iNPH can be effectively treated through shunt insertion [52]. However, as many patients who undergo this procedure experience short-lived or no benefit from the procedure, patient selection is suboptimal. Prompted by reports of better shunt outcomes in those without evidence of AD [20, 53, 54], multiple studies have sought to determine how amyloid PET could improve patient selection. We present a pooled analysis of three non-randomised studies that have examined the association between amyloid PET and the clinical response to shunt insertion.
Association between amyloid PET and shunt response
The pooled results of the three studies shows low sensitivity (33.3%) and a moderate specificity (78.3%) in identifying patients with a poor response to shunting. Proportionally more patients who responded to a shunt had a negative amyloid PET than a positive amyloid PET (61.5% versus 50%), although the difference was not statistically significant. Therefore, the main finding in this pooled analysis is that amyloid PET, when considered in isolation, does not accurately identify patients with suspected iNPH who are likely to respond to shunting.
Weaknesses of included studies
There are multiple inherent weaknesses within the studies included in this pooled analysis.
All of the studies were non-randomised and therefore inherit all of the limitations of such a study design. Furthermore, assessors of the clinical response to shunting were not blinded to the result of the amyloid PET, representing a potential source of bias.
All studies were small, yielding a total of only 38 patients. Therefore, each study was only powered to identify large effects. As such, differential effects on each component of the iNPH clinical triad could not be assessed. Similarly, in such small cohorts, it was not possible to control for other factors associated with shunt responsiveness, such as age [11, 55], duration of symptoms [11, 56–58], gait disturbance predominance over cognitive impairment [10, 11, 57, 58], the presence of co-morbidities [55, 59], and the structural imaging features of iNPH and AD.
In the study by Leinonen et al, amyloid imaging was performed between 9 and 38 months after the biopsy and shunt insertion. This is problematic because the effects of shunting on amyloid PET is unknown. Secondly, since amyloid deposition is progressive, the amyloid PET is likely to be an overestimate of the amyloid burden at the time the decision was taken to insert a shunt. Lastly, a significant interval between shunting and imaging may cause selection bias based on disease severity or, more significantly, the response to shunting.
In addition to these inherent weaknesses of the studies included in this pooled analysis, there was also significant variation between the studies in the clinical, radiological and non-radiological investigations performed, which has implications for pooling results.
Recruitment by Leinonen et al required only “enlarged ventricles” and any one of the iNPH clinical triad, whereas the other two studies also required sulcal effacement and two of the iNPH clinical triad. Leinonen et al performed 24-hour intracranial pressure (ICP) monitoring in all patients before consideration of shunt insertion; in this study, all but one patient responded to shunting. Rinne et al used ICP monitoring “if required”, although specific indications were not discussed. Hiraoka et al performed CSF tap testing. As inclusion criteria become less stringent, the pre-test probability for iNPH decreases and so does the expected response rate to shunting.
The method of assessing the clinical response to shunting was variable. Methods included the iNPHGS [60], the Black score [61] or a non-disclosed “clinical assessment”. Different methods are likely to influence the reported rate of shunt response, which has obvious implications when pooling results. Furthermore, the timing of the assessment ranged from 2 months to over 20 months. Clinical improvement may occur over many months, which is reflected in the ongoing changes in the parenchyma and CSF spares through the first postoperative year [62]. On the other hand, clinical improvements can be fleeting [63–65] and therefore follow-up of at least one year is often used in clinical trials [66]. In two of the studies, assessment was performed at three months or earlier. The value of a clinical improvement lasting three months is debatable, and, in many centres, this would be considered unsatisfactory.
Two different radiotracers were used in the three studies. Multiple radiotracers have been developed with differing pharmacokinetics although all are highly specific for Aβ [67] and correlation between radiotracer uptake is high [68–70]. Therefore, the diagnostic accuracy of different amyloid-specific radiotracers, and hence their role in patient selection for shunt insertion, is likely to be comparable.
Reasons for lack of association between amyloid PET and shunt response
Firstly, amyloid PET may accumulate in the brain for reasons that have no effect on shunt response. While Aβ deposition, alongside hyperphosphorylated tau protein, is a histopathological hallmark of AD [71], it is also observed in other neurodegenerative conditions such as Lewy Body Dementia [72, 73] and cerebral amyloid angiopathy [74]. Amyloid deposition also occurs in healthy aging [75–77], albeit with an increased risk of subsequent cognitive decline [78, 79]. Secondly, the potential for improvement post-shunting will depend on the degree of permanent neurological damage caused by NPH or any other comorbid condition [80]. Thirdly, a recent study showed CSF biomarkers of AD were associated with a positive response to tap-test [25]. This observation raises the possibility of a so-called neurodegenerative NPH (that would be amyloid PET positive) that is separate from an idiopathic NPH. Despite the result of this pooled analysis, amyloid PET may still have a role in the wider workup of patients for shunt insertion, particularly in identifying dual pathology. Even if amyloid PET does not predict immediate shunt outcomes, cerebral amyloid is likely to influence long-term prognosis, which would be relevant when counselling patients on the expected risks and benefits of shunt insertion.
Requirements for future study
There remains a need for a blinded and randomized study to definitively determine the role of qualitative and quantitative interpretation of amyloid PET in predicting shunt response in patients with suspected iNPH. The study should be adequately powered to assess for differential effects of each domain of iNPH and to control for disease severity and other clinical features associated with long-term shunt outcomes. The predictive power of amyloid PET should be compared with the features apparent on structural imaging and biomarkers from CSF analysis. Finally, adequate follow-up of at least a year is required due to the progressive nature of AD and the often-transient improvements experienced following shunting.