| 1. |
- Altomare, Daniele, et al.
(author)
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Applying the ATN scheme in a memory clinic population : The ABIDE project
- 2019
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In: Neurology. - 1526-632X. ; 93:17, s. 1635-1646
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To apply the ATN scheme to memory clinic patients, to assess whether it discriminates patient populations with specific features. METHODS: We included 305 memory clinic patients (33% subjective cognitive decline [SCD]: 60 ± 9 years, 61% M; 19% mild cognitive impairment [MCI]: 68 ± 9 years, 68% M; 48% dementia: 66 ± 10 years, 58% M) classified for positivity (±) of amyloid (A) ([18F]Florbetaben PET), tau (T) (CSF p-tau), and neurodegeneration (N) (medial temporal lobe atrophy). We assessed ATN profiles' demographic, clinical, and cognitive features at baseline, and cognitive decline over time. RESULTS: The proportion of A+T+N+ patients increased with syndrome severity (from 1% in SCD to 14% in MCI and 35% in dementia), while the opposite was true for A-T-N- (from 48% to 19% and 6%). Compared to A-T-N-, patients with the Alzheimer disease profiles (A+T+N- and A+T+N+) were older (both p < 0.05) and had a higher prevalence of APOE ε4 (both p < 0.05) and lower Mini-Mental State Examination (MMSE) (both p < 0.05), memory (both p < 0.05), and visuospatial abilities (both p < 0.05) at baseline. Non-Alzheimer profiles A-T-N+ and A-T+N+ showed more severe white matter hyperintensities (both p < 0.05) and worse language performance (both p < 0.05) than A-T-N-. A linear mixed model showed faster decline on MMSE over time in A+T+N- and A+T+N+ (p = 0.059 and p < 0.001 vs A-T-N-), attributable mainly to patients without dementia. CONCLUSIONS: The ATN scheme identified different biomarker profiles with overlapping baseline features and patterns of cognitive decline. The large number of profiles, which may have different implications in patients with vs without dementia, poses a challenge to the application of the ATN scheme.
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| 2. |
- Collij, Lyduine E., et al.
(author)
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Clinical outcomes up to 9 years after [18F]flutemetamol amyloid-PET in a symptomatic memory clinic population
- 2023
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In: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
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Journal article (peer-reviewed)abstract
- Background: Previous studies demonstrated increases in diagnostic confidence and change in patient management after amyloid-PET. However, studies investigating longitudinal outcomes over an extended period of time are limited. Therefore, we aimed to investigate clinical outcomes up to 9 years after amyloid-PET to support the clinical validity of the imaging technique. Methods: We analyzed longitudinal data from 200 patients (M age = 61.8, 45.5% female, M MMSE = 23.3) suspected of early-onset dementia that underwent [18F]flutemetamol-PET. Baseline amyloid status was determined through visual read (VR). Information on mortality was available with a mean follow-up of 6.7 years (range = 1.1–9.3). In a subset of 108 patients, longitudinal cognitive scores and clinical etiological diagnosis (eDx) at least 1 year after amyloid-PET acquisition were available (M = 3.06 years, range = 1.00–7.02). VR − and VR + patients were compared on mortality rates with Cox Hazard’s model, prevalence of stable eDx using chi-square test, and longitudinal cognition with linear mixed models. Neuropathological data was available for 4 patients (mean delay = 3.59 ± 1.82 years, range = 1.2–6.3). Results: At baseline, 184 (92.0%) patients were considered to have dementia. The majority of VR + patients had a primary etiological diagnosis of AD (122/128, 95.3%), while the VR − group consisted mostly of non-AD etiologies, most commonly frontotemporal lobar degeneration (30/72, 40.2%). Overall mortality rate was 48.5% and did not differ between VR − and VR + patients. eDx at follow-up was consistent with baseline diagnosis for 92/108 (85.2%) patients, with most changes observed in VR − cases (VR − = 14/35, 40% vs VR + = 2/73, 2.7%, χ 2 = 26.03, p < 0.001), who at no time received an AD diagnosis. VR + patients declined faster than VR − patients based on MMSE (β = − 1.17, p = 0.004), episodic memory (β = − 0.78, p = 0.003), fluency (β = − 1.44, p < 0.001), and attention scores (β = 16.76, p = 0.03). Amyloid-PET assessment was in line with post-mortem confirmation in all cases; two cases were VR + and showed widespread AD pathology, while the other two cases were VR − and showed limited amyloid pathology. Conclusion: In a symptomatic population, we observed that amyloid-status did not impact mortality rates, but is predictive of cognitive functioning over time across several domains. Also, we show particular validity for a negative amyloid-PET assessment, as these patients did not receive an AD diagnosis at follow-up.
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| 3. |
- Collij, Lyduine E., et al.
(author)
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Quantification of [18F]florbetaben amyloid-PET imaging in a mixed memory clinic population : The ABIDE project
- 2023
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2397-2407
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Journal article (peer-reviewed)abstract
- Introduction: We investigated amyloid-burden quantification in a mixed memory clinic population. Methods: [18F]Florbetaben amyloid-PET (positron emission tomography) scans of 348 patients were visually read and quantified using the Centiloid (CL) method. General linear models were used to assess CL differences across syndromic and etiological diagnosis. Linear mixed models were fitted to assess the predictive value of visual read (VR) and CL on longitudinal Mini-Mental Status Examination (MMSE). Results: CL was associated with syndromic (F = 4.42, p = 0.014) and etiological diagnosis (F = -12.66, p < 0.001), with Alzheimer's disease (AD) patients showing the highest amyloid burden (62.9 ± 27.5), followed by dementia with Lewy bodies (DLB) (25.3 ± 35.5) and cardiovascular disease (CVD) (16.7 ± 24.5), and finally frontotemporal lobe degeneration (FTLD) (5.0 ± 17.22, t = –12.66, p < 0.001). CL remained predictive of etiological diagnosis (t = –2.41, p = 0.017) within the VR+ population (N = 157). VR was not a significant predictor of MMSE (t = –1.53, p = 0.13) for the SCD population (N = 90), whereas CL was (t = -3.30, p = 0.001). Discussion: The extent of amyloid pathology through quantification holds clinical value, potentially in the context of differential diagnosis as well as prognosis.
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| 4. |
- de Wilde, Arno, et al.
(author)
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Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort : The ABIDE project
- 2019
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260.
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Journal article (peer-reviewed)abstract
- Introduction: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. Methods: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post–positron emission tomography diagnosis and management change between “AUC-consistent” and “AUC-inconsistent” patients. Results: Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post–positron emission tomography diagnosis (28%–21%) and management (32%–17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). Discussion: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.
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| 5. |
- De Wilde, Arno, et al.
(author)
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Discordant amyloid-β PET and CSF biomarkers and its clinical consequences
- 2019
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In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
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Journal article (peer-reviewed)abstract
- Background: In vivo, high cerebral amyloid-β load has been associated with (i) reduced concentrations of Aβ42 in cerebrospinal fluid and (ii) increased retention using amyloid-β positron emission tomography. Although these two amyloid-β biomarkers generally show good correspondence, ~ 10-20% of cases have discordant results. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories. Methods: We included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer's dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ϵ4 status, CSF tau, and clinical and neuropsychological progression. Results: We found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ϵ4 (28%, 55%, 70%, Z = - 10.6, P < 0.001), CSF total tau (25%, 45%, 78%, Z = - 13.7, P < 0.001), and phosphorylated tau (28%, 43%, 80%, Z = - 13.7, P < 0.001) positivity. In patients without dementia, linear mixed models showed that Mini-Mental State Examination and memory composite scores did not differ between concordant-negative (β [SE] - 0.13[0.08], P = 0.09) and discordant (β 0.08[0.15], P = 0.15) patients (P interaction = 0.19), while these scores declined in concordant-positive (β - 0.75[0.08] patients (P interaction < 0.001). In patients with dementia, longitudinal cognitive scores were not affected by amyloid-β biomarker concordance or discordance. Clinical progression rates from SCD to MCI or dementia (P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive. Conclusions: Discordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ϵ4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.
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| 6. |
- Duits, Flora H., et al.
(author)
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
- 2014
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In: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
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Journal article (peer-reviewed)abstract
- Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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| 7. |
- Ossenkoppele, Rik, et al.
(author)
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Tau PET correlates with different Alzheimer’s disease-related features compared to CSF and plasma p-tau biomarkers
- 2021
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In: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 13:8
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Journal article (peer-reviewed)abstract
- PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n=400) and ADNI (n=371). All had tau-PET ([18F]RO948 in BioFINDER-2, [18F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOEɛ4-carriership and Aβ-positivity, while increased tau-PET signal in the temporal cortex was associated withworse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aβ-pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.
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| 8. |
- Pelak, Victoria S., et al.
(author)
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Consensus recommendations for clinical assessment tools for the diagnosis of posterior cortical atrophy syndrome from the Atypical AD PIA of ISTAART
- 2023
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In: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - 2352-8729. ; 15:3
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Delay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed. METHODS: Recommendations were developed using results from a web-based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA. RESULTS: Survey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria. DISCUSSION: These consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials.
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| 9. |
- Reimand, Juhan, et al.
(author)
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Amyloid-β PET and CSF in an autopsy-confirmed cohort
- 2020
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In: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 7:11, s. 2150-2160
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Journal article (peer-reviewed)abstract
- Objective: Accumulation of amyloid-β is among the earliest changes in Alzheimer’s disease (AD). Amyloid-β positron emission tomography (PET) and Aβ42 in cerebrospinal fluid (CSF) both assess amyloid-β pathology in-vivo, but 10–20% of cases show discordant (CSF+/PET− or CSF-/PET+) results. The neuropathological correspondence with amyloid-β CSF/PET discordance is unknown. Methods: We included 21 patients from our tertiary memory clinic who had undergone both CSF Aβ42 analysis and amyloid-β PET, and had neuropathological data available. Amyloid-β PET and CSF results were compared with neuropathological ABC scores (comprising of Thal (A), Braak (B), and CERAD (C) stage, all ranging from 0 [low] to 3 [high]) and neuropathological diagnosis. Results: Neuropathological diagnosis was AD in 11 (52%) patients. Amyloid-β PET was positive in all A3, C2, and C3 cases and in one of the two A2 cases. CSF Aβ42 was positive in 92% of ≥A2 and 90% of ≥C2 cases. PET and CSF were discordant in three of 21 (14%) cases: CSF+/PET− in a patient with granulomatosis with polyangiitis (A0B0C0), CSF+/PET− in a patient with FTLD-TDP type B (A2B1C1), and CSF-/PET+ in a patient with AD (A3B3C3). Two CSF+/PET+ cases had a non-AD neuropathological diagnosis, that is FTLD-TDP type E (A3B1C1) and adult-onset leukoencephalopathy with axonal spheroids (A1B1C0). Interpretation: Our study demonstrates neuropathological underpinnings of amyloid-β CSF/PET discordance. Furthermore, amyloid-β biomarker positivity on both PET and CSF did not invariably result in an AD diagnosis at autopsy, illustrating the importance of considering relevant comorbidities when evaluating amyloid-β biomarker results.
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| 10. |
- Reimand, Juhan, et al.
(author)
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Association of amyloid-β CSF/PET discordance and tau load 5 years later
- 2020
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In: Neurology. - 1526-632X. ; 95:19, s. 2648-2657
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the association between discordant β-amyloid (Aβ) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later. METHODS: We included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aβ42 available. Aβ CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aβ) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aβ CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET- participants who during follow-up (1) progressed to Aβ CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET. RESULTS: Aβ CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET- (n = 80) participants were overall similar to the CSF-/PET- (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET- group (1.20 ± 0.13) did not differ from CSF-/PET- (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET- participants, 21/64 (33%) progressed to Aβ CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET. CONCLUSIONS: Aβ load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aβ levels on both PET and CSF, the CSF+/PET- group has a distinctly better prognosis.
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| 11. |
- Reimand, Juhan, et al.
(author)
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Why Is Amyloid-β PET Requested After Performing CSF Biomarkers?
- 2020
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In: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 73:2, s. 559-569
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Journal article (peer-reviewed)abstract
- BACKGROUND: Amyloid-β positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease. OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.
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| 12. |
- Singleton, Ellen, et al.
(author)
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Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer's disease
- 2021
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:8, s. 872-880
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Journal article (peer-reviewed)abstract
- Objective: The clinical phenotype of the rare behavioural variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination. Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7). Results: Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05). Conclusions: Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.
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| 13. |
- Ulugut, Hulya, et al.
(author)
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The natural history of primary progressive aphasia : beyond aphasia
- 2022
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 269:3, s. 1375-1385
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Journal article (peer-reviewed)abstract
- Introduction: Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes. Methods: In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed. Results: Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). Discussion: Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration.
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| 14. |
- van Maurik, Ingrid S., et al.
(author)
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Biomarker-based prognosis for people with mild cognitive impairment (ABIDE) : a modelling study
- 2019
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In: Lancet Neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 18:11, s. 1034-1044
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Journal article (peer-reviewed)abstract
- BACKGROUND: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.METHODS: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.FINDINGS: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76).INTERPRETATION: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.
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