Prevalence of &lt;b&gt;&lt;i&gt;C9ORF72&lt;/i&gt;&lt;/b&gt; Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus

Korhonen, Ville; Remes, Anne M.; Helisalmi, Seppo; Rauramaa, Tuomas; Sutela, Anna; Vanninen, Ritva; Suhonen, Noora-Maria; Haapasalo, Annakaisa; Hiltunen, Mikko; Jääskeläinen, Juha E.; Koivisto, Anne M.; Leinonen, Ville

doi:10.1159/000497306

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…The systematic analysis of iNPH criteria in our bv-FTLD cohort probably allowed us to evidence this previously unknown association. Interestingly, a recent study reported a 1.6% prevalence of C9orf72 expansion (one major genetic cause of bv-FTLD) in an iNPH group, whereas no such expansion was observed in the control group, 20 suggesting a genetic link between iNPH and bv-FTLD.…”

Section: Discussionmentioning

confidence: 97%

Idiopathic normal pressure hydrocephalus and frontotemporal dementia: an unexpected association

Lataillade

Boutoleau‐Bretonnière

Aguilar-Garcia

et al. 2022

Brain Communications

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Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer’s disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (n = 69) and the other with Alzheimer’s disease (n = 178). In a second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer’s disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity.

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Section: Discussionmentioning

confidence: 97%

Idiopathic normal pressure hydrocephalus and frontotemporal dementia: an unexpected association

Lataillade

Boutoleau‐Bretonnière

Aguilar-Garcia

et al. 2022

Brain Communications

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“…In this respect, it is notable that elderly patients with FTD and concomitant hydrocephalus can show clinical improvement following cerebrospinal fluid removal. 70 , 71 Assaying cerebrospinal fluid pressure in TDP-43 Q331K mice would therefore be of interest. Nonetheless, our observation that frank hydrocephalus occurred in a small number of juvenile TDP-43 Q331K mice is enough to suggest that a developmental contribution towards ventricular enlargement in mutants is likely.…”

Section: Discussionmentioning

confidence: 99%

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

Lin

Kim

Ahmed

et al. 2021

Brain Communications

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Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.

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“…While this ventriculomegaly could be due to loss of brain parenchyma, it could also reflect hydrocephalus. In this respect, it is notable that elderly patients with FTD and concomitant hydrocephalus can show clinical improvement following cerebrospinal fluid (CSF) removal (Korhonen et al, 2017;Korhonen et al, 2019). Assaying CSF pressure in TDP-43 Q331K mice would therefore be of interest.…”

Section: Discussionmentioning

confidence: 99%

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

Lin

Kim

Ahmed

et al. 2020

Preprint

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods.Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43 Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43 Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43 Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43 Q331K knock-in mice.

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Prevalence of <b><i>C9ORF72</i></b> Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus

Cited by 12 publications

References 37 publications

Idiopathic normal pressure hydrocephalus and frontotemporal dementia: an unexpected association

Idiopathic normal pressure hydrocephalus and frontotemporal dementia: an unexpected association

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

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