial magnetic stimulation on diagnostic confidence in patients with Alzheimer disease

et al. 2018

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BackgroundCholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0–100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis.MethodsOne hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step.ResultsTMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the “gold standard” diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers).ConclusionsTMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0423-6) contains supplementary material, which is available to authorized users.

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Clinical and neurophysiological characteristics of heterozygous NPC1 carriers

Benussi

Cotelli²,

Cantoni

et al. 2019

JIMD Reports

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Niemann‐Pick disease type C (NPC) is an uncommon lysosomal storage disorder, which is characterized neuropathologically by cholinergic dysfunction and presents clinically with a broad series of neurological signs and symptoms. NPC is inherited as an autosomal recessive trait, caused by mutations in the NPC1 or NPC2 genes. However, recent reports have raised concerns on heterozygous NPC1 gene mutation carriers, which historically have been considered as clinically unaffected, occasionally presenting with clinical parkinsonian syndromes or dementia. In the present study, we aimed at comprehensively assessing clinical, biochemical, and neurophysiological features in heterozygous NPC1 gene mutation carriers. We assessed cholinergic intracortical circuits with transcranial magnetic stimulation, executive functions and plasma oxysterol levels in two families comprising two monozygotic twins with a homozygous NPC1 p.P888S mutation, four patients with a compound heterozygous p.E451K and p.G992W mutation, 10 heterozygous NPC1 p.P888S carriers, 1 heterozygous NPC1 p.E451K carrier, and 11 noncarrier family members. We observed a significant impairment in cholinergic circuits, evaluated with short‐latency afferent inhibition (SAI), and executive abilities in homozygous/compound heterozygous patients and heterozygous asymptomatic NPC1 carriers, compared to noncarriers. Moreover, we reported a significant correlation between executive functions performances and both plasma oxysterol levels and neurophysiological parameters. These data suggest that heterozygous NPC1 carriers show subclinical deficits in cognition, possibly mediated by an impairment of cholinergic circuits, which in turn may mediate the onset of neurological disorders in a subset of patients.

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Preliminary Results on Long-Term Potentiation-Like Cortical Plasticity and Cholinergic Dysfunction After Miglustat Treatment in Niemann-Pick Disease Type C

Cited by 17 publications

References 36 publications

Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

The impact of transcranial magnetic stimulation on diagnostic confidence in patients with Alzheimer disease

Clinical and neurophysiological characteristics of heterozygous NPC1 carriers

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