Alzheimer’s disease differential diagnosis with normal pressure hydrocephalus

Alzheimer’s disease differential diagnosis with normal pressure hydrocephalus

see also Normal pressure hydrocephalus differential diagnosis

Easy and reliable tools for the differential diagnosis between idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s disease (AD) are needed.

Callosal angle: On a coronal section at the level of the posterior commissure, this angle is normally 110°; values around 100° are seen in Alzheimer’s disease. In hydrocephalus, the callosal angle is less than 90° as a rule 1)

The degree of dilatation of perihippocampal fissures (PHFs) appears to be a sensitive and specific marker for differentiating AD from NPH by both subjective and objective means, with a very small overlap between the two groups. This observation may have relevance in day-to-day practice 2).

Some of the symptoms of normal pressure hydrocephalus can overlap with those of Alzheimer’s disease, making it an important condition to consider in the differential diagnosis. Here are some points to consider when distinguishing NPH from Alzheimer’s:

Gait disturbances: One of the hallmark symptoms of NPH is gait disturbances, often described as a shuffling walk with small steps and difficulty initiating movement. This symptom is less commonly associated with Alzheimer’s disease.

Urinary incontinence: NPH can cause urinary urgency, frequency, and incontinence. While urinary incontinence can occur in the advanced stages of Alzheimer’s, it is not typically one of the early or prominent symptoms.

Cognitive symptoms: Both NPH and Alzheimer’s disease can cause cognitive impairment, including memory problems and difficulties with attention and concentration. However, in NPH, these cognitive symptoms often occur in combination with gait disturbances and urinary incontinence.

MRI findings: Brain imaging, particularly magnetic resonance imaging (MRI), is useful in differentiating NPH from Alzheimer’s. In NPH, MRI may reveal enlarged ventricles with a characteristic pattern called “ventriculomegaly,” indicating the buildup of cerebrospinal fluid. In contrast, Alzheimer’s disease may show brain atrophy in specific regions.

Response to treatment: Another distinguishing factor is the response to treatment. NPH can often be treated by draining excess cerebrospinal fluid through a surgical procedure called a shunt. If symptoms improve significantly following shunt placement, it suggests NPH rather than Alzheimer’s disease.

It is important to note that NPH and Alzheimer’s disease can coexist in some cases, further complicating the diagnosis. Therefore, a comprehensive evaluation by a healthcare professional, including a detailed medical history, physical examination, cognitive assessments, and neuroimaging, is necessary to differentiate between these conditions accurately.

In a cross-sectional study, iNPH and AD referring to the Neurology Unit of the University of Catania from the 1st of January 2020 to the 1st of December 2022 were enrolled. The following brain linear measurements were calculated: Evans Index (EI), the parieto-occipital Ratio (POR), and the Temporal-Ratio (TR). For each indexsensitivityspecificity, and area under the curve (AUC) were calculated. Moreover, a cumulative index, i.e. the brain linear measurement (BLM) index was also considered.

Fifty patients (25 iNPH and 25 AD) were enrolled. In differentiating iNPH from AD, EI had the highest AUC (0.956), POR had the highest specificity (100%), and TR had the highest sensitivity (92%). The BLM index differentiated iNPH and AD with a sensitivity of 96%, a specificity of 92%, and an AUC of 0.963 with the optimal cut-off value of 0.303.

EI, POR, and TR may be useful in the differential diagnosis between iNPH and AD. At an individual level, the BLM index represents a valid and reliable tool to achieve an accurate differentiation between these two conditions 3)

iNPH patients are present with lower CSF Aβ42 and p-tau concentrations than healthy individuals and lower t-tau and p-tau concentrations than AD patients. This could prove helpful for improving diagnosis, differential diagnosis, and possibly prognosis of iNPH patients 4).

Results suggest that levels of CSF Aβ42, p-tau, and t-tau, in particularly decreased t-tau, are of potential value in differentiating iNPH from LBDs and also confirm previous studies reporting t-tau level is lower and Aβ42 level is higher in iNPH than in AD 5)

A study analyzed and quantified the presence of AQP1 and AQP4 in the CSF of patients with iNPH and AD to determine whether these proteins can be used as biomarkers of iNPH. We examined AQP1 and AQP4 protein levels in the CSF of 179 participants (88 women) classified into 5 groups: possible iNPH (81 participants), hydrocephalus associated with other neurological disorders (13 participants), AD (41 participants), non-AD dementia (32 participants) and healthy controls (12 participants). We recorded each participant’s demographic and clinical variables and indicated, when available in the clinical history, the record of cardiovascular and respiratory complications. An ELISA showed virtually no AQP content in the CSF. Information on the vascular risk factors (available for 61 patients) confirmed some type of vascular risk factor in 86% of the patients with possible iNPH and 58% of the patients with AD. In conclusion, the ELISA analysis showed insufficient sensitivity to detect the presence of AQP1 and AQP4 in CSF, ruling out the possible use of these proteins as biomarkers for diagnosing iNPH 6)


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Hiraldo-González L, Trillo-Contreras JL, García-Miranda P, Pineda-Sánchez R, Ramírez-Lorca R, Rodrigo-Herrero S, Blanco MO, Oliver M, Bernal M, Franco-Macías E, Villadiego J, Echevarría M. Evaluation of aquaporins in the cerebrospinal fluid in patients with idiopathic normal pressure hydrocephalus. PLoS One. 2021 Oct 1;16(10):e0258165. doi: 10.1371/journal.pone.0258165. PMID: 34597351; PMCID: PMC8486078.

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