[ 11 C]PIB PET Is Associated with the Brain Biopsy Amyloid-β Load in Subjects Examined for Normal Pressure Hydrocephalus

Abstract

Background:

Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-β (Aβ) pathology.

Objective:

To compare the [¹¹C]PIB PET uptake in the patients with suspected iNPH to Aβ and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aβ, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer’s disease (AD).

Methods:

Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aβ and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [¹¹C]PIB PET. Aβ, total tau, and Pτ₁₈₁ were measured by ELISA from the ventricular (n = 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3–1).

Results:

[¹¹C]PIB uptake in the right frontal cortex (ρ= 0.60, p < 0.01) and the combined neocortical [¹¹C]PIB uptake score (ρ= 0.61, p < 0.01) were associated with a higher Aβ load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [¹¹C]PIB uptake was also associated with the ventricular CSF Aβ (ρ= –0.58, p = 0.03).

Conclusions:

The findings show that [¹¹C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aβ pathology in the patients with iNPH might also warrant treatment with current AD drugs.

Keywords

Amyloid,brain biopsy,cerebrospinal fluid,normal pressure hydrocephalus,positron emission tomography

INTRODUCTION

Idiopathic normal pressure hydrocephalus (iNPH) is one of the few diseases leading to dementia that can be treated effectively [1, 2]. The diagnosis is based on a clinical triad of gait impairment, cognitive decline, and urinary incontinence [3] and the radiological finding of ventricular enlargement. The invasive method of intracranial pressure monitoring increases the diagnostic accuracy [4]. The yentriculomegaly itself is not a specific feature of iNPH as it may be present through a secondary change due to atrophy [5], which may also be seen in other types of dementia. We may improve the response rate to the shunt surgery in iNPH patients if they are treated at the early stages of the disease [6].

Differential diagnostics to the other types of dementia may be problematic. This is especially the case in the patients suspected to have iNPH whose cognitive impairment dominates the clinical appearance [7, 8]. In such patients, it is critical to identify the true iNPH patients for the shunt operation because, in contrast to, for example, patients suffering from Alzheimer’s disease (AD) [4], the cognitive function of the iNPH patients as well as their quality of life do improve [2]. In addition, the co-morbidity of AD and iNPH may diminish the positive effect of the shunt operation in the iNPH patients [9], though there are also studies suggesting equal benefit from the shunt operation regardless of the AD pathology [7, 10]. In these studies, the AD diagnoses are based on small brain biopsies taken during the shunt operation and in theory, it is possible that the small cortical tissue sample causes false negative results, thus mixing the comparisons. Additionally, it is possible that the aged patients may have brain amyloid-β (Aβ) without clinical AD.

For AD, biomarkers such as positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) analyses are under development in order to improve the diagnostic accuracy. PET imaging with the PET tracer N-[methyl- C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (C-6-OH-BTA-1), known as [¹¹C]PIB, is shown to bind the fibrillar Aβ plaques typical for AD [11, 12], and it seems to separate the AD patients from the healthy controls [13, 14] as well as from the patients of other types of dementia [15]. Additionally, in the terms of clinical applicability, the visual assessment of [¹¹C]PIB images is consistent [16, 17]. There are also other PET tracers targeting Aβ such as [¹⁸F]FDDNP (2-(1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthylethylidene)malononitrile) [18], [¹⁸F]florbetaben (trans-4-(N-methyl-amino)-4'-2-[2-(2-¹⁸F]fluoroethoxy)-ethoxy]-ethoxy-stilbene or ¹⁸F-BAY94-9172, ¹⁸F-AV-1)[19], [¹⁸F]florbetapir ((E)-4-(2-(6-(2-(2-(2-¹⁸F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine or ¹⁸F-AV-45) [20, 21] and [¹⁸F]flutemetamol (2-3-[¹⁸F]fluoro-4-(methylamino)phenyl-1, 3-benzothiazol-6-ol) [22].

The Aβ_1-42 peptides related to AD can be measured from the CSF. There is evidence for the inverse correlation between postmortem ventricular CSF Aβ_1-42 [23] as well as the antemortem lumbar CSF Aβ_1-42 [24] and the amyloid plaques of the brain biopsies. There is also an inverse correlation between [¹¹C]PIB uptake and the lumbar CSF Aβ_1-42 [25]. Other measurable biomarkers of the CSF are the tau protein and its hyperphosphorylated form (HPτ), which can also be seen in the brain biopsies as neurofibrillary changes [26, 27]. In AD, total tau (t-tau) and HPτ in the CSF are associated with the amyloid load and neurofibrillary changes in the brain tissue [24]. Changes in the Aβ_1-42 levels in the CSF can already be detected 5 to 10 years before the onset of AD, whereas the t-tau and the HPτ changes seem to emerge later [28].∥Both retrospective and prospective studies have reported meaningful associations between the Aβ PET imaging and the neuropathological tissue Aβ quantification [29, 30]. Additionally, one autopsy analysis has shown a clear correlation between the tissue Aβ and PET amyloid imaging with [¹⁸F]florbetapir (ρ= 0.78) [21]. Unfortunately, in these studies, the number of the study subjects is relatively low.∥In the future, it would be advantageous to have better differential diagnostic methods to differentiate iNPH and atypical AD or other degenerative brain diseases and to detect possible co-morbidities. This would improve the treatment strategies in iNPH, e.g., in the evaluation to achieve positive responses before the operation, as well as in estimating the responses to the therapy after the shunt surgery. Further research and method validations are still needed to achieve this aim. In the previous work of ten subjects [30], we compared [¹¹C]PIB PET binding with the neuropathological findings in a brain biopsy. In the present study, we aim to compare [¹¹C]PIB PET findings in patients with suspected iNPH to Aβ and HPτ in the right frontal cortical biopsy, the CSF Aβ, the response to the CSF shunt, and the final clinical diagnosis of AD in 21 patients with suspected iNPH. Our hypothesis was that [¹¹C]PIB PET would be associated with the amount of Aβ plaques in the cortical brain biopsies and the CSF Aβ levels.

MATERIALS AND METHODS

Patients

All patients were referred to the Kuopio University Hospital (KUH) Department of Neurosurgery due to suspected (possible) iNPH based on impairment in gait and/or cognition and/or urinary continence, together with enlarged brain ventricles in CT or MRI, and underwent standard clinical examinations including an ICP monitoring between 2004 and 2009 (http://www.uef.fi/nph) [30, 31]. A frontal cortical brain biopsy was taken in the pursuance of the ICP recording [30]. A total of 21 patients out of 244 with iNPH or suspected iNPH (14 female and 7 male) agreed to participate in [¹¹C]PIB PET scans. The mean age at the ICP monitoring and at the brain biopsy was 71 years (SD 4.8 years; range 61–83 years) and at [¹¹C]PIB PET scan 72 years (SD: 4.5 years, range: 62–82 years). The subjects were divided into two groups according to the neuropathological biopsy findings related to AD. Of the 21 patients, 11 had Aβ pathological lesions related to AD in the biopsy specimen and 10 patients did not have such findings.

A neuropsychological examination was performed and the mean preoperative Mini-Mental State Examination (MMSE) score was 24 (SD: 3.8, range: 17–30). The Clinical Dementia Rating (CDR) score was 0 (3), 0.5 (10), 1 (7), and for 2 (1) subjects. The mean interval between the biopsies and the PET scans was 9 months (SD: 11 months, range: 0–36 months). (Table 1).

Table 1

The patient characteristics

Patient	Sex	ApoE ɛ	Age at the biopsy and the CSF sampling	Brain biopsy Aβ	CDR	MMSE	Time from the biopsy to PET	Shunt response	Final diagnosis at the end of follow-up
Pt # 1	M	34	69	+	1	24	27	NA	AD
Pt # 2	F	34	75	+	0.5	28	25	Yes	AD &iNPH
Pt # 3	F	34	70	+	1	20	11	Yes	AD/VaD &iNPH
Pt # 4	F	33	71	+	1	18	20	Yes	PD &iNPH Demented
Pt # 5	F	24	66	+	2	25	14	NA	AD
Pt # 6	F	33	74	+	0.5	21	0	Yes	iNPH
Pt # 7	F	34	73	+	0.5	17	3	Yes	AD &iNPH
Pt # 8	M	34	83	+	1	22	-1	NA	AD
Pt # 9	M	33	64	+	0.5	29	1	Yes	iNPH
Pt # 10	M	33	70	+	0.5	30	1	NA	MCI
Pt # 11	F	34	72	+	0.5	26	1	Yes	iNPH
Pt # 12	M	33	70	–	0	28	15	Yes	iNPH
Pt # 13	F	33	71	–	1	24	5	No	AD &iNPH
Pt # 14	F	33	72	–	1	22	1	NA	MCI
Pt # 15	F	33	74	–	0	22	22	Yes	iNPH
Pt # 16	F	NA	68	–	0.5	30	36	Yes	iNPH
Pt # 17	F	33	79	–	1	24	0	No	Dementia NOS &iNPH
Pt # 18	F	33	69	–	0	29	1	Yes	iNPH
Pt # 19	F	23	61	–	0.5	22	4	NA	MCI LOVA
Pt # 20	M	34	74	–	0.5	22	0	Yes	iNPH
Pt # 21	M	33	69	–	0.5	24	1	Yes	AD &iNPH
Mean ± SD			71±4.8		0.67±0.46	24±3.8	8.9±11

F, females; M, males; ApoE, apolipoprotein E; CDR, Clinical Dementia Rating; MMSE, Mini-Mental State Examination; AD, Alzheimer’s disease; iNPH, idiopathic normal pressure hydrocephalus; VaD, vascular dementia; PD, Parkinson’s disease; MCI, mild cognitive impairment; LOVA, long-standing overt ventriculomegaly in adult; NA, not available (=no shunting was performed); NOS, not otherwise specified.

Shunt and the shunt response

Of the 21 subjects, 15 eventually had the shunt treatment based on the 24-h ICP monitoring [31], and 13 of those did benefit from it while two did not.

Follow-up time and the final clinical diagnosis

The patients were followed-up clinically until death (n = 6) or the end of 2015 with a median follow-up time of 6 years. The final clinical diagnoses were determined by a neurologist specialized in memory disorders, blinded for the brain biopsy and PET scan results.

The frontal cortical brain biopsy sampling and the neuropathological examination

The detailed procedure of the brain biopsy sampling as well as the histological staining and examination are described in our previous publication [30]. A cylindrical cortical brain biopsy specimen of 2–5 mm × 3–7 mm was obtained from all 21 subjects from the right frontal cortex before the insertion of a ventricular catheter. The histological sections were prepared and stained with hematoxylin-eosin. The immunostaining was performed by using monoclonal antibodies directed to Aβ (6F/3D, M0872; Dako; dilution 1 : 100; pre-treatment 80% formic acid per 1 h) and HPτ (AT8, 3Br-3; Innogenetics; dilution 1 : 30) [31].

The amount of Aβ was semiquantitatively measured by dividing the number of plaques by the area of the gray matter (mm²). The cellular or the neuritic HPτ pathology was rated as negative or positive by using a light microscopy by a neuropathologist (5 positive and 16 negative samples).

The sampling of the blood and the cerebrospinal fluid

The ventricular CSF samples were collected from 15 subjects immediately after inserting the ventricular catheter. The lumbar CSF punctures were performed either prior to the ICP monitoring or 24–48 h after the ICP monitoring for nine subjects. The laboratory analyses were made in the quality-controlled and validated laboratory in Neurology and Neuroscience (http://www.uef.fi/neuro), University of Eastern Finland [32, 33]. The CSF levels of Aβ_1-42, total tau, and HPτ (P-tau-181) were measured by commercial ELISA kits (Innotest beta-amyloid1-42, InnotestTau-Ag, InnotestPhosphotau (181P), Innogenetics, Ghent, Belgium) according to the manufacturer’s protocol. The ApoE genotype was determined from the blood samples of 20 subjects.

[¹¹C]PIB PET imaging

The PET studies were performed in Turku PET Centre. The PET tracer N-[methyl- C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (C-6-OH-BTA-1), known as [¹¹C]PIB, was produced as reported earlier [14]. The mean injected dose was 463 MBq (SD: 71 MBq, range: 255–530 MBq). A dynamic PET scan of 90 min was performed with a GE Advance PET scanner (GE Medical Systems, Milwaukee, WI, USA) in the three- dimensional scanning mode by using the protocol described earlier [14]. For valid anatomical reference and to exclude other pathologies, the subjects were also scanned with a 1.5 T MRI scanner (Philips Intera 1,5 T, Best, The Netherlands).

Image processing and data analysis

For processing of the imaging data Statistical Parametric Mapping version 2 (SPM2) and MATLAB R2008b for Windows (The MathWorks Inc. Natick, MA, USA) were used. For each PET image, the frames were summed over time from 0 to 90 min. With this summed image, a normalization transformation matrix was calculated by using a ligand-specific [¹¹C]PIB template [14] after which the dynamic [¹¹C]PIB images were rewritten into the MNI space (Montreal Neurological Institute database).

The auto-ROI analysis was performed as described earlier [14]. With one subject, the automated ROI for the cerebellar cortex was not entirely correct, so for that one image an individual ROI set was used instead. The ROIs were delineated by using Imadeus Academic v. 1.5 (Forima Inc. Turku, Finland) bilaterally on the anterior cingulate, the caudate nucleus, the lateral frontal cortex, the parietal cortex, the occipital cortex, the posterior cingulate, the pons, the putamen, the thalamus, the subcortical white matter, the lateral temporal cortex, and the parahippocampal area. The regional time-radioactivity curves (TACs) were extracted and the regional tissue to reference the cerebellar cortex ratio values were calculated over 60 to 90 min.

Statistics

The statistical analyses were performed by using R statistical computing language (version 2.15.0) [34] and its packages “Deducer” (version 0.6-3) [35] and “stats” [34] with the help of Python (version 2.7.3) and the RPy2 (2.2.5) Python package. The Shapiro–Wilk test [36] was used to test the normal distribution of the data and p-values 0.05 were considered as significant, indicating that the data was not normally distributed.

For the statistical analysis, the combined neocortical score of [¹¹C]PIB uptake (the average of the ROIs in the posterior cingulate, the frontal, parietal, lateral temporal, and occipital cortices) was calculated. Spearman’s Correlation Coefficients were determined between the semi-quantitatively measured Aβ deposits in the biopsy samples and [¹¹C]PIB uptake values of the right frontal cortex as well as the combined neocortical area. Spearman’s correlation coefficient was used in order to get the most reliable results because the Aβ values were not normally distributed (Shapiro-Wilk normality test W = 0.75, p < 0.001) [37]. The correlations between the CSF samples and the Aβ deposits in the biopsy samples and [¹¹C]PIB uptake were also calculated by using Spearman’s method for the same reason.

The subjects were divided into groups according to the Aβ positiveness in the biopsies (11 positive and 10 negative) and also according to the ApoE ɛ4 genotype as ɛ4 positive versus negative subjects (8 positive and 12 negative, one value missing). Comparisons between the groups were made by using the Welch Two Sample t-test [38].

To demonstrate the association between the ApoE genotype ɛ4 and the tissue Aβ positivity, the Fisher’s exact test [39] for ordinal data was used instead of the chi square test due to the minimum expected number being less than 5.

RESULTS

The demographics (gender and age at the time of biopsies) and the cognitive status (MMSE and the CDR scores) at the time of the [¹¹C]PIB PET scans and the time from the biopsies to the PET examinations and the ApoE status of the patients are presented in Table 1.

There was a clear association between the semi-quantitatively measured Aβ accumulation in the brain biopsy and [¹¹C]PIB uptake in the right frontal cortex (Spearman’s ρ= 0.60, p = 0.004, Fig. 1) as well as the combined neocortical [¹¹C]PIB uptake score (the average of the posterior cingulate, the frontal cortex, the parietal cortex, the lateral temporal cortex and the occipital cortex) (Spearman’s ρ= 0.61, p < 0.01).

Fig.1

Scatterplot of the tissue Aβ (the number of the plaques divided by the area of the gray matter (mm²)) and [¹¹C]PIB uptake in the right frontal cortex expressed as the frontal cortex to the cerebellum ratio from 60 to 90 min.

When comparing the lumbar and the ventricular CSF measurements with the [¹¹C]PIB uptake or the semi-quantitatively measured Aβ plaques, no statistically significant correlations were found (Table 2). Additionally, ventricular CSF levels of the Aβ_1-42 or the tau proteins did not show a statistically significant correlation with those of lumbar equivalents. However, one subject who was tissue Aβ and [¹¹C]PIB negative had an atypically low ventricular Aβ_1-42 value of 230 pg/mL when considered to the mean of 690 pg/mL (SD 250 pg/mL) of the rest of tissue Aβ negative subjects (Fig. 2). This participant had increased tau but normal phospho-tau concentration in the CSF. The CSF sample was reanalyzed in order to avoid measuring errors. Without this outlier, the correlation between the ventricular and the tissue Aβ was ρ= –0.54 (p = 0.05) and between the ventricular Aβ_1-42 and the combined neocortical [¹¹C]PIB uptake score, the correlation was ρ= –0.58 (p = 0.03) (Fig. 2).

Table 2

Spearman’s correlation results between [¹¹C]PIB PET imaging and the biopsy Aβ or the ventricular or the lumbar cerebrospinal fluid (CSF) Aβ

	Semi-quantitatively measured biopsy Aβ (n = 21)	p	ventricular CSF Aβ (n = 15)	p	lumbar CSF Aβ (n = 9)	p
[¹¹C]PIB in the neocortical area (n = 21)	0.61	0.003	–0.46^a	0,08	–0.62	0.09
[¹¹C]PIB in the right frontal cortex (n = 21)	0.60	0.004	–0.14^b	0.61	–0.23	0.55
Semi-quantitatively measured biopsy Aβ (n = 21)	–	–	–0.36^c	0.19	0.12	0.76

^aWithout one outlier r = –0.58, p = 0.03.; ^bWithout one outlier r = –0.27, p = 0.35.; ^cWithout one outlier r = –0.54, p = 0.05.

Fig.2

Scatterplot of the ventricular CSF Aβ_1-42 (pg/mL) level and the composite neocortical [¹¹C]PIB uptake score. An outlier with a negative tissue biopsy for Aβ and a normal [¹¹C]PIB uptake, but low ventricular CSF Aβ concentration is marked with an asterix (*). Without this outlier the correlation between ventricular Aβ_1-42 and composite neocortical [¹¹C]PIB uptake score was r = –0.58, p = 0.03.

When the subjects were examined through the biopsy findings (11 positive and 10 negative for the Aβ plaques), significant differences were found in the neocortical [¹¹C]PIB uptake score (p = 0.01, CI from 0.12 to 0.79) and the right frontal cortex [¹¹C]PIB uptake (p = 0.01, CI from 0.14 to 1.0) and naturally between the biopsy Aβ (p = 0.002, CI from 7.1 to 22). However, there were no significant difference in the ventricular or the lumbar CSF measurements between the biopsy positive and negative patients even without the one outlier (data not shown).

Among the 10 biopsy Aβ negative subjects, only one subject was an ApoE ɛ4 carrier while there were 7 ApoE ɛ4 carriers among the 11 biopsy positive subjects. Fisher’s exact test confirmed clear association between the tissue Aβ and the ApoE genotype ɛ4 (p = 0.03, CI from 0.0014 to 1.00) (Table 3).

Table 3

A two-by-two table and Fisher’s exact test for the count data between the ApoE genotype ɛ4 and the tissue Aβ^a

	ApoEɛ4–	ApoEɛ4+	Total
Tissue Aβ+	4	7	11
Tissue Aβ–	8	1	9
Total	12	8	20^b

^ap-value for Fisher’s exact test 0.03; ^bOne ApoE value missing

Higher MMSE values were associated with lower lumbar CSF tau-levels (Pearson’s r = –0.77, p = 0.015) and a similar trend was seen with the MMSE versus the lumbar phospho-tau levels (Pearson’s r = –0.61, p = 0.081). No significant association was seen between the MMSE and the ventricular Aβ-, tau-, or phospho-tau levels. Neither was there a significant association between the MMSE and the combined neocortical [¹¹C]PIB uptake score.

DISCUSSION

We found that the brain tissue Aβ in the right frontal cortex biopsy specimen was associated with [¹¹C]PIB uptake both in the biopsy site of the right frontal cortex as well as in the whole neocortical area. On the contrary, there were no statistically significant correlations between the ventricular or the lumbar CSF samples and the tissue Aβ or [¹¹C]PIB accumulation in the whole study population. However, when excluding the one patient who was tissue Aβ and [¹¹C]PIB negative and who had an atypically low ventricular Aβ_1-42 value, there was an expected negative association between the ventricular and the tissue Aβ and between the ventricular Aβ_1-42 and the combined neocortical [¹¹C]PIB uptake score.

Our study is in agreement with the correlation between [¹¹C]PIB and the brain tissue Aβ shown earlier in a small patient population [40, 30]. The brain biopsies were obtained from the frontal cortex which is the typical brain area for the Aβ deposits, but as the whole brain was not histologically investigated, in theory it is still possible to miss Aβ plaques leading the patient being falsely judged as a negative. In our patient population, none of the biopsy negatives presented with an atypically high [¹¹C]PIB uptake (Fig. 1).

The levels of Aβ_1-42, total tau, and HPτ in the CSF samples were not associated with [¹¹C]PIB nor the tissue Aβ. Without the one outlier, the lower ventricular Aβ_1-42 was associated with higher tissue Aβ and [¹¹C]PIB accumulation in the combined neocortical area, but not with the biopsy site [¹¹C]PIB uptake. One possible explanation is that the more widespread and general brain Aβ load (represented as the neocortical [¹¹C]PIB uptake score) is better associated with the CSF Aβ_1-42 levels than the Aβ level in a tiny area in the frontal cortex (represented as the biopsy site [¹¹C]PIB uptake). Significant associations were expected because the correlation between the lumbar samples and [¹¹C]PIB PET is well documented [41] and also the correlation between the ventricular Aβ_1-42 postmortem samples and the tissue Aβ is suggested [23]. Actually, in a larger number of patients, significant inverse correlation between the ventricular [42] and the lumbar [43] Aβ_1-42 and the tissue Aβ was found [42]. The low ventricular Aβ_1-42 of our subjects could be a sign of forthcoming AD that had not yet developed amyloid plaques in the brain, thus being [¹¹C]PIB and biopsy negative. The lumbar Aβ_1-42 has been shown to be reduced by at least 9 years before the clinical onset of AD [28]. Of course, measurement error may lie behind this atypical ventricular Aβ_1-42. Finally, the low number of the lumbar CSF samples (n = 9) is also a possible cause for our non-significant correlation between the lumbar CSF samples and [¹¹C]PIB uptake in the tissue Aβ. In general, interpreting correlations with small sample sizes should be done cautiously.

The association between [¹¹C]PIB uptake and the biopsy Aβ did not merely concern the existence of Aβ and [¹¹C]PIB uptake in the biopsy site of the frontal cortex but also the amount of Aβ in the biopsy site and the composite neocortical [¹¹C]PIB uptake score. This suggests that if Aβ was found from a small biopsy in patients with iNPH, it seems to indicate a widespread amyloid load of the brain. There were few patients who were mildly positive for tissue Aβ but were [¹¹C]PIB negative. Those cases seem to have only fleecy plaques that are probably not visible by [¹¹C]PIB detecting the fibrillar Aβ. Future studies are needed to determine whether those patients are at an increased risk to develop AD or not.

During the clinical follow-up, seven patients had a clinical diagnosis of AD either alone or with comorbidities (Table 1). All 4 patients with tissue Aβ and HPτ developed clinical AD. Amyloid PET imaging was performed up to 36 months (mean 9 months) after the brain biopsies. Theoretically, there is a risk of changes related to AD appearing after the biopsy. However, since the Aβ accumulation is thought to be a slow process, we think that the time interval is not crucial. Theoretically, some biopsy negative cases could have turned out to be PIB positive, but no such cases were observed.

Higher MMSE values were associated with lower lumbar CSF tau-levels which is, according to the hypothesis (i.e., less indication of neuronal degeneration the better the MMSE score), and a similar trend was seen between the MMSE score and the CSF phospho-tau level. These associations should be interpreted with caution, since in NPH the cognitive decline could be due to NPH itself, concomitant AD pathology or concomitant vascular pathology or a combination of these processes.

Our findings indicate that the Aβ PET imaging can reliably detect simultaneous amyloid pathology among the iNPH patients. In our study, 13 out of 15 patients benefit from the shunt operation and seven of those were Aβ positive. There are also studies suggesting worse outcomes for iNPH with concomitant AD. Further research with longer follow-ups and larger data is still needed to predict the clinical response to the shunt operation and comorbid AD by using Aβ PET imaging [4 , 44–46]. In addition, the presence of the Aβ pathology increases the risk of AD in the patients with iNPH and a follow-up of cognitive functioning and the activities of daily living are needed after the shunt surgery.

Footnotes

ACKNOWLEDGMENTS

The study was financially supported by the Health Research Council of the Academy of Finland, The Finnish Medical Foundation, EVO grants from Kuopio University Hospital 5883, 5772708, 5772720, 5772722, and 5772725, the strategic funding from the University of Eastern Finland, Clinical Grant of the Southwest Hospital District of Turku (VTR, project 13464) and the Sigrid Juselius Foundation. The authors are grateful for MSc Anniina Savolainen for revising the English language.

Authors’ disclosures available online ().

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[ 11 C]PIB PET Is Associated with the Brain Biopsy Amyloid-β Load in Subjects Examined for Normal Pressure Hydrocephalus

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Keywords

INTRODUCTION

MATERIALS AND METHODS

Patients

Shunt and the shunt response

Follow-up time and the final clinical diagnosis

The frontal cortical brain biopsy sampling and the neuropathological examination

The sampling of the blood and the cerebrospinal fluid

[11C]PIB PET imaging

Image processing and data analysis

Statistics

RESULTS

DISCUSSION

Footnotes

ACKNOWLEDGMENTS

References

[¹¹C]PIB PET imaging