Assessment of 18 F-Florbetaben Amyloid PET Imaging in Patients with Suspected Alzheimer’s Disease and Isolated Increase in Cerebrospinal Fluid Tau Proteins

Abstract

Background/Objective:

The aim of this study was to assess, in routine, the rates with which an amyloid deposition was documented by ¹⁸F-florbetaben PET in patients with suspected Alzheimer’s disease (AD) but with isolated increases in cerebrospinal fluid (CSF) tau-protein concentrations, and the subsequent impact of these PET results on medical management.

Methods:

This prospective study included 34 patients with mild neurocognitive disorders (MND) and suspected AD (73±9 years, 16 women) and with abnormal CSF concentrations in total-tau (T-tau) and/or phosphorylated-tau (P-tau) proteins but normal Aβ₄₂ concentration and Aβ₄₂/Aβ₄₀ ratio. These patients were referred to ⁸F-florbetaben PET from which the PET-related changes in the confidence for AD diagnosis (low, intermediate, or high) and treatments were reported.

Results:

The PET examinations were positive for amyloid deposition (brain amyloid plaque load, BAPL score >1) in none of the 9 patients with an increase in only T-tau proteins and in 8 among the 25 (32%) with an increase in P-tau proteins (one BAPL score of 2 and seven BAPL scores of 3). Knowledge of the PET results was associated with subsequent changes in diagnostic confidence in 44% of patients (15/34) and in the intention-to-treat with a cholinesterase inhibitor drug in 18% (6/34).

Conclusion:

In patients with suspected AD and isolated increase in CSF tau protein concentrations, an amyloid deposition is documented by ¹⁸F-florbetaben PET in as much as one third of cases when the concentration of P-tau is abnormal, and PET results are associated with significant further changes in medical management.

Keywords

Alzheimer’s disease amyloid cerebrospinal fluid positron emission tomography

INTRODUCTION

Biomarkers are now integrated in the diagnostic flow charts of Alzheimer’s disease (AD), especially for the clinically atypical cases and young patients for assessing the two pathophysiological brain processes which need to be present for AD diagnosis, namely protein tau-related neurodegeneration and accumulation of amyloid-β (Aβ) protein. According to the 2011 recommendations of the National Institute on Aging and Alzheimer’s Association (NIA-AA), the combination, on the one hand, of an increase in cerebrospinal fluid (CSF) concentrations of total-tau (T-tau) and/or phosphorylated-tau (P-tau) protein(s) with, on the other, a decrease in the CSF concentration of Aβ₄₂ peptide is highly indicative of an AD pathological process [1]. However, the profile of CSF biomarkers of suspected AD can be dissociated with notably isolated increases in T-tau and/or P-tau proteins but normal Aβ concentrations, even when the Aβ₄₂/Aβ₄₀ ratio is taken into account [2]. On the one hand, such increases in T-tau and/or P-tau are sufficiently robust criteria for discriminating AD from non-AD-dementia [3], although on the other hand, their isolated increases may not lead to the diagnosis of AD according to the criteria from NIA-AA [1, 4]. Fortunately, Aβ abnormalities can also be detected directly within the brain owing to positron emission tomography (PET) tracers, such as ¹⁸F-florbetaben, with both high sensitivity and specificity (up to 98% and 94%, respectively) for this purpose [5], these levels being close to those reported with the Aβ CSF biomarker [6]. However, discordant results are not uncommon in the setting of AD diagnosis with a concordance rate of approximately 80% between amyloid PET and the CSF concentration of Aβ proteins [6, 7].

Several studies have previously investigated the additional information provided by amyloid PET imaging on the diagnostic work-up of patients with neurocognitive disorders [8 –14]. However, few of these studies have been conducted in routine and with appropriate use criteria [8, 13], while no amyloid PET study has previously been conducted in the particular population of patients with isolated increases in tau proteins.

In light of the above, the aim of the present study was to determine whether a definite brain amyloid deposition could be documented by ¹⁸F-florbetaben PET, in spite of normal Aβ CSF concentrations, in a significant proportion of patients with suspected AD but isolated increases in CSF tau protein concentrations, and to assess the further impact of PET results on medical management.

MATERIALS AND METHODS

Population

Between December 2015 and September 2017, 35 patients with mild neurocognitive disorders (MND) [14] and suspected AD, according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS ADRDA) criteria [1, 15], were enrolled in the present prospective MAF (Maladie d’Alzheimer Florbetaben) study (NCT02556502). The CSF analyses had been performed in the previous year and in the same laboratory (Department of Biochemistry, Molecular Biology and Nutrition, CHRU Nancy, France) and hence according to the same techniques with routine cut-offs [2, 16]. Moreover, two levels of supplier-provided internal quality controls were analyzed in each series, with the laboratory furthermore participating in the Alzheimer’s Association Quality Control Program by analyzing, 4 times yearly, two levels of external quality controls and one longitudinal control. CSF was collected in a 5 mL Gosselin polypropylene tube, maintained no more than 4 h at 4°C before transport to the laboratory for centrifugation and final storage at –80°C. A CSF control pool, previously sampled in the same polypropylene tubes and stored at –80°C, was used for the internal quality control of each patient analysis. Standards, samples, and controls were run in duplicate. Samples were re-assayed in case of variation coefficients above 10% for the duplicated assays. In order to be included, selected patients had to exhibit increase(s) in T-tau and/or P-tau concentrations (>350 pg/mL and/or >60 pg/mL, respectively) but normal Aβ₄₂ concentration (>600 pg/mL) and Aβ₄₂/Aβ₄₀ ratio (>0.07) before being referred to ¹⁸F-florbetaben PET scanning. The other inclusion criteria were: age ≥18 years old, absence of formal or relative contraindication to the conducting of ¹⁸F-florbetaben PET and affiliation to a health care system. Patients under guardianship or curatorship, pregnant women or nursing, as well as patients unable to undergo a ¹⁸F-florbetaben PET due to agitation or confusion, were not included.

All participants provided written informed consent for study participation, visits, and data source verification. No participant had a legal representative. This study was approved by the French ethics committee (CPP Est III) on September 15, 2015, received an authorization from the national competent authority (ANSM) on September 18, 2015, and adhered to the Declaration of Helsinki.

Study design

This single-center study was conducted in routine in the “memory clinic” of the University Hospital of Nancy (France) [17]. This clinic is a third-level center, involved in a regional network of expert centers and with a role of research and resource helping secondary-level centers for the management of patients with neurodegenerative diseases.

A multidisciplinary team meeting of medical specialists involved in the diagnostic network of AD, i.e., neurologist(s), geriatrician(s), neuropsychologist(s), and biochemist(s), was organized twice a month in order to screen eligible patients according to the inclusion criteria. During this initial meeting, a 3-point confidence score for AD diagnosis (low, intermediate, or high) was additionally obtained for each patient in a consensual manner by neurologist and geriatric experts (LH, AKS, and TRJ) according to the NIA-AA 2011 and the international working group (IWG)-2 criteria [1, 18]. In addition, a therapeutic management was planned for each patient by this same expert group regarding the intention-to-treat or not with a cholinesterase inhibitor treatment according to the AD guideline recommendations [19].

Patients were subsequently included in the study and referred for ¹⁸F-florbetaben PET no later than one month after the initial multidisciplinary team meeting. Finally, a second multidisciplinary team meeting was conducted with the same experts but in light of the PET results and in order to collect any change in the confidence score for AD diagnosis (i.e., 1-point or 2-point changes) and in the intention-to-treat with cholinesterase inhibitors, according to current recommendations based on amyloid PET results [1 , 19].

Recording and analysis of ¹⁸F-florbetaben PET images

All brain images were recorded on the same Biograph™ 6 hybrid PET/Computed Tomography (CT) system (Siemens Medical Solutions, Erlangen, Germany) after the intravenous injection of a bolus of 300 MBq (±10%) of ¹⁸F-florbetaben. After 90 min, the imaging protocol was initiated by a brain CT scan for attenuation correction, immediately followed by a 20 min brain PET recording. Total body irradiation was approximately 10 mSv for each patient with 7 mSv resulting from the ¹⁸F-florbetaben injection.

PET images were reconstructed with an iterative 3-dimensional Ordered Subset Expected Minimization (OSEM) method, corrected for attenuation and diffusion, and displayed through 2.7 mm isotropic voxels.

A consensual visual analysis of amyloid PET images was obtained from two experienced nuclear physicians (CM, AV) who were blinded to all patient data, including MRI images. Amyloid PET results were interpreted as either “positive” or “negative” in a conventional manner, according to the amount of ¹⁸F-florbetaben uptake observed on the lateral temporal cortex, frontal cortex, posterior cingulate cortex/precuneus and parietal cortex. Brain amyloid plaque load (BAPL) scores were defined, with scores >1 considered as positive, as currently recommended [5, 20].

Statistical analysis

Quantitative variables are expressed as means± standard deviations, and categorical variables as percentages. Mann-Whitney and Chi-2 tests were performed for the 2-group comparisons of quantitative and categorical variables, respectively. A p < 0.05 was determined as significant. Statistical analyses were performed with SPSS® 20.0 software.

RESULTS

Baseline patient characteristics and PET results

Thirty-five consecutive patients, with increased CSF levels of T-tau and/or P-tau proteins but normal Aβ₄₂ protein level and normal Aβ₄₂/Aβ₄₀ ratio were included. One patient was subsequently excluded following consent withdrawal, leaving 34 patients in the final study population. As detailed in Table 1, 16 (47%) were women, mean age was 73±9 years and mean Mini-Mental State Examination (MMSE) score was 22±5. According to the Clinical Dementia Rating (CDR) [21], none of our patients was classified as having CDR scores of 0 (no dementia) or 3 (severe dementia). Twenty-five patients presented an increase in CSF concentration of P-tau while 9 solely presented an increase in T-tau concentration.

Table 1

Patient characteristics

	Total N = 34	Increases in CSF T-tau only N = 9	Increases in CSF P-tau N = 25	p
Age (y)	73±9	70±9	74±9	0.28
Gender (female)	16 (47%)	6 (67%)	10 (40%)	0.17
MMSE (/30)	22±5	23±3	22±5	0.47
CDR
0.5	17 (50%)	5 (56%)	12 (48%)	0.70
1 or 2	17 (50%)	4 (44%)	13 (52%)
Educational level				0.57
None	2 (6%)	0	2 (8%)
Primary school	16 (47%)	4 (44%)	12 (48%)
High school up to 15 years old	3 (9%)	0	3 (12%)
High school up to 18 years old	6 (18%)	2 (22%)	4 (16%)
College and above	7 (20%)	3 (33%)	4 (16%)
CSF biomarkers
T-tau (pg/mL) (n < 350 pg/mL)	470±122	433±425	481±133	0.22
P-tau (pg/mL) (n < 60 pg/mL)	67±16	51±12	72±14	<0.01^*
Aβ₄₂ (pg/mL) (n > 600 pg/mL)	1051±264	1155±222	1013±272	0.11
Aβ₄₂/Aβ₄₀ ratio (n > 0, 07)	0.097±0.027	0.116±0.27	0.090±0.023	0.01^*

CDR, Clinical Dementia Rating; CSF, cerebrospinal fluid; MMSE, Mini-Mental State Examination; ^* p-value significant for comparisons between patients with increases in CSF T-tau only and patients with increases in CSF P-tau.

Based on the results from the initial multidisciplinary team meeting, a high level of confidence score for AD diagnosis was conferred to 5 patients (15%) with an intention-to-treat with cholinesterase inhibitors in the same 5 patients (15%).

PET results and subsequent changes in patient management

The PET examinations were positive for amyloid deposition (BAPL score >1) in none of the 9 patients with an increase in only T-tau proteins and in 8 among the 25 patients (32%) with an increase in P-tau proteins (one BAPL score of 2 and seven BAPL score of 3).

As detailed in Fig. 1, the knowledge of the PET results was associated with subsequent changes in diagnostic confidence for AD diagnosis in 44% of patients (15/34) and in the intention-to-treat with a cholinesterase drug in 18% (6/34). When the analysis was restricted to the subgroup of patients with an increase in P-tau proteins, these percentages were 40% (10/25) and 20% (5/25), respectively.

Fig.1

Changes in confidence level scores for the diagnosis of Alzheimer’s disease before and after amyloid PET scans according to the National Institute on Aging and Alzheimer’s Association (NIA-AA) 2011 and the International Working Group (IWG)-2 criteria, for the 34 patients with increases in CSF tau proteins (A) and the 25 patients with increases in CSF P-tau proteins (B). Green cells represent patients for whom a diagnostic confidence score was changed after amyloid PET: 2 patients from high to low, 4 patients from intermediate to high, and 9 patients from intermediate to low in A, and 1 patient from high to low, 4 patients from intermediate to high, and 5 patients from intermediate to low in B.

In particular, the knowledge of the PET results was associated with a dramatic decrease in the proportion of patients with an intermediate level of AD confidence score: from 41% to 3% in the overall population, and from 40% to 4% in the sub-group with P-tau increase (both p < 0.01) (Fig. 1).

Representative examples of amyloid PET scans are shown in Fig. 2 in patients with subsequent changes in diagnostic confidence for AD and in therapeutic management.

Fig.2

Axial ¹⁸F-florbetaben PET slices of 2 illustrated cases: A) Positive amyloid PET (brain amyloid plaque load score of 3) in an 80-year-old woman with immediate memory disorders mostly associated with mood modification (Aβ₄₂ = 793 pg/mL, Aβ₄₂/Aβ₄₀ = 0.072, T-tau = 425 pg/mL, P-tau = 72 pg/mL, Mini-Mental State Examination: 19/30) (upper panel). For this patient, performing an amyloid PET led to an increase in the diagnostic confidence score of Alzheimer’s disease (from intermediate to high level) and to the initiation of a cholinesterase inhibitor treatment. Note the large confluent area of higher grey matter tracer uptake than that observed in white matter (red arrows). B) Negative amyloid PET (brain amyloid plaque load score of 1) in a 67-year-old man with executive disorders and memory loss since 3 years (Aβ₄₂ = 735 pg/mL, Aβ₄₂/Aβ₄₀ = 0.072, T-tau = 687 pg/mL, P-tau = 84 pg/mL, Mini-Mental State Examination: 25/30) (lower panel). For this patient, performing an amyloid PET led to a decrease in the diagnostic confidence score of Alzheimer’s disease (from high to low level) and to the withdrawal of the initially planned cholinesterase inhibitor treatment. Note the lower gray matter uptake than that observed in white matter (green arrows).

DISCUSSION

In this particular population of patients with MND, suspected AD and CSF increases in tau proteins but normal Aβ concentrations, ¹⁸F-florbetaben PET was systematically negative for patients with increases in T-tau proteins only. However, an amyloid deposition was nonetheless documented by ¹⁸F-florbetaben PET in as much as one third of cases for patients with increases of P-tau proteins. Furthermore, the performing of ¹⁸F-florbetaben PET in these patients with isolated increases in tau proteins was associated with significant changes in expert confidence for AD diagnosis and in therapeutic management with cholinesterase inhibitor medication.

Our study was characterized by its routine approach [17] with amyloid PET being prescribed in accordance with current recommendations [1, 18], i.e., in patients for whom the diagnosis of AD was still uncertain after a comprehensive assessment including a full diagnostic workup with CSF analysis [22, 23, 22, 23]. Hence, the present study was focused on the assessment of ¹⁸F-florbetaben PET in patients with MND, suspected AD but isolated increases in CSF tau proteins. As a result, this population, representing approximately 4% of patients referred to a CSF analysis for a suspected AD during the same period, was highly selected. For this selection, the absence of any Aβ CSF abnormality was strengthened through the criterion of a normal Aβ₄₂/Aβ₄₀ ratio in addition to that of a normal Aβ₄₂ concentration [2]. As detailed in the Methods section, high quality requirements were applied for the CSF assays with, in particular, a test-re-test process, which was systematically programmed when the variation coefficient between assay and re-assay concentrations was greater than 10%.

From a practical medical standpoint, it is important to highlight that the characterization and monitoring of our patients, determined according to NIA-AA 2011 and IWG-2 criteria [1, 18], was significantly modified by the knowledge of ¹⁸F-florbetaben PET results. Significant improvements in the diagnostic confidence for AD were indeed observed herein (44%) including, in particular, a dramatic decrease in the rate of intermediate diagnostic confidence, especially from intermediate to low level scores, in keeping with previously published studies [8 , 24], along with concomitant changes in the referral to cholinesterase inhibitor medications in 18% of patients. This latter percentage is below those previously reported (24% to 38.5%) [8–10 , 13], likely because of the particular characteristic of our study patients among whom only 5 were initially referred to cholinesterase inhibitors.

Although a rather high correlation has previously been reported between Aβ CSF concentrations and amyloid PET results [6], the present study shows that dissociations are far from uncommon in atypical cases of CSF profiles. The particular characteristics of our study population with ambiguous CSF results is likely the main reason for the high rate of documented positive amyloid PET in spite of normal CSF concentrations of Aβ proteins (this rate may be expected to be much lower in patients with unambiguous CSF results). However, it should also be pointed out that Aβ CSF and amyloid PET provide a somewhat different information on amyloid load, with the amount of amyloid PET load being more strongly related to AD progression and to the severity of clinical symptoms than the CSF level of Aβ proteins [25]. Notwithstanding the latter, it should be underlined that Aβ CSF sensitivity for detecting amyloid deposition is contingent on the threshold used to define a positive test which representing a compromise between the sensitivity and specificity of this test. The use of more lenient thresholds may lead to improve sensitivity but with the likely inconvenience of affecting specificity [7]. While a better understanding of these dissociations would necessitate further longitudinal follow-up, it remains that the amyloid load observed herein with PET imaging was indisputable and particularly high, i.e., with a maximal BAPL score, in as many as 7 among the 8 positive PET patients.

According to the recent NIA-AA 2018 diagnostic standards, an increase in P-tau proteins and not in T-tau protein is required for the biological diagnosis of AD [4], although this was not the case when this study was first started. Nevertheless, all PET exams were negative in the 9 patients for whom only the CSF concentration of T-tau protein was increased, a finding that further strengthens the diagnostic importance of CSF concentration in P-tau proteins. In the population restricted to the 25 patients showing an increase in CSF P-tau protein concentration, almost one third of the latter presented a positive amyloid PET, and the rates of subsequent changes in diagnostic confidence and treatment referral were close to those of the general study population. From a more practical standpoint, the current study shows that amyloid PET may be useful in cases of isolated increase in P-tau proteins but not in cases of an increase in T-tau proteins only, in patients with MND and suspected AD.

In our population with abnormal CSF P-tau protein concentrations, the positivity of amyloid-PET could allow completing the biological pattern of AD, in spite of the normal CSF concentration of Aβ proteins [4], and thus lead to a re-classification in the category of MND due to AD according to the DSM-5 [14]. As a result, such patients should be identified as having a prodromal AD and not a non-Alzheimer pathophysiology (SNAP), a category where subsequent AD conversion are frequent with reported rates ranging from 21 to 47% [26]. In contrast, in those patients with negative amyloid PET, representing a non-negligible part of our population (76% of the patients), the diagnosis of AD can be discarded with a high degree of certainty owing to the high negative predictive value of amyloid PET, leading to a correct classification in the category of MND not due to AD according to the DSM-5 [14] (see Supplementary Figure 1 for biomarker changes related to amyloid PET results, according to the NIA-AA 2018 classification).

In conclusion, in patients with MND, suspected AD and an isolated increase in CSF tau protein concentration, amyloid deposition is frequently documented by ¹⁸F-florbetaben PET, especially in as much as one third of cases when the concentration of P-tau proteins is abnormal, and in which PET results are associated with significant subsequent changes in medical management. In keeping with a previously published study [8], the present study hence provides additional evidence that amyloid PET imaging constitutes a useful diagnostic tool in this highly selected population.

Footnotes

ACKNOWLEDGMENTS

This work has been carried out thanks to the support of the Nancyclotep Imaging Platform and Nancy University Hospital.

The authors thank Pierre Pothier for critical review of the manuscript.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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Assessment of 18 F-Florbetaben Amyloid PET Imaging in Patients with Suspected Alzheimer’s Disease and Isolated Increase in Cerebrospinal Fluid Tau Proteins

Abstract

Background/Objective:

Methods:

Results:

Conclusion:

Keywords

INTRODUCTION

MATERIALS AND METHODS

Population

Study design

Recording and analysis of 18F-florbetaben PET images

Statistical analysis

RESULTS

Baseline patient characteristics and PET results

PET results and subsequent changes in patient management

DISCUSSION

Footnotes

ACKNOWLEDGMENTS

References

Recording and analysis of ¹⁸F-florbetaben PET images