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  • 1
    In: JAMA Neurology, American Medical Association (AMA), Vol. 80, No. 6 ( 2023-06-01), p. 548-
    Abstract: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect. Objective To assess the clinical effect of amyloid PET in memory clinic patients. Design, Setting, and Participants The AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023. Intervention Amyloid PET. Main Outcome and Measure The main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months. Results A total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 ( P   & amp;lt; .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%] ; P   & amp;lt; .001; MCI: 45/108 [42%] vs 9/102 [9%] ; P   & amp;lt; .001; dementia: 39/80 [49%] vs 16/80 [20%] ; P   & amp;lt; .001). Conclusion and Relevance In this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients. Trial Registration EudraCT Number: 2017-002527-21
    Type of Medium: Online Resource
    ISSN: 2168-6149
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 2
    In: JAMA Network Open, American Medical Association (AMA), Vol. 6, No. 1 ( 2023-01-13), p. e2250921-
    Abstract: Individuals who are amyloid-positive with subjective cognitive decline and clinical features increasing the likelihood of preclinical Alzheimer disease (SCD+) are at higher risk of developing dementia. Some individuals with SCD+ undergo amyloid-positron emission tomography (PET) as part of research studies and frequently wish to know their amyloid status; however, the disclosure of a positive amyloid-PET result might have psychological risks. Objective To assess the psychological outcomes of the amyloid-PET result disclosure in individuals with SCD+ and explore which variables are associated with a safer disclosure in individuals who are amyloid positive. Design, Setting, and Participants This prospective, multicenter study was conducted as part of The Amyloid Imaging to Prevent Alzheimer Disease Diagnostic and Patient Management Study (AMYPAD-DPMS) (recruitment period: from April 2018 to October 2020). The setting was 5 European memory clinics, and participants included patients with SCD+ who underwent amyloid-PET. Statistical analysis was performed from July to October 2022. Exposures Disclosure of amyloid-PET result. Main Outcomes and Measures Psychological outcomes were defined as (1) disclosure related distress, assessed using the Impact of Event Scale–Revised (IES-R; scores of at least 33 indicate probable presence of posttraumatic stress disorder [PTSD]); and (2) anxiety and depression, assessed using the Hospital Anxiety and Depression scale (HADS; scores of at least 15 indicate probable presence of severe mood disorder symptoms). Results After disclosure, 27 patients with amyloid-positive SCD+ (median [IQR] age, 70 [66-74] years; gender: 14 men [52%]; median [IQR] education: 15 [13 to 17] years, median [IQR] Mini-Mental State Examination [MMSE] score, 29 [28 to 30] ) had higher median (IQR) IES-R total score (10 [2 to 14] vs 0 [0 to 2] ; P   & amp;lt; .001), IES-R avoidance (0.00 [0.00 to 0.69] vs 0.00 [0.00 to 0.00] ; P   & amp;lt; .001), IES-R intrusions (0.50 [0.13 to 0.75] vs 0.00 [0.00 to 0.25] ; P   & amp;lt; .001), and IES-R hyperarousal (0.33 [0.00 to 0.67] vs 0.00 [0.00 to 0.00] ; P   & amp;lt; .001) scores than the 78 patients who were amyloid-negative (median [IQR], age, 67 [64 to 74] years, 45 men [58%], median [IQR] education: 15 [12 to 17] years, median [IQR] MMSE score: 29 [28 to 30]). There were no observed differences between amyloid-positive and amyloid-negative patients in the median (IQR) HADS Anxiety (–1.0 [–3.0 to 1.8] vs –2.0 [–4.8 to 1.0]; P  = .06) and Depression (–1.0 [–2.0 to 0.0] vs –1.0 [–3.0 to 0.0] ; P  = .46) deltas (score after disclosure – scores at baseline). In patients with amyloid-positive SCD+, despite the small sample size, higher education was associated with lower disclosure-related distress (ρ = –0.43; P  = .02) whereas the presence of study partner was associated with higher disclosure-related distress ( W  = 7.5; P  = .03). No participants with amyloid-positive SCD+ showed probable presence of PTSD or severe anxiety or depression symptoms at follow-up. Conclusions and Relevance The disclosure of a positive amyloid-PET result to patients with SCD+ was associated with a bigger psychological change, yet such change did not reach the threshold for clinical concern.
    Type of Medium: Online Resource
    ISSN: 2574-3805
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    detail.hit.zdb_id: 2931249-8
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  • 3
    In: Brain Connectivity, Mary Ann Liebert Inc, Vol. 13, No. 5 ( 2023-06-01), p. 287-296
    Type of Medium: Online Resource
    ISSN: 2158-0014 , 2158-0022
    Language: English
    Publisher: Mary Ann Liebert Inc
    Publication Date: 2023
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  • 4
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: The recent development of positron emission tomography (PET) radiotracers for tau aggregates allows visualizing tau pathology in vivo . The aim of this study was to investigate the associations between regional tau‐PET binding, measured using [18F]‐MK6240, a promising second‐generation tau‐PET tracer, and clinical and cognitive outcomes. Method 125 participants were recruited between June 2019 and April 2022 at the Memory Clinic of Saint‐Luc University Hospital. Each participant underwent [ F18]‐MK6240 tau‐PET, MRI, cognitive assessment, and either lumbar punction or [F18] ‐Flutemetamol amyloid‐PET. A visual read of tau‐PET images was performed according to the Braak stage classification. Tau‐PET imaging data were also quantitatively processed using PMOD‐Neuro tools and Freesurfer. Cognition was assessed using four composite scores evaluating memory, language, executive and visuospatial functions. Result Braak 0 visual reads included 12 cognitively unimpaired, 7 SCI, 5 MCI due to AD (MCI AD), and 7 non‐AD patients (Fig.1). The number of MCI AD cases ranged from Braak 0 to Braak 5 categories, while the number of patients with AD dementia ranged from Braak 4 to Braak 6. Only 3 non‐AD cases had positive scans (1 APP Aβ‐, 1 FTLD, 1 PART). On average, in Braak 0‐2 cases, all cognitive composite scores were in the normal range (Fig.2). In Braak 3‐4 cases, only episodic memory was impaired, while in Braak 5‐6 cases all cognitive domains were impaired. Conclusion Visual Braak staging of [ F18]‐MK6240 PET images match es clinical diagnosis of MCI, AD dementia and non‐AD dementia. Moreover, cases with neocortical temporal uptake (Braak 3‐4) accordingly presented isolated episodic memory, while cases with extensive neocortical uptake (Braak 5‐6) were impaired in almost all cognitive domains. Correlational analyses are currently ongoing to test whether the associations between regional tau burden and cognitive scores map onto established brain‐behavior relationships.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 5
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: Brain function can be assessed using both resting‐state functional magnetic resonance imaging (rs‐fMRI) and Fluorodeoxyglucose (FDG) PET imaging. The associations between these biomarkers and their evolution with Alzheimer’s disease (AD) are unclear. We aimed to evaluate the associations between the default mode network (DMN) connectivity and glucose metabolism in mild cognitive impairment (MCI) patients with (Aβ + ) and without (Aβ ‐ ) AD pathology. Method Forty MCI patients (19 Aβ ‐ /21 Aβ + ) performed between 2 to 4 rs‐fMRI acquisitions with an average follow‐up duration of 15 months. At baseline, DMN metabolism was estimated using [18F]‐FDG‐PET SUVr of the isthmus cingulate region‐of‐interest extracted from the Desikan‐Killiany atlas; and Aβ was measured using [18F] ‐Flutemetamol‐PET. We used a Centiloid‐threshold 〉 26 to define Aβ + . Multiple regressions were used to assess the FDG‐fMRI associations in the DMN, comparing the two subgroups using FDG‐Aβ interaction models. Table 1 provides demographics and follow‐up durations. All analyses were adjusted for age and sex. Results In the entire sample, DMN connectivity and metabolism were not significantly associated to each other. However, we observed an interaction between Aβ status and FDG metabolism (0.23, p=0.03) such that, in the high‐Aβ subgroup, lower FDG metabolism was signiticantly associated with lower DMN connectivity (Fig. 1). In the low‐Aβ subgroup, no associations were observed. We also observed an FDG‐Aβ interaction when predicting longitudinal changes in DMN (‐0.27, p=0.04) such that, in the high‐Aβ subgroup, lower FDG metabolism was associated with a subsequent increase in DMN connectivity over time (Fig. 2). Conclusion In high‐Aβ MCI patients, DMN connectivity is positively associated with FDG metabolism measured at baseline. However, the longitudinal association is negative with lower metabolism predicting increasing connectivity over time. Future research is needed to understand the mechanisms behind this inverse relationship. Hypothetically, a synchronous decrease in metabolism in several regions of the DMN could lead to an increase in the correlation between resting‐state activity measured in these regions.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 6
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
    Abstract: Patients with mild cognitive impairment (MCI) are at‐risk of progression to Alzheimer’s dementia (AD), particularly if they have elevated amyloid (Aβ), the hallmark pathology of AD. However, a proportion of Aβ‐negative MCI also progress to dementia in clinical practice. We sought to investigate (1) whether subthreshold Aβ load, brain metabolism, or atrophy could predict progression to dementia in patients with Aβ‐negative MCI, and (2) whether the regional pattern was distinct from patients with Aβ‐positive MCI. Method Seventy‐nine older adults underwent [18F]‐FDG‐PET to estimate their brain metabolism, [18F] ‐Flutemetamol‐PET to assess their Aβ load, and 3D‐T1 MRI. Aβ load was expressed in Centiloids and a threshold of 43 corresponding to visual assessment was used to define Aβ positivity. FDG data were expressed as Standardized Uptake Value ratios (SUVr) scaled on pons with partial volume correction. MRI‐PET co‐registration was performed with PetSurfer. Eight Aβ‐negative MCI progressed to dementia after four years. We compared their FDG and thicknesses maps to 25 Aβ‐negative normal older adults, 31 Aβ‐negative stable MCI, and 15 Aβ‐positive MCI who also progressed to AD dementia after four years. Demographics and follow‐up durations are provided in Table1. Result Subthreshold Aβ did not predict progression to dementia among Aβ‐negative MCI (p=0.81). Vertex‐wise analyses highlighted temporo‐parietal hypometabolism in the Aβ‐negative MCI who progressed to dementia, compared to stable Aβ‐negative controls (Fig. 1), and to a lesser extent compared to stable Aβ‐negative MCI patients (Fig. 2). However, their cerebral metabolism was similar to the one observed in Aβ‐positive MCI (Fig.3). Finally, the regional pattern of cortical thinning in progressive Aβ‐negative MCI was less typical of AD (Fig.4). Adjusting for age, sex, e4 status, or Aβ did not modify these observations. Conclusion Temporoparietal FDG predicts subsequent dementia in Aβ‐negative MCI patients, suggesting a close association with clinical progression. The FDG regional pattern is however not specific of Aβ pathophysiology.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 7
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    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: MK‐6240 is a promising second‐generation tau‐positron emission tomography (PET) tracer for evaluation of cerebral tauopathy in patients with and without cognitive impairment. To further validate the use of MK‐6240 in Memory Clinics, we aimed to evaluate the association between MK‐6240 PET results and well‐validated cerebrospinal fluid (CSF) tau and amyloid protein quantifications. Method We acquired MK‐6240 tau‐PET and 3D‐T1 MRI in 44 patients attending our Memory Clinic who accepted lumbar puncture. PET data were processed using PMOD 4.1 Neuro tool: we created three clusters of brain segments based on Braak pathological stages (1‐2; 3‐4 and 5‐6). Standardized uptake value ratio (SUVr) measures were calculated without partial volume correction for these three regions, using cerebellar grey matter as region of reference. SUVr measures in the three regions were correlated to CSF measures of total tau, phospho‐tau 181 (P‐tau) and amyloid (Aβ42) proteins. Linear regressions were calculated for each pair of data. Result Table 1 provides the characteristics of the participants, as well as CSF and PET data. Fig. 1‐3 provides illustrative cases. We observed that SUVr significantly correlated with total (t‐tau) and P‐tau levels for each of the three Braak regions, but best correlated for the Braak 3‐4 region (t‐tau: r 2 =0.184; p=0.004 and p‐tau: r 2 =0.227; p=0.001, see Fig. 4). Only the Braak 1‐2 SUVr significantly correlated with CSF Aβ42 levels (r 2 =0.121; p=0.021, Fig. 4, line 3). The SUVr thresholds who best discriminate between CSF t‐tau positive and negative cases (based on our clinical threshold of 381pg/ml) were respectively: 1.54 SUVr (Braak1‐2), 1.35SUVr (Braak3‐4), 1.17SUVr (Braak5‐6). Conclusion Amyloid CSF levels only correlated with tau‐PET signal in the Braak 1‐2 region, suggesting an association between these two early pathological processes. In contrast, total and phosphorylated tau CSF levels best correlated with tau‐PET signal in the Braak 3‐4 region, suggesting that tau pathology has to reach the temporal neocortex prior to elevate a “global” tau‐measure such as the one measured in the CSF.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 8
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 48, No. 1 ( 2021-01), p. 302-310
    Abstract: To evaluate cerebral amyloid-β(Aβ) pathology in older adults with cognitive complaints, visual assessment of PET images is approved as the routine method for image interpretation. In research studies however, Aβ-PET semi-quantitative measures are associated with greater risk of progression to dementia; but until recently, these measures lacked standardization. Therefore, the Centiloid scale, providing standardized Aβ-PET semi-quantitation, was recently validated. We aimed to determine the predictive values of visual assessments and Centiloids in non-demented patients, using long-term progression to dementia as our standard of truth. Methods One hundred sixty non-demented participants (age, 54–86) were enrolled in a monocentric [ 18 F] flutemetamol Aβ-PET study. Flutemetamol images were interpreted visually following the manufacturers recommendations. SUVr values were converted to the Centiloid scale using the GAAIN guidelines. Ninety-eight persons were followed until dementia diagnosis or were clinically stable for a median of 6 years (min = 4.0; max = 8.0). Twenty-five patients with short follow-up (median = 2.0 years; min = 0.8; max = 3.9) and 37 patients with no follow-up were excluded. We computed ROC curves predicting subsequent dementia using baseline PET data and calculated negative (NPV) and positive (PPV) predictive values. Results In the 98 participants with long follow-up, Centiloid = 26 provided the highest overall predictive value = 87% (NPV = 85%, PPV = 88%). Visual assessment corresponded to Centiloid = 40, which predicted dementia with an overall predictive value = 86% (NPV = 81%, PPV = 92%). Inclusion of the 25 patients who only had a 2-year follow-up decreased the PPV = 67% (NPV = 88%), reflecting the many positive cases that did not progress to dementia after short follow-ups. Conclusion A Centiloid threshold = 26 optimally predicts progression to dementia 6 years after PET. Visual assessment provides similar predictive value, with higher specificity and lower sensitivity. Trial registration Eudra-CT number: 2011-001756-12
    Type of Medium: Online Resource
    ISSN: 1619-7070 , 1619-7089
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2098375-X
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  • 9
    In: Frontiers in Neuroscience, Frontiers Media SA, Vol. 13 ( 2019)
    Type of Medium: Online Resource
    ISSN: 1662-453X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2411902-7
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  • 10
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Few resting‐state functional magnetic resonance imaging (rs‐fMRI) studies were carried out in patients with mild cognitive impairment (MCI). Most were cross‐sectional and brought conflicting results with both decrease and increase of rs‐fMRI connectivity reported. We used a recently developed atlas of resting‐state networks specific for late adulthood to investigate longitudinal changes in rs‐fMRI in MCI patients, both within and between networks. Method Sixty older adults underwent rs‐fMRI using the Atlas55+ [1] to assess intra and inter‐network functional connectivity and a baseline [18F]‐Flutemetamol‐PET to estimate their Amyloid‐β (Aβ) load. Sixteen stable Aβ‐negative clinically normal volunteers performed a baseline rs‐fMRI scan while 44 MCI patients performed 2 to 4 acquisitions with an average follow‐up duration of 14,5 months. Aβ was expressed in Centiloids and a threshold of 27 was used to define Aβ positivity based on previous work [2] . Intra and inter‐network functional connectivity analyses were performed using both progression to dementia and Aβ status as grouping variables. Demographics and follow‐up durations are provided in Table 1. Linear mixed‐models with random intercept and slope predicted changes in rs‐fMRI over time, adjusting for age, sex, education and e4 status. Result We observed that MCI patients who progressed to dementia during follow‐up had increased intra‐network connectivity over time, compared to stable MCI. Specifically, the time‐by‐outcome (progression vs stable) interaction for the intra‐network functional connectivity in the default‐mode, the executive control and the visual networks were significant (Fig. 1‐3). Similar results were found when limiting analyses to Aβ positive MCI and adjusting for volume effects, except for the visual network. Baseline intra‐network functional connectivity did not differ between groups (all p‐values 〉 0,05). Inter‐network functional connectivity did not change between groups over time (all p 〉 0,05). Conclusion In Alzheimer's Disease, intra‐network functional connectivity increases during the progression of MCI to dementia compared to stable MCI. References:1. Doucet, Gaelle E et al. Cereb Cortex . 2021;31(3):1719‐1731. doi:10.1093/cercor/bhaa321. 2. Hanseeuw, Bernard J et al. Eur J Nucl Med Mol Imaging. 2021;48(1):302‐310. doi:10.1007/s00259‐020‐04942‐4.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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