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. 2024 Jan 24;34(2):bhae001. doi: 10.1093/cercor/bhae001

Utility of cortical tissue analysis in normal pressure hydrocephalus

Ana B W Greenberg 1,2, Kedous Y Mekbib 3,4, Neel H Mehta 5, Emre Kiziltug 6, Phan Q Duy 7, Hannah R Smith 8, Antti Junkkari 9, Ville Leinonen 10, Bradley T Hyman 11, Diane Chan 12, William T Curry Jr 13, Steven E Arnold 14, Frederick G Barker II 15, Matthew P Frosch 16, Kristopher T Kahle 17,18,19,✉
PMCID: PMC10839843  PMID: 38275188

Abstract

Clinical improvement following neurosurgical cerebrospinal fluid shunting for presumed idiopathic normal pressure hydrocephalus is variable. Idiopathic normal pressure hydrocephalus patients may have undetected Alzheimer’s disease-related cortical pathology that confounds diagnosis and clinical outcomes. In this study, we sought to determine the utility of cortical tissue immuno-analysis in predicting shunting outcomes in idiopathic normal pressure hydrocephalus patients. We performed a pooled analysis using a systematic review as well as analysis of a new, original patient cohort. Of the 2707 screened studies, 3 studies with a total of 229 idiopathic normal pressure hydrocephalus patients were selected for inclusion in this meta-analysis alongside our original cohort. Pooled statistics of shunting outcomes for the 229 idiopathic normal pressure hydrocephalus patients and our new cohort of 36 idiopathic normal pressure hydrocephalus patients revealed that patients with Aβ + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with negative pathology. Idiopathic normal pressure hydrocephalus patients with Alzheimer’s disease -related cortical pathology may be at a higher risk of treatment facing unfavorable outcomes following cerebrospinal fluid shunting. Thus, cortical tissue analysis from living patients may be a useful diagnostic and prognostic adjunct for patients with presumed idiopathic normal pressure hydrocephalus and potentially other neurodegenerative conditions affecting the cerebral cortex.

Keywords: Amyloid Beta, Biomarker, Dementia, Shunt Outcome, Tau

Introduction

Symptoms and clinical presentation

Normal pressure hydrocephalus (NPH) is a form of adult hydrocephalus (Williams et al. 2019) and features expansion of the cerebrospinal fluid (CSF)-filled spaces accompanied by nonspecific symptoms of gait ataxia, cognitive impairment, and urinary incontinence. Despite being commonly seen in other conditions affecting the elderly, these three symptoms are a hallmark of NPH, and thus are often referred to as a “classical triad” of symptoms (Nassar and Lippa 2016).

Prevalence

The current global population affected by dementia is estimated to be over 55 million, and this number rises by almost 10 million new cases each year (World Health Organization 2021). Of this worldwide count, it is estimated that about 1.3% of dementia cases in subjects over 65 years old present with idiopathic normal pressure hydrocephalus (iNPH), although the exact epidemiology of iNPH remains uncertain (Martín-Láez et al. 2015). This prevalence also varies as a function of age: the prevalence of iNPH is estimated to be four times higher in patients over 80 years old than patients 65–79 years old (Andersson et al. 2019). Despite the uncertain incidence of iNPH, the condition appears to be broadly underdiagnosed (Jaraj et al. 2014; Martín-Láez et al. 2015; Picascia et al. 2015).

Diagnosis

Two diagnostic guidelines for iNPH exist (Relkin et al. 2005; NAKAJIMA et al. 2021), and both describe a similar, preoperative, step-by-step system for assigning patients to different iNPH probability groups based on clinical assessment, presence of comorbidities, and radiographic evaluation of the degree of ventriculomegaly (including decreased callosal angle and Evan’s index ≥0.3). As standard practice in our local cohort, suspected iNPH patients undergo a CSF-diversion trial via lumbar drain or large-volume lumbar puncture as an additional diagnostic and prognostic measure. Transient clinical improvement following temporary CSF diversion is associated with subsequent positive shunting outcomes (Marmarou et al. 2005).

Treatment and success rate

The primary treatment for iNPH is surgical placement of a ventriculoperitoneal (VP) shunt to allow for continuous CSF diversion. Following installation of a surgical shunt, clinical outcomes can vary widely. Between 58 and 91% of patients undergoing shunt placement will have a sustained clinical response within approximately 1 year (Kahlon et al. 2007; Klinge et al. 2012; Illán-Gala et al. 2017; Popal et al. 2021). Improvements in gait and urinary control are more common following shunting, while cognitive improvement is often less predictable (Kahlon et al. 2007).

iNPH and AD

The most common form of dementia, AD affects as many as 38.5 million people worldwide (World Health Organization 2021). Not only does AD share a patient age demographic with iNPH, but it also overlaps with iNPH in clinical presentation of cognitive decline. Additionally, severe cerebral volume loss due to AD has a similar radiographic appearance to the ventriculomegaly that is a principal diagnostic feature of iNPH. The degenerative cerebral volume loss known as hydrocephalus ex vacuo is a manifestation of the compensatory enlargement of the ventricles seen in AD patients. Despite having a similar radiographic appearance, hydrocephalus ex vacuo in AD patients has a markedly different prognostic value than does the ventriculomegaly seen in iNPH patients (Kim et al. 2021). Due to these confounding factors, it is possible for people with iNPH to be instead erroneously diagnosed with AD. The opposite also holds true (Espay et al. 2017). A misdiagnosis of AD, however, holds clinical significance in that it would deprive true iNPH patients of effective treatment (Kazui et al. 2015).

In iNPH patients with comorbid AD or neurodegenerative pathology associated with AD, the additional neurodegenerative burden may contribute to poor shunting outcomes, particularly with respect to cognition (Hiraoka et al. 2015; Pomeraniec et al. 2016). This phenomenon, though, also applies to numerous other comorbidities that hamper treatment outcome (Malm et al. 2013). It is of great importance to elucidate the relationship between iNPH and AD-associated pathology, as it might provide additional insight to better diagnose and treat this growing patient population.

In sum, misdiagnosis of and/or concomitant AD-related pathology may impede proper treatment and clinical improvement in individuals with iNPH. A thorough investigation into potential presence of AD-related features in surgical shunt candidates for iNPH prior to shunt placement may help in selecting candidates who will exhibit positive clinical outcomes. In this meta-analysis, we explore the utility of detecting AD pathology, amyloid-beta (Aβ) and hyperphosphorylated tau (HPτ) in cortical tissue for predicting shunt outcome. Our analysis suggests cortical tissue analysis could be a useful diagnostic and prognostic adjunct for patients with presumed iNPH.

Methods

  • (i) Systematic review and meta-analysis

This systematic review and meta-analysis was conducted according to the reporting guidelines set forth in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) (Page et al. 2021).

Search strategy and information sources

Using the terms normal pressure hydrocephalus, biopsy, and outcome, we searched PubMed, Cochrane Library, and Google Scholar for studies reporting correlation of surgical shunting outcomes with comorbidity of NPH and Alzheimer’s disease. We did not use additional search filters or limits (except for Cochrane Library, for which we exclusively looked at trials). We last consulted PubMed on 2022 December 12, and Cochrane Library and Google Scholar on 2022 December 5.

Eligibility criteria and selection process

Original articles were selected for inclusion based on the following: diagnostic criteria, specific shunting procedure carried out, neuropathologic measures on cortical biopsy, and temporal and other limits for clinical follow-up evaluations after shunt placement. Regarding diagnostic criteria, all iNPH diagnostic methods must have utilized in participant selection: (Abu Hamdeh et al. 2018) radiographic identification of ventriculomegaly, (Ågren-Wilsson et al. 2007) clinical assessment and identification of hallmark symptomology, (Andersson et al. 2019) no other apparent cause for clinical presentation (i.e. presenting with iNPH not acquired hydrocephalus with NPH syndrome (Williams et al. 2019)). In terms of specific type of shunting, we selected articles for review that carried out VP shunting and excluded articles that carried out other forms of shunting such as lumboperitoneal shunting. Regarding neuropathologic criteria, sections of cortical biopsy must have been assessed for presence of both Aβ and HPτ. For Aβ pathology, both diffuse and neuritic plaques must have been counted as pathological features. Additionally, we excluded articles that did not carry out clinical assessment of all triad symptoms following shunt surgery and those that did not perform postoperative evaluations of patients within one year following surgical shunting to minimize confounding factors (Klinge et al. 2005).

To assess whether a study met inclusion criteria, we screened all search results for relevance of titles and abstracts and selected relevant articles for a full-text review based on identification of key terms. Following the full-text review, articles were selected for final inclusion if they met all eligibility criteria.

Study risk of bias assessment

Each included study was assessed for quality and risk of bias using guidelines set forth by the Oxford Centre for Evidence-based Medicine (OCEBM Working Group) and Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) (Whiting et al. 2011).

Data collection and data items

From the included studies, data were populated into an extraction table by two independent reviewers (A.B.W.G., K.Y.M.). Data extracted included number of patients in each neuropathological group (Aβ+/HPτ+, Aβ+/HPτ−, Aβ−/HPτ+, and Aβ−/HPτ−) as a function of shunt outcome measure. Shunt outcome measures included assessment of improvement in at least one triad symptom compared to preoperative assessment of functional status reported observationally or by score on an iNPH grading scale.

From our final selection, there were several studies that fit all inclusion criteria but did not publish explicit numbers of patients in each neuropathological group as a function of shunt outcome measure, despite having noted the collection of this data. Corresponding authors of such studies were directly contacted via email by A.B.W.G. on 2022 December 5 with a request for the supplemental data, which data, if provided, were included in the meta-analysis as described above.

Effect measures and preliminary synthesis methods

Studies included in this meta-analysis reported binary (Yes/No clinical improvement following shunt placement) or continuous (change in iNPH scale score following shunt placement) outcome measures. To synthesize disparate measures across studies, we converted all outcome measures into either of the two following outcomes: “shunt responsive” and “shunt nonresponsive.”

The “shunt responsive” group included patients clinically evaluated as having an observable improvement in at least one triad symptom and patients who had a significant increase in iNPH scale score. An increase of ≥ five points on the iNPH scale score corresponded to a clinically significant shunt response (Abu Hamdeh et al. 2018).

The “shunt nonresponsive” group included patients who did not show observable clinical improvement in any triad symptom (measured by physician evaluation or by change in iNPH scale score). This “shunt nonresponsive” group included patients who either showed no change in functional status or showed deterioration.

Reporting bias and certainty of evidence assessments

Study assessments including reporting bias and certainty of evidence were carried out independently by two reviewers (A.B.W.G. and K.Y.M.) according to the Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses for cohort studies (Wells et al. 2019). In this meta-analysis, “Exposed” = positive biopsy, and “Outcome” = shunt responsiveness.

  • (ii) Original cohort

This original cohort study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology Statement (von Elm et al. 2008).

Ethical statement

Permission for this clinical research was obtained from the Institutional Review Board at Massachusetts General Hospital (MA, United States), and all patients provided written, informed consent.

Patient selection

Patients suspected for iNPH primarily underwent clinical observation by a neurologist and were then referred for a neurosurgical consultation at Massachusetts General Hospital, where selected patients also underwent preoperative and postoperative clinical evaluation. All included patients were classified as probable iNPH cases according to diagnostic guidelines set forth by Nakajima et al. (2021) (modified for exclusion of CSF analysis as diagnostic criterion).

For preoperative screening, patients who exhibited triad symptoms in conjunction with radiographic evidence of ventriculomegaly (including decreased callosal angle and Evan’s index ≥0.3) (in absence of another cause) then underwent a CSF-diversion trial. Patients who exhibited transient improvement in any triad symptom following the temporary CSF-diversion were then considered as candidates for shunt surgery. All shunts placed used a VP shunt system.

Postoperative assessment included clinical evaluation of all triad symptoms as compared to the patient’s functional status prior to shunt placement. For our analysis, postoperative improvement (or lack thereof) observational measures were extracted and synthesized from multidisciplinary evaluations, including from neurosurgery, neurology, and physical/occupational therapy in the follow-up assessments within two to three months and one year after shunt placement. Gait was assessed for speed and pattern with visual and timed measurements including the Timed Up and Go test; cognitive status and changes in urinary control were assessed by self-reported and/or spouse or caretaker observations.

Patients included in this study underwent shunt surgery between 2021 December and 2022 October.

Tissue collection and processing protocol

During neurosurgery, and prior to installment of the VP shunt, cortical tissue that would otherwise be discarded because of its presence in the stereotactically-defined cortesectomy tract employed to accommodate the subsequently placed CSF ventricular catheter, and therefore less than the diameter of the catheter itself, was acquired from the right parieto-occipital neocortex. Acquired cortical tissue was then assessed via light microscopy for immunoreactive presence of Aβ and HPτ by a neuropathologist.

Data collection and data items

Patient data, including the number of patients in each neuropathological group (Aβ+/HPτ+, Aβ+/HPτ , Aβ−/HPτ+, and Aβ−/HPτ−) were extracted as a function of shunt outcome measure. Shunt outcome measures included assessment of observable and/or patient-reported improvement at least one triad symptom compared to preoperative evaluation.

To create binary (Yes/No clinical improvement following shunt placement) measures from clinical observation records, we converted all outcome measures into either of the two following outcomes: “shunt responsive” and “shunt nonresponsive.” The “shunt responsive” group included patients who were clinically evaluated as having an observable and/or self-reported improvement in at least one triad symptom. The “shunt nonresponsive” group included patients who did not exhibit and/or report apparent clinical improvement in any symptom. This “shunt nonresponsive” group included patients who either had no apparent change in functional status or had deterioration.

Potential sources of bias

To minimize bias in data extraction, we analyzed relevant patient data and subsequently sorted patients into the binary categories of “shunt responsive” and “shunt nonresponsive” while blinded to biopsy pathology. Additionally, shunt outcomes were determined as “shunt responsive” or “shunt nonresponsive” by using multiple sources of data, including any patient- or caretaker-reported observations, clinical observations from neurosurgery and neurology, and formal assessments by trained physical therapists. Further, these comparative observations were all made by those with direct knowledge of the patient’s functional status prior to shunt placement.

  • (iii) Combined meta-analysis: pooled study cohort and original cohort

Synthesis methods and statistical analysis

For each individual study and for our original cohort, odds ratios (ORs) were selected as the summary effect measure, and a pooled statistic was calculated using a fixed-effect Mantel–Haenszel (M-H) test (Deeks et al. 2022), using P-value (P ≤ 0.05) and a 95% confidence interval (CI) to assess significance. “Events” for the tests were shunt responsiveness, and “non-events” were shunt nonresponsiveness. ORs (and M-H tests) were calculated for the non-event, i.e. to assess the odds of a patient being shunt nonresponsive, given that they had a positive biopsy.

Additionally, to assess statistical heterogeneity between selected studies, Chi2 and I2 statistics were calculated for each M-H test. The following cutoffs were used as a guide for I2 significance: P ≤ 0.10 and 0–40%: likely inconsequential heterogeneity; 30–60%: possible moderate heterogeneity; 50–90%: suggests substantial heterogeneity; 75–100%: likely considerable heterogeneity (Deeks et al. 2022).

Statistical analyses were run using Review Manager (RevMan 2020) version 5.4 (April 5) for individual study ORs and for the M-H test. RevMan was used to create forest plot and OR figures and GraphPad Prism (2022, San Diego, California, United States) was used to create descriptive bar graphs.

Results

  • (i) Systematic review and meta-analysis

Study selection

Our search of databases and registers identified 2707 articles (Supplementary Fig. 1). Of these, 225 screened articles were investigated for title/abstract relevance. Following initial screening, 181 articles were excluded, and 44 articles remained for a full-text review.

Fig. 1.

Fig. 1

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Graphical study overview. Abstract workflow depicting our original cohort study and meta-analysis. Figure created with BioRender.com. Abbreviations: Aβ = amyloid-beta, HPτ = hyperphosphorylated tau, iNPH = idiopathic normal pressure hydrocephalus.

Corresponding authors of articles (Golomb et al. 2000; Savolainen et al. 2000; Hamilton et al. 2010; Patel et al. 2012; Junkkari et al. 2019) that met inclusion criteria but that did not publish required data were contacted with a request for supplemental data. Of the authors contacted, only Dr Antti Junkkari of The Broad Institute of MIT and Harvard (MA, United States) was able to provide necessary supplemental data meriting study inclusion (Junkkari et al. 2019). One additional study (Kojoukhova et al. 2017) was excluded at the full-text stage due to complete cohort overlap with another eligible study (Pyykkö et al. 2014). Three studies (Pyykkö et al. 2014; Abu Hamdeh et al. 2018; Junkkari et al. 2019) remained for final inclusion.

Study characteristics and risk of bias in studies

Selected studies reported disparate measures for demographic measurements of patient age. Race and ethnicity metrics were not reported in selected studies. Demographic values are tabulated as reported and as available in the original, published studies (Table 1), and risk of bias in studies was assessed in detail (Supplementary Table 1).

Table 1.

Patient demographics for included studies.

Abu Hamdeh et al. (2018) Junkkari et al. (2019) Pyykkö et al. (2014)
Institution, country Uppsala University, Sweden Kuopio University Hospital, Finland Kuopio University Hospital, Finland
Study design, quality of evidence ratinga Prospective cohort study, 3 Prospective cohort study, 3 Prospective cohort study, 3
Clinical follow-up time, months 3 3 2–3
Total no. of included (biopsied and shunted) patients with diagnosis of iNPH 20 161b 48c
Outcome measure Clinical response in classical triad symptoms assessed by modified iNPH scale (Hellström et al. 2012) pre- and postoperatively Physician-graded clinical response by assessing clinical triad symptoms pre- and postoperatively Physician-graded clinical response by assessing clinical triad symptoms pre- and postoperatively
Biopsy location Right frontal area anterior to coronal suture Right frontal area anterior to coronal suture Right frontal area anterior to coronal suture
SR NR SR NR SR NR
Total No. 11 9 136 25 43 5
Age, mean (range), years 74 (65–85) 74 (64–80) d d 72.7 (63.8–87.3)f,g 82.8 (79.9–86.2)g
Female (No. (%)) 2 (18) 5 (56) e e 23 (48) 3 (60)
Biopsy pathology (no. (%))
Aβ+/HPτ+ 2 (18) 0 (0) 16 (12) 1 (4) 4 (9) 1 (20)
Aβ+/HPτ− 2 (18) 8 (89) 55 (40) 14 (56) 13 (30) 2 (40)
Aβ−/HPτ+ 2 (18) 0 (0) 1 (1) 0 (0) 3 (7) 0 (0)
Aβ-/HPτ− 5 (46) 1 (11) 64 (47) 10 (40 23 (54) 2 (40)
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Abbreviations: SR = shunt responsive, NR = shunt nonresponsive, Aβ = amyloid-beta, HPτ = hyperphosphorylated tau

aRating of 1–5 assigned according to rating scheme modified from the Oxford Centre for Evidence-based Medicine.

bExcluding 14 patients with inviable/no biopsies (two SR and 12 NR).

cExcluding five patients that overlapped with the study population in Junkkari et al. (2019).

dDistinction between SR and NR is not possible for this measurement. This study (Junkkari et al. 2019) reported mean age for each prognostic test group (“Tap Positive and Infusion test not Performed” = 74.3 years; “Tap Negative and Infusion Test Not Performed” = 73.5 years; “Tap Negative and Infusion test Positive” = 74.1 years; and “Tap Negative and Infusion Test Negative” = 72.4 years).

eDistinction between SR and NR is not possible for this measurement. This study (Junkkari et al. 2019) reported sex for each prognostic test group (Female (No. (%)): “Tap Positive and Infusion test not Performed” = 44% (Picascia et al. 2015); “Tap Negative and Infusion Test Not Performed” = 45% (GraphPad Prism [Computer Program] 2022); “Tap Negative and Infusion test Positive” = 53% (Hiraoka et al. 2015); and “Tap Negative and Infusion Test Negative” = 57% (Espay et al. 2017)).

fThese statistics were extracted from the original study population (Pyykkö et al. 2014) before the five overlapping patients were removed from further analysis.

gValue reported as median (range), not mean (range).

Fig. 2.

Fig. 2

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Groups for statistical comparison organized by tissue neuropathology. Abstract graphic depicting the tissue neuropathology groupings for each statistical comparison. Figure created with BioRender.com. Abbreviations: Aβ = amyloid-beta, HPτ = hyperphosphorylated tau.

Results of preliminary syntheses

Overall, of the 229 shunt-treated iNPH patients in the pooled study cohort, 190 exhibited shunt responsiveness. Of these 190 shunt responsive patients, 22 (12%) exhibited Aβ+/HPτ + pathology, 70 (37%) exhibited Aβ+/HPτ− pathology, 6 (3%) exhibited Aβ−/HPτ + pathology, and 92 (48%) exhibited Aβ−/HPτ− pathology (Fig. 3A, left and 3B). Of the 36 shunt nonresponsive patients, 2 (5%) exhibited Aβ+/HPτ + pathology, 24 (62%) exhibited Aβ+/HPτ− pathology, 0 (0%) exhibited Aβ−/HPτ + pathology, and 13 (33%) exhibited Aβ−/HPτ− pathology.

Fig. 3.

Fig. 3

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Distribution of the pooled study cohort (A, left; B) and original cohort (A, right; C). (A, left) preliminary synthesis of pooled study cohort by biopsy pathology and shunt responsiveness; (A, right) patient numbers for original cohort by biopsy pathology and shunt responsiveness; (B) distribution of pooled study cohort by biopsy pathology and shunt responsiveness; (C) distribution of original cohort by biopsy pathology and shunt responsiveness. Abbreviations: SR = shunt responsive, NR = shunt nonresponsive, Aβ = amyloid-beta, HPτ = hyperphosphorylated tau. Any + group = combination of pathology groups with Aβ + and/or HPτ+. Aβ + group = combination of pathology groups with Aβ + regardless of presence of HPτ.

Reporting biases and certainty of evidence

Statistical comparisons carried out in this meta-analysis included all patients fitting predetermined diagnostic criteria from the included studies. Potential risk of reporting bias arose from the dichotomization of shunt response and the use of subjective outcome measures. Certainty of evidence assessments are summarized in Supplementary Table 2.

  • (ii) Original cohort

In our analysis of 49 consecutive, shunt-treated iNPH patients, one patient who had Aβ+/HPτ− pathology was excluded due to death several days following shunt placement (precluding follow-up within the necessary temporal window). An additional two patients (one with Aβ+/HPτ− and the other with Aβ−/HPτ− pathology) were also excluded due to the lack of follow-up within the necessary temporal window at the time of data extraction. An additional 10 patients were excluded due to technically inadequate or lack of biopsy material.

Of the remaining 36 patients, 30 exhibited shunt responsiveness. Of these 30 shunt responsive patients, 1 (3%) exhibited Aβ+/HPτ + pathology, 15 (50%) exhibited Aβ+/HPτ− pathology, 0 (0%) exhibited Aβ−/HPτ + pathology, and 14 (47%) exhibited Aβ−/HPτ− pathology (Fig. 3A, right and 3C). Of the six shunt nonresponsive patients, one (17%) exhibited Aβ+/HPτ + pathology, four (67%) exhibited Aβ+/HPτ− pathology, zero (0%) exhibited Aβ−/HPτ + pathology, and one (17%) exhibited Aβ−/HPτ− pathology.

  • (iii) Combined meta-analysis: pooled study cohort and original cohort

Results of syntheses

Comparison of patients with Aβ+/HPτ + pathology to patients with Aβ−/HPτ− pathology revealed that patients with Aβ+/HPτ + were more likely to exhibit shunt nonresponsiveness than Aβ−/HPτ− patients (M-H = 1.04 [0.31, 3.57], P = 0.94) (Fig. 4A). Abu Hamdeh et al. (2018) and Junkkari et al. (2019) had ORs favoring those with Aβ+/HPτ + pathology as more likely to exhibit shunt responsiveness. Conversely, both Pyykkö et al. (2014) and our original cohort had ORs favoring those with Aβ+/HPτ + pathology as more likely to exhibit shunt nonresponsiveness. Tests in this comparison lacked statistical significance. Heterogeneity across studies for this test was likely inconsequential (Chi2 = 3.59, P > 0.10, I2 = 16%).

Fig. 4.

Fig. 4

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ORs and M-H tests. Forest plots for each biopsy group comparison, positive pathology versus negative pathology groups. ORs are calculated for the non-event (for the odds of a shunt nonresponsive outcome). Abbreviations and notes: Aβ = amyloid-beta, HPτ = hyperphosphorylated tau, M-H = Mantel Haenszel; events = shunt responsive outcomes, non-events = shunt nonresponsive outcomes. Any + group = combination of pathology groups with Aβ + and/or HPτ+. Aβ + group = combination of pathology groups with Aβ + regardless of presence of HPτ.

Comparison of patients with Aβ+/HPτ− pathology to patients with Aβ−/HPτ− pathology revealed that patients with Aβ+/HPτ− pathology were significantly more likely to be shunt nonresponsive than Aβ−/HPτ− patients (M-H = 2.28 [1.12, 4.66], P = 0.02) (Fig. 4B). This directionality was seen not only in the M-H test, but also across all composite studies. Heterogeneity across studies for this test was likely inconsequential (Chi2 = 3.37, P > 0.10, I2 = 11%).

Patients with Aβ−/HPτ + pathology were more likely to be shunt nonresponsive than Aβ−/HPτ− patients (M-H = 1.25 [0.18, 8.66], P = 0.82) (Fig. 4C). This M-H trend was not seen across all composite studies, as Abu Hamdeh et al. (2018) had OR (Non-event) = 0.73 [0.02, 25.09], and ORs for our cohort were not able to be calculated due to sample size of 0. Tests in this comparison lacked statistical significance. Heterogeneity across studies for this test was likely inconsequential (Chi2 = 0.18, P > 0.10, I2 = 0%).

In comparing the combined “Any +” group, consisting of all patients with Aβ + and/or HPτ + pathology, to the Aβ−/HPτ− group, a trend was seen (Fig. 4D). Although at a nonsignificant level, across all composite studies, patients with Aβ + and/or HPτ + pathology were more likely to be shunt nonresponsive than Aβ−/HPτ− patients. This same (nonsignificant) trend favoring patients with positive pathology exhibiting shunt nonresponsiveness was corroborated by the M-H test (M-H = 1.88 [0.94, 3.75], P = 0.08). Heterogeneity across studies for this test was likely inconsequential (Chi2 = 2.22, P > 0.10, I2 = 0%).

Across all composite studies, patients with Aβ + pathology (patients with Aβ+/HPτ + and patients with Aβ+/HPτ− pathology) were more likely to exhibit shunt nonresponsiveness than patients with Aβ + pathology. The combined pooled M-H statistic revealed that patients with Aβ + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with Aβ + pathology (M-H = 2.16 [1.09, 4.28], P = 0.03) (Fig. 4E). Heterogeneity across studies for this test was likely inconsequential (Chi2 = 3.72, P > 0.10, I2 = 19%).

Discussion

In this combined meta-analysis of 229 shunt-treated iNPH patients from three studies and 36 shunt-treated iNPH patients from our original cohort, we found that lack of favorable outcome is associated with presence of AD-related pathology on cortical tissue analysis. Specifically, the presence of Aβ pathology was significantly predictive of a shunt nonresponsive outcome when comparing both the Aβ+/HPτ− group and the Aβ + group to the Aβ−/HPτ− group.

Overall, all comparisons of positive pathology groups to the Aβ−/HPτ− group revealed statistics trending in the same direction. This consistent directionality suggests that patients with positive pathology were more likely to exhibit shunt nonresponsiveness, and this increased likelihood reached statistical significance for certain cortical pathology groups. Due to the inherently disparate nature of pooled data from different studies in meta-analyses, concordant, nonsignificant trends favoring one direction (with low heterogeneity) might be considered to hold some level of indicative value, regardless of statistical significance. Thus, despite lacking significance across all measures, the consistent positive directionality of all M-H statistics may point to positive pathology as a potential indicator of increased likelihood of shunt nonresponsiveness, and any lack of significance may be, in part, due to low patient numbers.

In this study, we selected cortical tissue analysis as an indicator for AD-related pathology; however, there are several alternatives that include CSF analysis of various species of Aβ and tau (Hansson et al. 2019; van Harten et al. 2022) and Aβ positron emission tomography (PET) imaging. Plasma Aβ and tau markers have been reported in the literature and were recently approved by the FDA (Shen et al. 2020). Although these biomarkers have been widely studied in the neurodegenerative sphere, CSF and plasma markers are likely affected by altered CSF dynamic flow secondary to hydrocephalus. For example, one recent study successfully examined pre-operative CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) to predict Mini Mental State Examination score and gait performance in iNPH patients (Lukkarinen et al. 2022). Despite these encouraging findings, other evaluations suggest that CSF t-tau and p-tau levels are more similar to levels found in normal controls rather than in AD pathology (Ågren-Wilsson et al. 2007; Kapaki et al. 2007). Further, another study has observed low CSF levels of NfL, amyloid precursor protein-derived fragments, and tau proteins pre-shunting in iNPH patients, with notable increases in the aforementioned biomarker levels post-shunting. These findings attributed differential biomarker profiles pre- and post-surgery to altered periventricular clearance and metabolism of these markers due to the hydrocephalus (Jeppsson et al. 2013). As such, biomarkers of AD pathology in the CSF and plasma may have limited utility in diagnostic separation of isolated NPH from comorbid NPH, and unique intracranial flow and metabolic profiles must be better understood to improve standardization and diagnostic imaging (Mehta et al. 2022) before these biomarkers can provide clinically meaningful prognosticative value. For these reasons, CSF or plasma analyses have not been extensively studied or implemented in the setting of iNPH (Graff-Radford 2014; Vanninen et al. 2021). Conversely, PET imaging primarily detects insoluble species and may be an appealing diagnostic tool due to its noninvasive nature (Rinne et al. 2012); however, this method only offers correlative evidence of the neuropathology detected by cortical biopsy. Moreover, PET imaging is limited by low spatial and temporal resolution (Zhu and Zhu 2019), and, at early stages and/or low levels of neurodegeneration, PET imaging may suggest false negative results due to limited sensitivity (Rinne et al. 2012). Specific to NPH, the cortical compression that commonly occurs in NPH patients can also visually impede proper interpretation of PET images (Rinne et al. 2012). Immunohistochemical analysis of cortical biopsies is preferred to these alternative methods, and immunostaining can detect both soluble and insoluble Aβ species with high sensitivity (Esparza et al. 2016; Abu Hamdeh et al. 2018). Cortical biopsy may not offer perspective on the entire cortical surface or systemic state; however, detected features on cortical biopsy are definitive signs of the presence of pathological features. For these reasons, we analyzed cortical biopsy pathology as the most direct measure of AD-related pathology.

In considering neurodegenerative features on cortical biopsy, we selected Aβ and HPτ as pathological proteins for analysis. Although the inclusion of both features for analysis limited the number of eligible studies for our meta-analysis, we settled on this necessary limitation for two reasons: first, the presence of both Aβ and HPτ together has been shown to be more strongly associated with presence or later development of AD than Aβ alone (Leinonen et al. 2010); second, we aimed to decrease the number of patients with nonspecific pathology, such as Aβ features as a result of non-AD amyloidopathies and/or general senescence. Further, we included both neuritic and diffuse plaques as pathological features for two reasons: (Abu Hamdeh et al. 2018) due to the relevance of both plaque types to our investigation, and (Ågren-Wilsson et al. 2007) to reduce the risk of biased patient selection due to potential errors in distinguishing between neuritic and diffuse plaques, which is a known difficulty (Boluda et al. 2014).

An additional consideration in our analysis was the timepoint of postoperative evaluation. Positive outcomes in classical triad symptoms following shunting are often transient and have been reported to decrease at long-term (≥ 1 year) follow-up time points as compared to short-term (≤ 6 months; Greenberg et al., 1977; Savolainen et al. 2002; Takeuchi and Yajima 2019). This is likely due to several factors: consideration of long-term outcome increases the presence of multiple confounding factors, including declining general health due to comorbidities and/or senescence, and the phenomenon that dementia is a progressive disorder and will continue to cause decline, albeit perhaps at a slower rate, following shunt placement. With increasing time following shunt placement, these confounding factors should only increase and further cloud proper assessment of outcome. Additionally, long-term follow-ups are less reliable especially with elderly subjects, as retention can be impaired by unrelated mortality, illness and declining overall health, and even ability to procure and/or endure transportation for clinical evaluation (Kahlon et al. 2007; Forsat et al. 2020). It has been noted, though, that short-term (≤ 6 months following shunt placement) outcomes are more likely to be influenced by shunt complications such as death due to unrelated comorbidities (Klinge et al. 2005). Klinge et al. (2005) thus propose the 1-year post-shunt period as the timepoint with fewer of the aforementioned confounding factors. In this study, we included subjects at follow-up timepoints between 2 to 3 months and 1 year after shunt placement to minimize the numerous complications from long-term follow-ups and to maximize study population within reason. We acknowledge the added factor of shunt complications in assessing outcomes due to the shorter-term follow-up; this added consideration shifts our study to a more conservative viewpoint in assessing positive outcomes following surgery.

As noted above, a known complication in studying patients with dementia, including iNPH, is that these are progressive disorders. Thus, perhaps including patients with no change in symptoms in the shunt nonresponsive group is inexact. Any halt to the progressive deterioration associated with iNPH, whether manifested as positive clinical improvement or no further deterioration (i.e. no change in symptoms), might, in fact, be a sign of shunt responsiveness. However, given that many patients seek surgical treatment for iNPH due to dissatisfaction with their current functional state and that there is an expectation of amelioration of symptoms following shunt surgery, we maintain that shunt responsiveness should only include patients who exhibit apparent postoperative clinical improvement.

In current clinical practice, cortical tissue is collected at the time of CSF shunt placement due to ethical and practical considerations, and results are thus used as a retrospective lens to explain (poor) shunting outcomes. Our analysis suggests that prospective tissue analysis may be a useful diagnostic and prognostic adjunct for patients with iNPH under consideration for shunting. First-pass diagnostic tissue analysis may be used to identify concurrent neurodegenerative pathologies that can predict post-shunting outcomes and clinical course (Pomeraniec et al. 2016; Pyykkö et al. 2014). This may be further rendered feasible via less invasive alternatives such as endoscopic third ventriculostomy, which shows clinical equipoise to CSF shunting but with low morbidity and avoidance of hardware placement (Meier 2003; Gangemi et al. 2008; Mehta et al. 2023). However, it is unclear just how effective an endoscopic biopsy may be at providing adequate longitudinal clinical improvement. Further work examining the procedural and minimally invasive techniques that can incorporate cortical tissue analysis into the standard of care prior to shunting for iNPH may help clarify the nuanced diagnosis and management of this heterogenous disease.

Limitations

As a primary note, the relationship between AD pathology and iNPH shunt outcome studied herein is limited to correlation between presence of Aβ and/or HPτ and shunt outcome and does not explain possible AD comorbidity or its relevance to iNPH. Furthermore, it is important to underscore that tissue sampling and subsequent dichotomization of presence or absence of neuropathological features is reductive in multiple ways. First, neuropathology can be present in many different forms, and grading neuropathology as presence or absence of a selected feature is a relatively crude distinction. Second, tissue analysis of one area is not necessarily representative of the systemic state of the cortical surface. This is an inherent limitation. The original cohort and the included studies in this meta-analysis reported neuropathology as qualitative presence or absence of Aβ and/or HPτ to understand the broad relationship between neuropathology and iNPH shunt outcomes. In future studies, investigating with a more granular view of neuropathology could be informative.

Our results may have been limited by relatively low patient numbers in several comparisons, specifically for patients with HPτ + pathology. In our original cohort, no statistical analyses could be carried out for patients with Aβ−/HPτ + pathology, as there were no eligible patients with this neuropathology. The small number of studies in our meta-analysis was a further limitation. These considerations are due to the stringent guidelines we employed, detailed above, to gather a pooled patient cohort with limited confounding factors and thus with the highest possible predictive value.

Due to the small sample sizes of the composite Aβ+/HPτ + and the Aβ−/HPτ + groups, we did not investigate how the presence of HPτ pathology alone might predict shunt responsiveness. In addition to small sample size, HPτ features alone would likely be a less reliable measure than Aβ features alone as detected in neocortical biopsy. This is because, while Aβ aggregation is detected in neocortex throughout all stages of β-amyloidosis (Thal et al. 2002), HPτ is only detected in the neocortex during later stages of neurofibrillary changes (Braak et al. 2006). Therefore, given the neocortical biopsy location utilized in this meta-analysis, the presence of HPτ could have been missed. This is also perhaps why we observed low numbers of patients with HPτ pathology.

Further, although the dichotomization of the shunt response scale was a necessary step in combining studies with disparate measures, this step decreased granularity and sensitivity of our outcome measure. Additionally, the lack of a validated, objective outcome measure across all studies introduced potential bias into our study. We attempted to minimize this potential bias in our original cohort study by considering multiple evaluatory reports by multiple trained professionals, but this remains to be a weakness of our meta-analysis and of our own cohort analytics.

A final consideration includes the demographics of the pooled study patient cohort and our original patient cohort. Racial and ethnic statistics for the pooled patient cohort were not available, and our own patient cohort had limited diversity, with most of our patients being White and non-Hispanic (Table 2). Further studies with larger, more diverse patient cohorts are necessary to draw generalizable implications from the relationships explored in these analyses.

Table 2.

Patient demographics for the original cohort.

Original cohort
Clinical follow-up time, mean (range), months 6 (2–12)
Total No. of included (biopsied and shunted) patients with diagnosis of iNPH 36
Outcome measure Physician-graded clinical response by assessing clinical triad symptoms pre- and postoperatively
Biopsy location Right frontal area anterior to coronal suture
SR NR
Total no. 30 6
Age, mean (range), years 76 (60–91) 74 (65–86)
Female (no. (%)) 10 (33) 1 (17)
Race (no. (%))
 White 28 (93) 6 (100)
 Other 2 (7) 0 (0)
Ethnicity (No. (%))
 Hispanic 3 (10) 1 (17)
 Not Hispanic 25 (83) 5 (83)
 Unavailable 2 (7) 0 (0)
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Abbreviations: SR = shunt responsive, NR = shunt nonresponsive, Aβ = amyloid-beta, HPτ = hyperphosphorylated tau

Conclusion

This study was designed to assess the predictive value of AD-related pathology in postoperative clinical outcome. Our combined meta-analysis and original cohort analysis found that presence of positive pathology, specifically of Aβ, on cortical tissue analysis was associated with unfavorable clinical response. Thus, immunohistochemical analysis of cortical tissue could be considered a potential useful prognostic and diagnostic tool for patients with presumed iNPH.

Supplementary Material

CerCor_NPH_Tissue_Supplementary_Figure_and_Tables_12-27-23_bhae001
Click here for additional data file. (153.9KB, docx)

Contributor Information

Ana B W Greenberg, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States; Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, United States.

Kedous Y Mekbib, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States; Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, United States.

Neel H Mehta, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Emre Kiziltug, Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, United States.

Phan Q Duy, Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, United States.

Hannah R Smith, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Antti Junkkari, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States.

Ville Leinonen, Department of Neurosurgery, Kuopio University Hospital, Kuopio 70211, Finland.

Bradley T Hyman, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States.

Diane Chan, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States.

William T Curry Jr, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Steven E Arnold, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States.

Frederick G Barker II, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Matthew P Frosch, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, United States.

Kristopher T Kahle, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States; Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States; Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Massachusetts General Hospital, Boston, MA 02114, United States.

CRediT statement

Ana B.W. Greenberg (Conceptualization, Formal analysis, Investigation, Writing—original draft, Writing—review & editing), Kedous Y. Mekbib (Investigation, Writing—review & editing), Neel H. Mehta (Writing—review & editing), Emre Kiziltug (Investigation, Writing—review & editing), Phan Duy (Investigation, Writing—review & editing), Hannah R. Smith (Investigation, Writing—review & editing), Antti Junkkari (Investigation, Writing—review & editing), Ville Leinonen (Investigation, Writing—review & editing), Bradley Hyman (Investigation, Writing—review & editing), Diane Chan (Investigation, Writing—review & editing), William T. Curry (Investigation, Writing—review & editing), Steven E. Arnold (Investigation, Writing—review & editing), Frederick G. Barker (Investigation, Writing—review & editing), Matthew P. Frosch (Investigation, Writing—review & editing), Kristopher T. Kahle (Conceptualization, Investigation, Project administration, Supervision, Writing—original draft, Writing—review & editing).

Study concept and design

A.B.W.G., K.T.K. Patient recruitment and consenting: A.B.W.G., H.R.S., K.T.K. Biopsy collection: K.T.K. Neuropathological analysis: M.P.F. Data collection: A.B.W.G., A.J., V.L. Drafting of the manuscript: A.B.W.G. Statistical analysis: A.B.W.G. Critical manuscript revision: A.B.W.G., A.J., B.T.H., D.C., E.K., F.G.B., K.T.K., K.Y.M., M.P.F., N.H.M., P.Q.D., S.E.A., W.T.C., V.L. Obtained funding: K.T.K. Study supervision: K.T.K.

Funding

This study was funded by the National Institutes of Health (5RO1NS111029-04).

Conflict of interest statement: None declared.

Data sharing

All quantitative data used for this study have been included in the main text and Supplementary Materials. Additional data may be available upon request from the corresponding author.

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