Computerized decision support is an effective approach to select memory clinic patients for amyloid-PET

Background: The use of amyloid-PET in dementia workup is upcoming. At the same time, amyloid-PET is costly and limitedly available. While the appropriate use criteria (AUC) aim for optimal use of amyloid-PET, their limited sensitivity hinders the translation to clinical practice. Therefore, there is a need for tools that guide selection of patients for whom amyloid-PET has the most clinical utility. We aimed to develop a computerized decision support approach to select patients for amyloid-PET. // Methods: We included 286 subjects (135 controls, 108 Alzheimer’s disease dementia, 33 frontotemporal lobe dementia, and 10 vascular dementia) from the Amsterdam Dementia Cohort, with available neuropsychology, APOE, MRI and [18F]florbetaben amyloid-PET. In our computerized decision support approach, using supervised machine learning based on the DSI classifier, we first classified the subjects using only neuropsychology, APOE, and quantified MRI. Then, for subjects with uncertain classification (probability of correct class (PCC) < 0.75) we enriched classification by adding (hypothetical) amyloid positive (AD-like) and negative (normal) PET visual read results and assessed whether the diagnosis became more certain in at least one scenario (PPC≥0.75). If this was the case, the actual visual read result was used in the final classification. We compared the proportion of PET scans and patients diagnosed with sufficient certainty in the computerized approach with three scenarios: 1) without amyloid-PET, 2) amyloid-PET according to the AUC, and 3) amyloid-PET for all patients. // Results: The computerized approach advised PET in n = 60(21%) patients, leading to a diagnosis with sufficient certainty in n = 188(66%) patients. This approach was more efficient than the other three scenarios: 1) without amyloid-PET, diagnostic classification was obtained in n = 155(54%), 2) applying the AUC resulted in amyloid-PET in n = 113(40%) and diagnostic classification in n = 156(55%), and 3) performing amyloid-PET in all resulted in diagnostic classification in n = 154(54%). // Conclusion: Our computerized data-driven approach selected 21% of memory clinic patients for amyloid-PET, without compromising diagnostic performance. Our work contributes to a cost-effective implementation and could support clinicians in making a balanced decision in ordering additional amyloid PET during the dementia workup

Alzheimers Dement

INTRODUCTION: Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death. METHODS: Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento). RESULTS: Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years. DISCUSSION: Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis

Clinical Effect of Early vs Late Amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS Randomized Clinical Trial

IMPORTANCE: 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 < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .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

Lower cerebral blood flow in subjects with Alzheimer's dementia, mild cognitive impairment, and subjective cognitive decline using two-dimensional phase-contrast magnetic resonance imaging

Introduction In this cross-sectional study, we aimed to detect differences in cerebral blood flow (CBF) between subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD), using two-dimensional phase-contrast magnetic resonance imaging. Methods We included 74 AD patients (67 years, 51% female), 36 MCI patients (66 years, 33% female), and 62 patients with SCD (60 years, 32% female) from the Amsterdam Dementia Cohort. Patients with SCD are those who visited the memory clinic with subjective cognitive complaints without objective cognitive impairment. Whole-brain CBF (mL/100 g/min) was calculated using total volume flow measured with two-dimensional phase-contrast magnetic resonance imaging and normalized for brain volume. Results Mean CBF values (SD) were lower in AD compared to SCD (age and sex adjusted 70 ± 26 vs. 82 ± 24 mL/100 g/min, P <.05). Mean CBF values of MCI were comparable to AD. Across clinical groups, lower CBF was associated with lower scores on the Mini–Mental State Examination (age and sex adjusted stβ = 0.19 per mL/100 g/min; P =.02). Discussion Lower whole-brain CBF is seen in AD patients compared to SCD patients and is associated with worse cognitive function

Steeper memory decline after COVID-19 lockdown measures

BACKGROUND: During COVID-19 lockdown measures, memory clinic patients reported worries for faster cognitive decline, due to loss of structure and feelings of loneliness and depression. We aimed to investigate the impact of the COVID-19 lockdown on rate of cognitive decline in a mixed memory clinic population, compared to matched historical controls. METHODS: We included patients who visited Alzheimer Center Amsterdam 6 months to 1 week before the first Dutch COVID-19 lockdown, and had a second visit 1 year later, after this lockdown period (n = 113; 66 ± 7 years old; 30% female; n = 55 dementia, n = 31 mild cognitive impairment (MCI), n = 18 subjective cognitive decline (SCD), n = 9 postponed diagnosis). Historical controls (visit in 2016/2017 and second visit 1 year later (n = 640)) were matched 1:1 to lockdown patients by optimal Mahalanobis distance matching (both groups n = 113). Groups were well matched. Differences between lockdown patients and historical controls over time in Mini-Mental State Examination, Trail Making Test part A and B, Rey-Auditory Verbal Learning Test (RAVLT) immediate and delayed recall, and category fluency scores were analyzed using linear mixed effect models with random intercepts. We examined differences in rate of cognitive decline between whole groups, and after stratification in SCD, MCI, and dementia separately. RESULTS: Lockdown patients had a faster rate of memory decline compared to controls on both RAVLT immediate [B(SE) =  - 2.62 (1.07), p = 0.015] and delayed recall [B(SE) =  - 1.07 (0.34), p = 0.002]. Stratification by syndrome diagnosis showed that this effect was largely attributable to non-demented participants, as we observed faster memory decline during lockdown in SCD and MCI (RAVLT immediate [SCD: B(SE) =  - 6.85 (2.97), p = 0.027; MCI: B(SE) =  - 6.14 (1.78), p = 0.001] and delayed recall [SCD: B(SE) =  - 2.45 (1.11), p = 0.035; MCI: B(SE) =  - 1.50 (0.51), p = 0.005]), but not in dementia. CONCLUSION: Memory clinic patients, specifically in pre-dementia stages, showed faster memory decline during COVID-19 lockdown, providing evidence that lockdown regulations had a deleterious effect on brain health. In individuals that may have been able to deal with accumulating, subclinical neuropathology under normal and structured circumstances, the additional stress of lockdown regulations may have acted as a "second hit," resulting in less beneficial disease trajectory

ABIDE Delphi study: Topics to discuss in diagnostic consultations in memory clinics

Background: Information given to patients and caregivers during the clinician-patient encounter varies considerably between memory clinic professionals. Patients and caregivers express a clear desire for more information. It is unclear what information patients and caregivers value most during the diagnostic process and whether this is concordant with professionals' opinion. We aimed to identify a topic list on which health care professionals, patients, and caregivers agree that these should be discussed during diagnostic consultations in memory clinics. Further, we aimed to establish the optimal moment for each topic to be discussed during the diagnostic process. Methods: We performed a three-round Delphi consensus study. Professionals (N = 80), patients (N = 66), and caregivers (N = 76) rated the importance of 44 informative topics through an online questionnaire. Consensus was defined as a topic rating of 6 or 7 on a 7-point Likert scale by ≥ 75% of each panel. In round 2 and 3, a survey was added to identify the optimal moment during the diagnostic process to discuss each topic. Results: By round 3, consensus was achieved on 17 topics divided into four categories, information about (1) diagnostic testing, (2) test results, (3) diagnosis, and (4) practical implications. Eight additional topics showed significant differences between panels. Most notable panel differences regard the risk for developing dementia and the distinction between Alzheimer's disease and dementia, which patients and caregivers evaluated as more important compared to professionals. The optimal moment to discuss topics during the diagnostic process was identified for the 17 core topics, and the eight topics with significant differences. Conclusions: We present a core list of informative topics, which professionals, patients, and caregivers agree they should be discussed during the diagnostic process in a memory clinic. The topic list can support professionals and empower patients and caregivers during diagnostic physician-patient consultations

Biomarker testing in MCI patients—deciding who to test

Background: We aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value. Methods: MCI patients were selected from the Amsterdam Dementia Cohort (n = 402). Three-year progression probabilities to dementia were predicted using previously published models with and without CSF data (amyloid-beta1-42 (Abeta), phosphorylated tau (p-tau)). We incrementally augmented the proportion of patients undergoing CSF, starting with the 10% patients with prognostic probabilities based on clinical data around the median (percentile 45–55), until all patients received CSF. The optimal proportion was defined as the proportion where the stepwise algorithm showed similar prognostic discrimination (Harrell’s C) and accuracy (three-year Brier scores) compared to CSF testing of all patients. We used the BioFINDER study (n = 221) for validation. Results: The optimal proportion of MCI patients to receive CSF testing selected by the stepwise approach was 50%. CSF testing in only this proportion improved the performance of the model with clinical data only from Harrell’s C = 0.60, Brier = 0.198 (Harrell’s C = 0.61, Brier = 0.197 if the information on magnetic resonance imaging was available) to Harrell’s C = 0.67 and Brier = 0.190, and performed similarly to a model in which all patients received CSF testing. Applying the stepwise approach in the BioFINDER study would again select half of the MCI patients and yielded robust results with respect to prognostic performance. Interpretation: CSF biomarker testing adds prognostic value in half of the MCI patients. As such, we achieve a CSF saving recommendation while simultaneously retaining optimal prognostic accuracy

Life satisfaction across the entire trajectory of Alzheimer's disease: A mediation analysis

Introduction: We studied life satisfaction across Alzheimer's disease (AD) stages and studied mobility and meaningful activities as mediators of the associations between these AD stages and life satisfaction. Methods: In this cross-sectional study, we included n = 269 amyloid-positive patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD dementia from the Amsterdam Dementia Cohort. Life satisfaction was measured with the satisfaction with life scale. The mediating role of transportation, work, sports, and hobbies on life satisfaction was examined in single and multiple mediator models. Results: Patients with dementia are less satisfied with life compared to SCD and MCI. These differences in life satisfaction are explained by reduced participation in meaningful activities, which in turn, was largely attributable to decreased transportation use. Discussion: Our findings suggest that improving access to transportation, therewith allowing participation in meaningful activities help to maintain life satisfaction and may be an important target for intervention

A more precise diagnosis by means of amyloid PET contributes to delayed institutionalization, lower mortality, and reduced care costs in a tertiary memory clinic setting

Introduction: We aim to study the effect of a more precise diagnosis, by means of amyloid positron emission tomography (PET), on institutionalization, mortality, and health-care costs. Methods: Between October 27, 2014 and December 31, 2016, we offered amyloid PET to all patients as part of their diagnostic work-up. Patients who accepted to undergo amyloid PET (n = 449) were propensity score matched with patients without amyloid PET (n = 571, i.e., no PET). Matched groups (both n = 444) were compared on rate of institutionalization, mortality, and health-care costs in the years after diagnosis. Results: Amyloid PET patients had a lower risk of institutionalization (10% [n = 45] vs. 21% [n = 92]; hazard ratio [HR] = 0.48 [0.33–0.70]) and mortality rate (11% [n = 49] vs. 18% [n = 81]; HR = 0.51 [0.36–0.73]) and lower health-care costs in the years after diagnosis compared to matched no-PET patients (β = −4573.49 [−6524.76 to −2523.74], P-value < 0.001). Discussion: A more precise diagnosis in tertiary memory clinic patients positively influenced the endpoints of institutionalization, death, and health-care costs

A more precise diagnosis by means of amyloid PET contributes to delayed institutionalization, lower mortality, and reduced care costs in a tertiary memory clinic setting

INTRODUCTION: We aim to study the effect of a more precise diagnosis, by means of amyloid positron emission tomography (PET), on institutionalization, mortality, and health-care costs. METHODS: Between October 27, 2014 and December 31, 2016, we offered amyloid PET to all patients as part of their diagnostic work-up. Patients who accepted to undergo amyloid PET (n = 449) were propensity score matched with patients without amyloid PET (n = 571, i.e., no PET). Matched groups (both n = 444) were compared on rate of institutionalization, mortality, and health-care costs in the years after diagnosis. RESULTS: Amyloid PET patients had a lower risk of institutionalization (10% [n = 45] vs. 21% [n = 92]; hazard ratio [HR] = 0.48 [0.33-0.70]) and mortality rate (11% [n = 49] vs. 18% [n = 81]; HR = 0.51 [0.36-0.73]) and lower health-care costs in the years after diagnosis compared to matched no-PET patients (β = -4573.49 [-6524.76 to -2523.74], P-value < 0.001). DISCUSSION: A more precise diagnosis in tertiary memory clinic patients positively influenced the endpoints of institutionalization, death, and health-care costs