Predicting Development of Alzheimer’s Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus

Luikku, Antti; Hall, Anette; Nerg, Ossi; Koivisto, Anne M.; Hiltunen, Mikko; Helisalmi, Seppo; Herukka, Sanna‐Kaisa; Junkkari, Antti; Sutela, Anna; Kojoukhova, Maria; Korhonen, Ville; Mattila, Jussi; Lötjönen, Jyrki; Rummukainen, Jaana; Alafuzoff, Irina; Jääskeläinen, Juha E.; Remes, Anne M.; Solomon, Alina; Kivipelto, Miia; Soininen, Hilkka; Rauramaa, Tuomas; Leinonen, Ville

doi:10.3233/jad-190334

Cited by 37 publications

(36 citation statements)

References 45 publications

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“…Altogether, 201 patients with probable iNPH according to Relkin criteria [ 3 ] were shunted by right frontal puncture and ventriculoperitoneal CSF shunt (PS Medical Strata II valve) between January 2009 and December 2015 at the Kuopio University Hospital following a previously described protocol [ 29 ] ( Supplementary Table 1 ). Brain biopsies of 41 patients were taken during shunt surgery and analyzed according to the established protocol [ 30 ]. The biopsy was taken from the right frontal cortex, 3 cm from the midline and anterior to the coronal suture, and the size of the cylinder-shaped sample was 2–5 mm in diameter and 3–7 mm in length.…”

Section: Methodsmentioning

confidence: 99%

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Lukkarinen

Tesseur

Pemberton

et al. 2021

JAD

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Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3–73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but Aβ42 increased notably by 140–810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

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Section: Methodsmentioning

confidence: 99%

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Lukkarinen

Tesseur

Pemberton

et al. 2021

JAD

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“…Further experimental studies are needed to fully elucidate the relative contribution of venules and arteries to the clearance of ISF from the parenchyma. There is an increased incidence of AD pathology, including CAA, in patients with idiopathic normal pressure hydrocephalus (iNPH), most likely as a result of disturbances in the dynamics of CSF‐ISF 57 . Patients with iNPH could therefore be a valuable model for the study of interactions CSF–ISF.…”

Section: Interconnections Between Csf and Isf In The Brainmentioning

confidence: 99%

Clearance of interstitial fluid (ISF) and CSF (CLIC) group—part of Vascular Professional Interest Area (PIA)

Carare

Aldea

Agarwal

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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Two of the key functions of arteries in the brain are (1) the well‐recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri‐arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

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“…AD is the most common pathology found in about 30%–40% of patients with iNPH at autopsy, 14,15 brain biopsies obtained during shunt surgeries, and amyloid positron emission tomography (PET) scans 16 . This finding has also been attributed to unrelated aging processes because this frequency is also seen in autopsy studies of adults without dementia who were older than 75 years and in amyloid PET studies of the general population 17,18 .…”

Section: What We Knowmentioning

confidence: 99%

Gaps, Controversies, and Proposed Roadmap for Research in Normal Pressure Hydrocephalus

et al. 2020

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A BS TRACT: Idiopathic normal pressure hydrocephalus is considered common but remains underinvestigated. There are no uniformly accepted diagnostic criteria and therapeutic guidelines. We summarize the accumulated evidence regarding the definition, pathophysiology, diagnosis, and treatment of idiopathic normal pressure hydrocephalus, highlighting the many gaps and controversies, including diagnostic challenges, the frequent association with neurodegeneration and vascular disease, and the many unknowns regarding patient selection and outcome predictors. A roadmap to fill these gaps and solve the controversies around this condition is also proposed. More evidence is required with respect to diagnostic criteria, the value of ancillary testing, prospective population-based studies and novel trial designs. Furthermore, a need exists to develop new advanced options in shunt technology.

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Predicting Development of Alzheimer’s Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus

Cited by 37 publications

References 45 publications

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Clearance of interstitial fluid (ISF) and CSF (CLIC) group—part of Vascular Professional Interest Area (PIA)

Gaps, Controversies, and Proposed Roadmap for Research in Normal Pressure Hydrocephalus

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