Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline.

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (ß=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (ß=0.006, p < 0.01) and global tau SUVR (ß=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients.

BACKGROUND: Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient persons at-risk of dementia. Plasma biomarkers have been shown to be highly correlated with traditional imaging biomarkers. However, their comparative predictive value versus traditional AD biomarkers is still unclear in cognitively unimpaired (CU) subjects and with mild cognitive impairment (MCI). METHODS: Plasma (Aß42/40, p-tau181, p-tau231, NfL, and GFAP) and neuroimaging (hippocampal volume, centiloid of amyloid-PET, and tau-SUVR of tau-PET) biomarkers were assessed at baseline in 218 non-demented subjects (CU = 140; MCI = 78) from the Geneva Memory Center. Global cognition (MMSE) was evaluated at baseline and at follow-ups up to 5.7 years. We used linear mixed-effects models and Cox proportional-hazards regression to assess the association between biomarkers and cognitive decline. Lastly, sample size calculations using the linear mixed-effects models were performed on subjects positive for amyloid-PET combined with tau-PET and plasma biomarker positivity. RESULTS: Cognitive decline was significantly predicted in MCI by baseline plasma NfL (ß=-0.55), GFAP (ß=-0.36), hippocampal volume (ß = 0.44), centiloid (ß=-0.38), and tau-SUVR (ß=-0.66) (all p < 0.05). Subgroup analysis with amyloid-positive MCI participants also showed that only NfL and GFAP were the only significant predictors of cognitive decline among plasma biomarkers. Overall, NfL and tau-SUVR showed the highest prognostic values (hazard ratios of 7.3 and 5.9). Lastly, we demonstrated that adding NfL to the inclusion criteria could reduce the sample sizes of future AD clinical trials by up to one-fourth in subjects with amyloid-PET positivity or by half in subjects with amyloid-PET and tau-PET positivity. CONCLUSIONS: Plasma NfL and GFAP predict cognitive decline in a similar manner to traditional imaging techniques in amyloid-positive MCI patients. Hence, even though they are non-specific biomarkers of AD, both can be implemented in memory clinic workups as important prognostic biomarkers. Likewise, future clinical trials might employ plasma biomarkers as additional inclusion criteria to stratify patients at higher risk of cognitive decline to reduce sample sizes and enhance effectiveness.

The Taxonomy of Subjective Cognitive Decline: Proposal and First Clinical Evidence from the Geneva Memory Clinic Cohort.

INTRODUCTION: Subjective cognitive decline (SCD) is characterized by subjective cognitive concerns without objective cognitive impairment and is considered a risk factor for cognitive decline and dementia. However, most SCD patients will not develop neurodegenerative disorders, yet they may suffer from minor psychiatric, neurological, or somatic comorbidities. The aim of the present study was to provide a taxonomy of the heterogeneous SCD entity and to conduct a preliminary validation using data from a memory clinic sample. METHODS: Participants were fifty-five SCD individuals consecutively recruited at the Geneva Memory Center. Based on clinical reports, they were classified into three clinically pre-defined subgroups: (i) those with psychological or psychiatric comorbidities (Psy), (ii) those with somatic comorbidities (SomCom), (iii) and those with no apparent cause (NAC). Baseline demographics, clinical, cognitive, and biomarker differences among the SCD subgroups were assessed. Longitudinal cognitive changes (average 3 years follow-up) were modeled using a linear mixed model. RESULTS: Out of the 55 SCD cases, 16 were SomCom, 18 Psy, and 21 NAC. 47% were female, mean age was 71 years. We observed higher frequency of APOE ε4 carriers in NAC (53%) compared to SomCom (14%) and Psy (0%, p = 0.023) and lower level of plasma Aß42 in NAC (6.8 ± 1.0) compared to SomCom (8.4 ± 1.1; p = 0.031). SomCom subjects were older (74 years) than Psy (67 years, p = 0.011), and had greater medial temporal lobe atrophy (1.0 ± 1.0) than Psy (0.2 ± 0.6) and NAC (0.4 ± 0.5, p = 0.005). SomCom has worse episodic memory performances (14.5 ± 3.5) than Psy (15.8 ± 0.4) and NAC (15.8 ± 0.7, p = 0.032). We observed a slightly steeper, yet not statistically significant, cognitive decline in NAC (ß = -0.48) compared to Psy (ß = -0.28) and SomCom (ß = -0.24). CONCLUSIONS: NAC features a higher proportion of APOE ε4 carriers, lower plasma Aß42 and a trend towards steeper cognitive decline than SomCom and Psy. Taken together, these findings suggest that NACs are at higher risk of cognitive decline due to AD. The proposed clinical taxonomy might be implemented in clinical practice to identify SCD at higher risk. However, such taxonomy should be tested on an independent cohort with a larger sample size.

Neuroimaging-guided diagnosis of possible FTLD-FUS pathology: a case report.

BACKGROUND: This case report presents a patient with progressive memory loss and choreiform movements. CASE PRESENTATION: Neuropsychological tests indicated multi-domain amnestic mild cognitive impairment (aMCI), and neurological examination revealed asymmetrical involuntary hyperkinetic movements. Imaging studies showed severe left-sided atrophy and hypometabolism in the left frontal and temporoparietal cortex. [18F]Flortaucipir PET exhibited moderately increased tracer uptake in hypometabolic areas. The diagnosis initially considered Alzheimer's disease (AD), frontotemporal degeneration (FTD), and corticobasal degeneration (CBD), cerebral hemiatrophy syndrome, but imaging and cerebrospinal fluid analysis excluded AD and suggested fused-in-sarcoma-associated FTD (FTLD-FUS), a subtype of the behavioural variant of FTD. CONCLUSIONS: Our case highlights that despite the lack of specific FUS biomarkers the combination of clinical features and neuroimaging biomarkers can guide choosing the most likely differential diagnosis in a complex neurological case. Imaging in particular allowed an accurate measure of the topography and severity of neurodegeneration and the exclusion of AD-related pathology.

Validating the accuracy of deep learning for the diagnosis of pneumonia on chest x-ray against a robust multimodal reference diagnosis: a post hoc analysis of two prospective studies.

BACKGROUND: Artificial intelligence (AI) seems promising in diagnosing pneumonia on chest x-rays (CXR), but deep learning (DL) algorithms have primarily been compared with radiologists, whose diagnosis can be not completely accurate. Therefore, we evaluated the accuracy of DL in diagnosing pneumonia on CXR using a more robust reference diagnosis. METHODS: We trained a DL convolutional neural network model to diagnose pneumonia and evaluated its accuracy in two prospective pneumonia cohorts including 430 patients, for whom the reference diagnosis was determined a posteriori by a multidisciplinary expert panel using multimodal data. The performance of the DL model was compared with that of senior radiologists and emergency physicians reviewing CXRs and that of radiologists reviewing computed tomography (CT) performed concomitantly. RESULTS: Radiologists and DL showed a similar accuracy on CXR for both cohorts (p ≥ 0.269): cohort 1, radiologist 1 75.5% (95% confidence interval 69.1-80.9), radiologist 2 71.0% (64.4-76.8), DL 71.0% (64.4-76.8); cohort 2, radiologist 70.9% (64.7-76.4), DL 72.6% (66.5-78.0). The accuracy of radiologists and DL was significantly higher (p ≤ 0.022) than that of emergency physicians (cohort 1 64.0% [57.1-70.3], cohort 2 63.0% [55.6-69.0]). Accuracy was significantly higher for CT (cohort 1 79.0% [72.8-84.1], cohort 2 89.6% [84.9-92.9]) than for CXR readers including radiologists, clinicians, and DL (all p-values < 0.001). CONCLUSIONS: When compared with a robust reference diagnosis, the performance of AI models to identify pneumonia on CXRs was inferior than previously reported but similar to that of radiologists and better than that of emergency physicians. RELEVANCE STATEMENT: The clinical relevance of AI models for pneumonia diagnosis may have been overestimated. AI models should be benchmarked against robust reference multimodal diagnosis to avoid overestimating its performance. TRIAL REGISTRATION: NCT02467192 , and NCT01574066 . KEY POINT: • We evaluated an openly-access convolutional neural network (CNN) model to diagnose pneumonia on CXRs. • CNN was validated against a strong multimodal reference diagnosis. • In our study, the CNN performance (area under the receiver operating characteristics curve 0.74) was lower than that previously reported when validated against radiologists' diagnosis (0.99 in a recent meta-analysis). • The CNN performance was significantly higher than emergency physicians' (p ≤ 0.022) and comparable to that of board-certified radiologists (p ≥ 0.269).

Insights into single-timepoint ASL hemodynamics: what visual assessment and spatial coefficient of variation can tell.

PURPOSE: Arterial spin labeling (ASL) represents a noninvasive perfusion biomarker, and, in the study of nonvascular disease, the use of the single-timepoint ASL technique is recommended. However, the obtained cerebral blood flow (CBF) maps may be highly influenced by delayed arterial transit time (ATT). Our aim was to assess the complexity of hemodynamic information of single-timepoint CBF maps using a new visual scale and comparing it with an ATT proxy, the "coefficient of spatial variation" (sCoV). MATERIAL AND METHODS: Individual CBF maps were estimated in a memory clinic population (mild cognitive impairment, dementia and cognitively unimpaired controls) and classified into four levels of delayed perfusion based on a visual rating scale. Calculated measures included global/regional sCoVs and common CBF statistics, as mean, median and standard deviation. One-way ANOVA was performed to compare these measures across the four groups of delayed perfusion. Spearman correlation was used to study the association of global sCoV with clinical data and CBF statistics. RESULTS: One hundred and forty-four participants (72 ± 7 years, 53% women) were included in the study. The proportion of maps with none, mild, moderate, and severe delayed perfusion was 15, 20, 37, and 28%, respectively. SCoV demonstrated a significant increase (p < 0.05) across the four groups, except when comparing none vs mild delayed perfusion groups (pBonf > 0.05). Global sCoV values, as an ATT proxy, ranged from 67 ± 4% (none) to 121 ± 24% (severe delayed) and were significantly associated with age and CBF statistics (p < 0.05). CONCLUSION: The impact of ATT delay in single-time CBF maps requires the use of a visual scale or sCoV in clinical or research settings.

A comparison of visual assessment and semi-quantification for the diagnostic and prognostic use of [18F]flortaucipir PET in a memory clinic cohort.

PURPOSE: [18F]Flortaucipir PET is a powerful diagnostic and prognostic tool for Alzheimer's disease (AD). Tau status definition is mainly based in the literature on semi-quantitative measures while in clinical settings visual assessment is usually preferred. We compared visual assessment with established semi-quantitative measures to classify subjects and predict the risk of cognitive decline in a memory clinic population. METHODS: We included 245 individuals from the Geneva Memory Clinic who underwent [18F]flortaucipir PET. Amyloid status was available for 207 individuals and clinical follow-up for 135. All scans were blindly evaluated by three independent raters who visually classified the scans according to Braak stages. Standardized uptake value ratio (SUVR) values were obtained from a global meta-ROI to define tau positivity, and the Simplified Temporo-Occipital Classification (STOC) was applied to obtain semi-quantitatively tau stages. The agreement between measures was tested using Cohen's kappa (k). ROC analysis and linear mixed-effects models were applied to test the diagnostic and prognostic values of tau status and stages obtained with the visual and semi-quantitative approaches. RESULTS: We found good inter-rater reliability in the visual interpretation of tau Braak stages, independently from the rater's expertise (k>0.68, p<0.01). A good agreement was equally found between visual and SUVR-based classifications for tau status (k=0.67, p<0.01). All tau-assessment modalities significantly discriminated amyloid-positive MCI and demented subjects from others (AUC>0.80) and amyloid-positive from negative subjects (AUC>0.85). Linear mixed-effect models showed that tau-positive individuals presented a significantly faster cognitive decline than the tau-negative group (p<0.01), independently from the classification method. CONCLUSION: Our results show that visual assessment is reliable for defining tau status and stages in a memory clinic population. The high inter-rater reliability, the substantial agreement, and the similar diagnostic and prognostic performance of visual rating and semi-quantitative methods demonstrate that [18F]flortaucipir PET can be robustly assessed visually in clinical practice.

Head-to-head study of diagnostic accuracy of plasma and cerebrospinal fluid p-tau217 versus p-tau181 and p-tau231 in a memory clinic cohort.

BACKGROUND AND OBJECTIVE: Phosphorylated tau (p-tau) 217 has recently received attention because it seems more reliable than other p-tau variants for identifying Alzheimer's disease (AD) pathology. Thus, we aimed to compare the diagnostic accuracy of plasma and CSF p-tau217 with p-tau181 and p-tau231 in a memory clinic cohort. METHODS: The study included 114 participants (CU = 33; MCI = 67; Dementia = 14). The p-tau variants were correlated versus continuous measures of amyloid (A) and tau (T)-PET. The p-tau phospho-epitopes were assessed through: (i) effect sizes (δ) between diagnostic and A ± and T ± groups; (ii) receiver operating characteristic (ROC) analyses in A-PET and T-PET. RESULTS: The correlations between both plasma and CSF p-tau217 with A-PET and T-PET (r range 0.64-0.83) were stronger than those of p-tau181 (r range 0.44-0.79) and p-tau231 (r range 0.46-0.76). Plasma p-tau217 showed significantly higher diagnostic accuracy than p-tau181 and p-tau231 in (i) differences between diagnostic and biomarker groups (δrange: p-tau217 = 0.55-0.96; p-tau181 = 0.51-0.67; p-tau231 = 0.53-0.71); (ii) ROC curves to identify A-PET and T-PET positivity (AUCaverage: p-tau217 = 0.96; p-tau181 = 0.76; p-tau231 = 0.79). On the other hand, CSF p-tau217 (AUCaverage = 0.95) did not reveal significant differences in A-PET and T-PET AUC than p-tau181 (AUCaverage = 0.88) and p-tau231 (AUCaverage = 0.89). DISCUSSION: Plasma p-tau217 demonstrated better performance in the identification of AD pathology and clinical phenotypes in comparison with other variants of p-tau in a memory clinic cohort. Furthermore, p-tau217 had comparable performance in plasma and CSF. Our findings suggest the potential of plasma p-tau217 in the diagnosis and screening for AD, which could allow for a decreased use of invasive biomarkers in the future.

The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive decline.

INTRODUCTION: Tau and neurodegeneration strongly correlate with cognitive impairment, as compared to amyloid. However, their contribution in explaining cognition and predicting cognitive decline in memory clinics remains unclarified. METHODS: We included 94 participants with Mini-Mental State Examination (MMSE), tau positron emission tomography (PET), amyloid PET, fluorodeoxyglucose (FDG) PET, and MRI scans from Geneva Memory Center. Linear regression and mediation analyses tested the independent and combined association between biomarkers, cognitive performance, and decline. Linear mixed-effects and Cox proportional hazards models assessed biomarkers' prognostic values. RESULTS: Metabolism had the strongest association with cognition (r = 0.712; p < 0.001), followed by tau (r = -0.682; p < 0.001). Neocortical tau showed the strongest association with cognitive decline (r = -0.677; p < 0.001). Metabolism mediated the association between tau and cognition and marginally mediated the one with decline. Tau positivity represented the strongest risk factor for decline (hazard ratio = 32). DISCUSSION: Tau and neurodegeneration synergistically contribute to global cognitive impairment while tau drives decline. The tau PET superior prognostic value supports its implementation in memory clinics. HIGHLIGHTS: Hypometabolism has the strongest association with concurrent cognitive impairment. Neocortical tau pathology is the main determinant of cognitive decline over time. FDG-PET has a superior value compared to MRI as a measure of neurodegeneration. The prognostic value of tau-PET exceeded all other neuroimaging modalities.

Clinical outcomes of 3T magnetic resonance imaging-guided lumbar and sacral foraminal injections.

PURPOSE: This article evaluates the feasibility, safety, and efficacy of MRI-guided lumbar or sacral nerve root infiltration for chronic back pain. We compared the outcomes of our MRI-guided infiltrations with data from CT-guided infiltrations reported in the literature and explored the potential advantages of MRI guidance. METHOD: Forty-eight MRI-guided nerve root infiltrations were performed using a 3 T MRI machine. The optimal needle path was determined using breathhold T2-weighted sequences, and the needle was advanced under interleaved guidance based on breathhold PD-weighted images. Pain levels were assessed using a numeric rating scale (NRS) before the procedure and up to 5 months after, during follow-up. Procedure success was evaluated by comparing patients' pain levels before and after the infiltration. RESULTS: The MRI-guided infiltrations yielded pain reduction 1 week after the infiltration in 92% of cases, with an average NRS substantial change of 3.9 points. Pain reduction persisted after 5 months for 51% of procedures. No procedure-related complications occurred. The use of a 22G needle and reconstructed subtraction images from T2 FatSat sequences improved the workflow. CONCLUSION: Our study showed that MRI-guided nerve root infiltration is a feasible, safe, and effective treatment option for chronic back pain. Precise positioning of the needle tip and accurate distribution of the injected solution contributed to the effectiveness of MRI-guided infiltration, which appeared to be as accurate as CT-guided procedures. Further research is needed to explore the potential benefits of metal artifact reduction sequences to optimize chronic back pain management.

ATN profile classification across two independent prospective cohorts.

Background: The ATN model represents a research framework used to describe in subjects the presence or absence of Alzheimer's disease (AD) pathology through biomarkers. The aim of this study was to describe the prevalence of different ATN profiles using quantitative imaging biomarkers in two independent cohorts, and to evaluate the pertinence of ATN biomarkers to identify comparable populations across independent cohorts. Methods: A total of 172 subjects from the Geneva Memory Clinic and 113 volunteers from a study on healthy aging at the University Hospital of Zurich underwent amyloid (A) and tau (T) PET, as well as T1-weigthed MRI scans using site-specific protocols. Subjects were classified by cognition (cognitively unimpaired, CU, or impaired, CI) based on clinical assessment by experts. Amyloid data converted into the standardized centiloid scale, tau PET data normalized to cerebellar uptake, and hippocampal volume expressed as a ratio over total intracranial volume ratio were considered as biomarkers for A, T, and neurodegeneration (N), respectively. Positivity for each biomarker was defined based on previously published thresholds. Subjects were then classified according to the ATN model. Differences among profiles were tested using Kruskal-Wallis ANOVA, and between cohorts using Wilcoxon tests. Results: Twenty-nine percent of subjects from the Geneva cohorts were classified with a normal (A-T-N-) profile, while the Zurich cohort included 64% of subjects in the same category. Meanwhile, 63% of the Geneva and 16% of the Zurich cohort were classified within the AD continuum (being A+ regardless of other biomarkers' statuses). Within cohorts, ATN profiles were significantly different for age and mini-mental state examination scores, but not for years of education. Age was not significantly different between cohorts. In general, imaging A and T biomarkers were significantly different between cohorts, but they were no longer significantly different when stratifying the cohorts by ATN profile. N was not significantly different between cohorts. Conclusion: Stratifying subjects into ATN profiles provides comparable groups of subjects even when individual recruitment followed different criteria.

Unsupervised [18F]Flortaucipir cutoffs for tau positivity and staging in Alzheimer's disease.

PURPOSE: Several [18F]Flortaucipir cutoffs have been proposed for tau PET positivity (T+) in Alzheimer's disease (AD), but none were data-driven. The aim of this study was to establish and validate unsupervised T+ cutoffs by applying Gaussian mixture models (GMM). METHODS: Amyloid negative (A-) cognitively normal (CN) and amyloid positive (A+) AD-related dementia (ADRD) subjects from ADNI (n=269) were included. ADNI (n=475) and Geneva Memory Clinic (GMC) cohorts (n=98) were used for validation. GMM-based cutoffs were extracted for the temporal meta-ROI, and validated against previously published cutoffs and visual rating. RESULTS: GMM-based cutoffs classified less subjects as T+, mainly in the A- CN (<3.4% vs >28.5%) and A+ CN (<14.5% vs >42.9%) groups and showed higher agreement with visual rating (ICC=0.91 vs ICC<0.62) than published cutoffs. CONCLUSION: We provided reliable data-driven [18F]Flortaucipir cutoffs for in vivo T+ detection in AD. These cutoffs might be useful to select participants in clinical and research studies.

Patterns of amyloid accumulation in amyloid-negative cases.

Amyloid staging models showed that regional abnormality occurs before global positivity. Several studies assumed that the trajectory of amyloid spread is homogeneous, but clinical evidence suggests that it is highly heterogeneous. We tested whether different amyloid-ß (Aß) patterns exist by applying clustering on negative scans and investigating their demographics, clinical, cognitive, and biomarkers correlates, and cognitive trajectories. 151 individuals from Geneva and Zurich cohorts with T1-MRI, negative Aß positron emission tomography (PET,centiloid<12) and clinical assessment were included. N=123 underwent tau PET, and N=65 follow-up neuropsychological assessment. We performed k-means clustering using 33 Aß regional Standardized Uptake Vales ratio. Demographics, clinical, cognitive, and biomarkers differences were investigated. Longitudinal cognitive changes by baseline cluster status were estimated using a linear mixed model. The cluster analysis identified two clusters: temporal predominant (TP) and cingulate predominant (CP). TP tau deposition was higher than CP. A trend for a higher cognitive decline in TP compared to CP was observed. This study suggests the existence of two Aß deposition patterns in the earliest phases of Aß accumulation, differently prone to tau pathology and cognitive decline.

Prognostic value of imaging-based ATN profiles in a memory clinic cohort.

PURPOSE: The ATN model represents a research framework used to classify subjects based on the presence or absence of Alzheimer's disease (AD) pathology through biomarkers for amyloid (A), tau (T), and neurodegeneration (N). The aim of this study was to assess the relationship between ATN profiles defined through imaging and cognitive decline in a memory clinic cohort. METHODS: One hundred-eight patients from the memory clinic of Geneva University Hospitals underwent complete clinical and neuropsychological evaluation at baseline and 23 ± 5 months after inclusion, magnetic resonance imaging, amyloid and tau PET scans. ATN profiles were divided into four groups: normal, AD pathological change (AD-PC: A + T-N-, A + T-N +), AD pathology (AD-P: A + T + N-, A + T + N +), and suspected non-AD pathology (SNAP: A-T + N-, A-T-N + , A-T + N +). RESULTS: Mini-Mental State Examination (MMSE) scores were significantly different among groups, both at baseline and follow-up, with the normal group having higher average MMSE scores than the other groups. MMSE scores changed significantly after 2 years only in AD-PC and AD-P groups. AD-P profile classification also had the largest number of decliners at follow-up (55%) and the steepest global cognitive decline compared to the normal group. Cox regression showed that participants within the AD-P group had a higher risk of cognitive decline (HR = 6.15, CI = 2.59-14.59), followed by AD-PC (HR = 3.16, CI = 1.17-8.52). CONCLUSION: Of the different group classifications, AD-P was found to have the most significant effect on cognitive decline over a period of 2 years, highlighting the value of both amyloid and tau PET molecular imaging as prognostic imaging biomarkers in clinical practice.

Plasma biomarkers for Alzheimer's disease: a field-test in a memory clinic.

BACKGROUND: The key Alzheimer's disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aß42 and p-tau181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers. METHODS: Participants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months. RESULTS: Overall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up to r=0.50 (p<0.001) among amyloid, r=0.43 (p=0.002) among tau, and r=-0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers. CONCLUSION: The implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care.

The taxonomy of subjective cognitive decline: proposal and first clinical evidence from the Geneva memory clinic cohort.

Background: Subjective Cognitive Decline (SCD) is characterized by subjective cognitive complaints without objective cognitive impairment and is considered a risk factor for cognitive decline and dementia. However, most SCD patients will not develop neurodegenerative disorders, yet they may suffer from minor psychiatric, neurological, or somatic comorbidities. The aim of the present study is to provide a taxonomy of the heterogeneous SCD entity by isolating homogenous SCD subgroups with specific clinical features and cognitive trajectories. Methods: Participants were fifty-five SCD individuals consecutively recruited at the Geneva Memory Center. Based on clinical reports, they were classified into three clinically pre-defined subgroups: (i) those with psychological or psychiatric comorbidities (Psy), (ii) those with somatic comorbidities (SomCom), (iii) and those with no apparent cause (NAC). Baseline demographics, clinical, cognitive, and biomarker differences among the SCD subgroups were assessed. Longitudinal cognitive changes (average 3 years follow-up) were modeled using a linear mixed model. Results: Out of the 55 SCD cases, 16 were SomCom, 18 Psy, and 21 NAC. 47% were female, mean age was 71 years. We observed higher frequency of APOE ε4 carriers in NAC (53%) compared to SomCom (14%) and Psy (0%, P=0.023) and lower level of plasma Aß42 in NAC (6.8±1.0) compared to SomCom (8.4±1.1; P=0.031). SomCom subjects were older (74 years) than Psy (67 years, P=0.011), and had greater medial temporal lobe atrophy(1.0±1.0) than Psy (0.2±0.6) and NAC (0.4±0.5, P=0.005). SomCom have worse episodic memory performances(14.5±3.5) than Psy (15.8±0.4) and SomCom (15.1±0.7, P=0.032). We observed a slightly steeper, yet not statistically significant, cognitive decline in NAC (ß=-0.48) compared to Psy (ß=-0.28) and SomCom (ß=-0.24). Conclusions: NAC feature higher proportion of APOE ε4 carriers, lower plasma Aß42, worse memory performance, and a trend towards steeper cognitive decline than SomCom and Psy. Taken together, these findings suggest that NAC are at higher risk of cognitive decline due to AD. The proposed clinical taxonomy might be implemented in clinical practice to identify SCD at higher risk. However, such taxonomy should be tested on an independent cohort with larger sample size.

Early-phase 18F-Florbetapir and 18F-Flutemetamol images as proxies of brain metabolism in a memory clinic setting.

Background: Alzheimer's disease (AD) neuropathologic changes are ß-amyloid (Aß) deposition, pathologic tau, and neurodegeneration. Dual-phase amyloid-PET might be able to evaluate Aß deposition and neurodegeneration with a single tracer injection. Early-phase amyloid-PET scans provide a proxy for cerebral perfusion, which has shown good correlations with neural dysfunction measured through metabolic consumption, while the late frames depict amyloid distribution. Our study aims to assess the comparability between early-phase amyloid-PET scans and 18F-fluorodeoxyglucose (18F-FDG)-PET brain topography at the individual level, and their ability to discriminate patients. Methods: 166 subjects evaluated at the Geneva Memory Center, ranging from cognitively unimpaired to Mild Cognitive Impairment (MCI) and dementia, underwent early-phase amyloid-PET - using either 18F-florbetapir (eFBP) (n = 94) or 18F-flutemetamol (eFMM) (n = 72) - and 18F-FDG-PET. Aß status was assessed. Standardized uptake value ratios (SUVR) were extracted to evaluate the correlation of eFBP/eFMM and their respective 18F-FDG-PET scans. The single-subject procedure was applied to investigate hypometabolism and hypoperfusion maps and their spatial overlap by Dice coefficient. Receiver operating characteristic analyses were performed to compare the discriminative power of eFBP/eFMM, and 18F-FDG-PET SUVR in AD-related metaROI between Aß-negative healthy controls and cases in the AD continuum. Results: Positive correlations were found between eFBP/eFMM and 18F-FDG-PET SUVR independently of Aß status and Aß radiotracer (R>0.72, p<0.001). eFBP/eFMM single-subject analysis revealed clusters of significant hypoperfusion with good correspondence to hypometabolism topographies, independently of the underlying neurodegenerative patterns. Both eFBP/eFMM and 18F-FDG-PET SUVR significantly discriminated AD patients from controls in the AD-related metaROIs (AUCFBP = 0.888; AUCFMM=0.801), with 18F-FDG-PET performing slightly better, however not significantly (all p-value higher than 0.05), than others (AUCFDG=0.915 and 0.832 for subjects evaluated with 18F-FBP and 18F-FMM, respectively). Conclusion: The distribution of perfusion was comparable to that of metabolism at the single-subject level by parametric analysis, particularly in the presence of a high neurodegeneration burden. Our findings indicate that eFBP/eFMM imaging can replace 18F-FDG-PET imaging, as they reveal typical neurodegenerative patterns, or allow to exclude the presence of neurodegeneration. The finding shows cost-saving capacities of amyloid-PET and supports the routine use of the modality for individual classification in clinical practice.

Relaxation time of brain tissue in the elderly assessed by synthetic MRI.

BACKGROUND: Synthetic MRI (SyMRI) is a quantitative technique that allows measurements of T1 and T2 relaxation times (RTs). Brain RT evolution across lifespan is well described for the younger population. The aim was to study RTs of brain parenchyma in a healthy geriatric population in order to define the normal value of structures in this group population. Normal values for geriatric population could help find biomarker for age-related brain disease. MATERIALS AND METHODS: Fifty-four normal-functioning individuals (22 females, 32 males) with mean age of 83 years (range 56-98) underwent SyMRI. RT values in manually defined ROIs (centrum semiovale, middle cerebellar peduncles, thalamus, and insular cortex) and in segmented whole-brain components (brain parenchyma, gray matter, white matter, myelin, CSF, and stromal structures) were extracted from the SyMRI segmentation software. Patients' results were combined into the group age. Main ROI-based and whole-brain results were compared for the all dataset and for age group results as well. RESULTS: For white matter, RTs between ROI-based analyses and whole-brain results for T2 and for T1 were statistically different and a trend of increasing T1 in centrum semiovale and cerebellar peduncle was observed. For gray matter, thalamic T1 was statistically different from insular T1. A difference was also found between left and right insula (p < .0001). T1 RTs of ROI-based and whole-brain-based analyses were statistically different (p < .0001). No significant difference in T1 and T2 was found between age groups on ROI-based analysis, but T1 in centrum semiovale and thalamus increased with age. No statistical difference between age groups was found for the various segmented volumes except for myelin between 65-74 years of age and the 95-105 years of age groups (p = .038). CONCLUSIONS: SyMRI is a new tool that allows faster imaging and permits to obtain quantitative T1 and T2. By defining RT values of different brain components of normal-functioning elderly individuals, this technique may be used as a biomarker for clinical disorders like dementia.

A Novel Concept of Transperineal Focused Ultrasound Transducer for Prostate Cancer Local Deep Hyperthermia Treatments.

Design, embodiment, and experimental study of a novel concept of extracorporeal phased array ultrasound transducer for prostate cancer regional deep hyperthermia treatments using a transperineal acoustic window is presented. An optimized design of hyperthermia applicator was derived from a modelling software where acoustic and thermal fields were computed based on anatomical data. Performance tests have been experimentally conducted on gel phantoms and tissues, under 3T MRI guidance using PRFS thermometry. Feedback controlled hyperthermia (ΔT = 5 °C during 20min) was performed on two ex vivo lamb carcasses with prostate mimicking pelvic tissue, to demonstrate capability of spatio-temporal temperature control and to assess potential risks and side effects. Our optimization approach yielded a therapeutic ultrasound transducer consisting of 192 elements of variable shape and surface, pseudo randomly distributed on 6 columns, using a frequency of 700 kHz. Radius of curvature was 140 mm and active water circulation was included for cooling. The measured focusing capabilities covered a volume of 24 × 50 × 60 mm3. Acoustic coupling of excellent quality was achieved. No interference was detected between sonication and MR acquisitions. On ex vivo experiments the target temperature elevation of 5 °C was reached after 5 min and maintained during another 15 min with the predictive temperature controller showing 0.2 °C accuracy. No significant temperature rise was observed on skin and bonny structures. Reported results represent a promising step toward the implementation of transperineal ultrasound hyperthermia in a pilot study of reirradiation in prostate cancer patients.