Comorbidity and differential diagnosis of idiopathic normal pressure hydrocephalus and Alzheimer disease

BACKGROUND: The progression of intellectual and memory impairment is a pressing public health challenge and often leads to disability in older adults. Idiopathic normal pressure hydrocephalus represents one of the causes of dementia and is frequently comorbid with neurodegenerative disorders, particularly Alzheimer disease. Such comorbidity substantially complicates differential diagnosis. Therefore, the search of diagnostic algorithms that allow clinicians to address this problem is essential.

AIM: This work aimed to improve the diagnostic accuracy of idiopathic normal pressure hydrocephalus, Alzheimer disease, and their combination by applying a comprehensive clinical, neuropsychological, laboratory, and neuroimaging assessment.

METHODS: All patients (171 individuals) were divided into groups according to the disease. All subjects underwent extended neuropsychological testing, gait assessment using standardized scales, neuroimaging interpretation using neuroradiological scales, and cerebrospinal fluid biomarker assay of amyloidogenic and tau-pathology–related proteins.

RESULTS: Patients with normal pressure hydrocephalus demonstrated a predominantly dysregulatory cognitive impairment pattern, whereas memory impairment was secondary. In the combined Alzheimer disease–idiopathic normal pressure hydrocephalus syndrome, both dysregulatory and amnestic patterns coexisted (with the amnestic component predominating). Markedly reduced gait speed was a highly sensitive marker of idiopathic normal pressure hydrocephalus. Patients with the comorbidity also demonstrated reduced gait speed, although to a lesser degree. Cerebrospinal fluid biomarker profile in normal pressure hydrocephalus was characterized by reduced tau and phosphorylated tau levels with normal β-amyloid. In contrast, comorbid patients demonstrated reduced β-amyloid and increased tau and phosphorylated tau concentrations. Neuroimaging analysis revealed that idiopathic normal pressure hydrocephalus is characterized by pronounced ventricular enlargement in the absence of substantial cortical atrophy. Typical features include an acute callosal angle, elevated Evans Index and Z-Evans Index, and a < 1.0 brain-to-ventricle ratio. In combined Alzheimer disease–idiopathic normal pressure hydrocephalus syndrome, the neuroimaging pattern integrates the features of both diseases. The severity of cortical atrophy assessed using the medial temporal lobe atrophy scale and Koedam scale is closely associated with cerebrospinal fluid biomarker alterations. Key diagnostic features were identified that allow the clinician to suspect the combined Alzheimer disease–idiopathic normal pressure hydrocephalus syndrome.

CONCLUSION: Identification of specific cognitive impairment, gait speed reduction, characteristic neuroimaging findings, and cerebrospinal fluid biomarker profile as part of comprehensive diagnostic approach enables timely and clear differential diagnosis between idiopathic normal pressure hydrocephalus, Alzheimer disease, and their combination.