Dynamic functional networks in idiopathic normal pressure hydrocephalus: Alterations and reversibility byCSFtap test

Abstract

Idiopathic Normal Pressure Hydrocephalus (iNPH)—the leading cause of reversible dementia in aging—is characterized by ventriculomegaly and gait, cognitive and urinary impairments. Despite its high prevalence estimated at 6% among the elderlies, iNPH remains underdiagnosed and undertreated due to the lack of iNPH‐specific diagnostic markers and limited understanding of pathophysiological mechanisms. INPH diagnosis is also complicated by the frequent occurrence of comorbidities, the most common one being Alzheimer's disease (AD). Here we investigate the resting‐state functional magnetic resonance imaging dynamics of 26 iNPH patients before and after a CSF tap test, and of 48 normal older adults. Alzheimer's pathology was evaluated by CSF biomarkers. We show that the interactions between the default mode, and the executive‐control, salience and attention networks are impaired in iNPH, explain gait and executive disturbances in patients, and are not driven by AD‐pathology. In particular, AD molecular biomarkers are associated with functional changes distinct from iNPH functional alterations. Finally, we demonstrate a partial normalization of brain dynamics 24 hr after a CSF tap test, indicating functional plasticity mechanisms. We conclude that functional changes involving the default mode cross‐network interactions reflect iNPH pathophysiological mechanisms and track treatment response, possibly contributing to iNPH differential diagnosis and better clinical management.

CSF tap test in idiopathic normal pressure hydrocephalus: still a necessary prognostic test?

“…The TUG, another indicator of dynamic balance, did not contribute to RSP/nRSP prediction but positively correlated with step width in nRSP only [nRSP: ρ TUG, step width = 0.74 (p = 0.0033); RSP: ρ TUG, step width = 0.07 (p = 0.80); eFigure 2]. These results are in line with previous studies indicating that balancerelated gait parameters do not improve after CSFTT [16,23] and patients with moderate-to-severe postural instability do not show long-term improvement after shunting [36]. However, recent findings on younger iNPH patients show improved dynamic equilibrium after shunting, suggesting that a patient stratification based on age and disease duration may provide a better characterization of symptom reversibility [37].…”

“…Subcortical perfusion [ 34 ] and default mode network (DMN) function [ 15 , 16 ] have been implicated in the pathophysiology of iNPH. The THAL was segmented using FreeSurfer6.0.0, and the PCC—the main DMN hub—was identified based on a fMRI-based segmentation [ 16 ] (Fig. 1 b).…”

“…Data were preprocessed and analyzed as previously described [ 16 ]. The DMN activity was characterized using a whole-brain co-activation pattern analysis with the PCC as seed region (Fig.…”

“…Although the pathophysiology of iNPH is not clear yet, different mechanisms have been proposed including periventricular axonal neurodegeneration and small vessel damage [ 14 ]. Moreover, alterations of large-scale brain functional organization have been observed, with particular involvement of the default mode network (DMN) [ 15 ], and partial functional normalization after CSFTT suggesting a role in determining outcome [ 16 ]. Integrating advanced neuroimaging methods probing iNPH pathophysiological mechanisms may identify reversible mechanisms that will eventually improve the diagnostic procedure and contribute to the prediction of CSFTT outcome, shading new light on the factors underlying short-term symptom reversibility.…”

Dynamic stability during gait in idiopathic normal pressure hydrocephalus and Parkinson's disease

“…Based on the underlying pathophysiology, PD can manifest as a subcortical hypokinetic gait disorder, 8,9 whereas iNPH can manifest as a frontal higher‐level gait disorder with disequilibrium 10‐12 . In addition, several functional imaging studies have suggested that, in addition to the frontal areas of the brain, subcortical areas are also affected in iNPH 13‐15 . Thus, we speculate that PD and iNPH have different dynamic stability during gait.…”