Genetics of Idiopathic Normal Pressure Hydrocephalus

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

Idiopathic normal pressure hydrocephalus (iNPH) is often undiagnosed or misdiagnosed because it presents with symptoms of gait dysfunction, urinary incontinence, and dementia that are common in other disorders.
The diagnosis of iNPH depends on several factors, including enlarged ventricles, advanced age, and clinical improvement after CSF drainage.
The cause of iNPH has not been clearly established, although several reports of familial iNPH have been published in the literature. The incidence of familial iNPH has been reported to be between 7% and 11%. Additionally, there have been several reports of autosomal dominant inheritance.
To date, surveys of iNPH patients have identified a possible affected family member in less than 10% of cases. Intron loss in the SFMBT1 gene, which has been associated with iNPH, occurs in 10% to 21% of Finnish and Norwegian iNPH patients. Based on these data, one might predict that at least 10% to 20% of iNPH patients are genetically susceptible to this disorder. This represents a minimum estimate because it focuses only on SFMBT1 and does not consider CFAP43, NME8, or other yet to be discovered iNPH-associated genes. Additional genetic studies of patients with sporadic iNPH are needed.
Defects in cilia-related genes have been associated with congenital hydrocephalus in humans and animals. The finding that genetic variations involving cilia-related genes such as CFAP43, NME8, and SFMBT1 are associated with iNPH raises the possibility that iNPH may be caused by defects in ventricular ciliated epithelia.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by ventriculomegaly ( Fig. 41.1 ), gait apraxia, urinary incontinence, and dementia. ^, Gait dysfunction is the most commonly observed symptom of iNPH, occurring in about 90% of cases. The gait dysfunction of iNPH is characterized by decreased step height, decreased stride length, decreased cadence, and impaired balance ( Fig. 41.2 ). Because the symptoms of iNPH are commonly seen in other neurological disorders such as Alzheimer disease and Parkinson disease, ^, it often remains undiagnosed or is misdiagnosed.

Unlike these neurodegenerative disorders, however, the symptoms of shunt-responsive iNPH can be improved by CSF drainage. Indeed, ventricular enlargement, the presence of the characteristic iNPH symptoms, and a response to shunt placement are necessary for establishing a certain diagnosis of shunt-responsive iNPH ^, ( Figs. 41.3 and 41.4 ). The lack of knowledge about the etiology of iNPH and the empirical method of diagnosis has led some practitioners to question whether iNPH exists as a distinct disease entity. This skepticism has contributed to the low rates of diagnosis of the disorder.

iNPH is a neurological disorder of aging. In a study that examined clinical variables associated with shunt-responsive iNPH, it was observed that only 1 of 418 patients with proven shunt-responsive iNPH was younger than 60 years of age. It is estimated that approximately 700,000 Americans are affected by iNPH, with the average age at diagnosis being 75 years. The prevalence of iNPH has been estimated to be 1.4% to 2.9% in individuals older than 65 years of age and 5.6% in those older than 75 years of age. ^, The prevalence of iNPH in nursing homes has been estimated to be between 9% and 14%.

Although first described in 1965, the etiology and pathophysiology of sporadic iNPH remain a mystery. Radiographically, patients with iNPH are noted to have enlarged cerebral ventricles (see Fig. 41.1B ), periventricular white matter abnormalities, alterations in size of the subarachnoid spaces (i.e., disproportionately enlarged subarachnoid spaces [DESH]), and abnormal CSF flow through the cerebral aqueduct on MRI. A common measure of ventriculomegaly is the Evans index, although this is not specific to iNPH (see Fig. 41.1C ). Another classic imaging finding in iNPH is the pronounced atrophy in the Sylvian fissure compared with the crowding of the gyri at the vertex (measured as the callosal angle) (see Fig. 41.1D ). ^, Abnormal physiologic findings observed in iNPH patients include ventricular CSF stasis, abnormal cerebrovascular reactivity, and increased amplitude of intracranial pressure waves. Patients with iNPH are also more likely to develop periventricular white matter disease on MRI. Importantly, brain atrophy is not a striking feature. Although several theories have been proposed to explain these phenomena, experimental evidence to support these theories has been limited. Associations between iNPH and hypertension, hypercholesterolemia, diabetes, and alcohol consumption have been reported, but the physiologic mechanisms underlying these associations are not known. ^,

Pathology of iNPH

The neuropathologic characteristics of iNPH are incompletely known. However, efforts have been made to study them in animals and humans. Although advanced age is a risk factor for iNPH, evidence suggests that iNPH is not a neurodegenerative disease like Alzheimer disease or Parkinson disease. ^, Published studies have reported tangles and plaques in only 10% to 66% of brain biopsies obtained from iNPH patients. Leinonen et al. studied cortical brain biopsies in 469 patients with presumed iNPH and found that 42% had amyloid-β aggregates and 9% had both amyloid-β and hyperphosphorylated tau. In addition, they also analyzed the pathology findings in brains obtained from 10 postmortem patients with presumed iNPH. They found that three of these post-mortem specimens displayed amyloid-β aggregates, one displayed corticobasilar degeneration, and five displayed evidence of vascular pathology. Thus, neurodegeneration was not a consistent or prevalent finding in these studies. A prospective observational study published by Eide and Hansson in 2017 investigated whether there is altered expression of water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) in 44 iNPH patients when compared with 13 controls. They found that there was a significant correlation ( P < 0.001) between the presence of astrogliosis and the reduction of AQP4 and Dp71 at the astrocytic perivascular endfeet in iNPH patients. They proposed that this mechanism may contribute to vascular pathology such as subischemia. However, these findings did not address the question of the origins of iNPH.

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