ArcheD, a residual neural network for prediction of cerebrospinal fluid amyloid-beta from amyloid PET images.

Detection and measurement of amyloid-beta (Aß) in the brain is a key factor for early identification and diagnosis of Alzheimer's disease (AD). We aimed to develop a deep learning model to predict Aß cerebrospinal fluid (CSF) concentration directly from amyloid PET images, independent of tracers, brain reference regions or preselected regions of interest. We used 1870 Aß PET images and CSF measurements to train and validate a convolutional neural network ("ArcheD"). We evaluated the ArcheD performance in relation to episodic memory and the standardized uptake value ratio (SUVR) of cortical Aß. We also compared the brain region's relevance for the model's CSF prediction within clinical-based and biological-based classifications. ArcheD-predicted Aß CSF values correlated with measured Aß CSF values (r = 0.92; q < 0.01), SUVR (rAV45 = -0.64, rFBB = -0.69; q < 0.01) and episodic memory measures (0.33 < r < 0.44; q < 0.01). For both classifications, cerebral white matter significantly contributed to CSF prediction (q < 0.01), specifically in non-symptomatic and early stages of AD. However, in late-stage disease, the brain stem, subcortical areas, cortical lobes, limbic lobe and basal forebrain made more significant contributions (q < 0.01). Considering cortical grey matter separately, the parietal lobe was the strongest predictor of CSF amyloid levels in those with prodromal or early AD, while the temporal lobe played a more crucial role for those with AD. In summary, ArcheD reliably predicted Aß CSF concentration from Aß PET scans, offering potential clinical utility for Aß level determination.

No impact of attenuation and scatter correction on the interpretation of dopamine transporter SPECT in patients with clinically uncertain parkinsonian syndrome.

PURPOSE: The benefit from attenuation and scatter correction (ASC) of dopamine transporter (DAT)-SPECT for the detection of nigrostriatal degeneration in clinical routine is still a matter of debate. The current study evaluated the impact of ASC on visual interpretation and semi-quantitative analysis of DAT-SPECT in a large patient sample. METHODS: One thousand seven hundred forty consecutive DAT-SPECT with 123I-FP-CIT from clinical routine were included retrospectively. SPECT images were reconstructed iteratively without and with ASC. Attenuation correction was based on uniform attenuation maps, scatter correction on simulation. All SPECT images were categorized with respect to the presence versus the absence of Parkinson-typical reduction of striatal 123I-FP-CIT uptake by three independent readers. Image reading was performed twice to assess intra-reader variability. The specific 123I-FP-CIT binding ratio (SBR) was used for automatic categorization, separately with and without ASC. RESULTS: The mean proportion of cases with discrepant categorization by the same reader between the two reading sessions was practically the same without and with ASC, about 2.2%. The proportion of DAT-SPECT with discrepant categorization without versus with ASC by the same reader was 1.66% ± 0.50% (1.09-1.95%), not exceeding the benchmark of 2.2% from intra-reader variability. This also applied to automatic categorization of the DAT-SPECT images based on the putamen SBR (1.78% discrepant cases between without versus with ASC). CONCLUSION: Given the large sample size, the current findings provide strong evidence against a relevant impact of ASC with uniform attenuation and simulation-based scatter correction on the clinical utility of DAT-SPECT to detect nigrostriatal degeneration in patients with clinically uncertain parkinsonian syndrome.

Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC.

INTRODUCTION: Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients. METHODS: Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles. RESULTS: Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course. DISCUSSION: An autopsy-derived temporo-limbic FDG-PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE-NC.

Impact of age and sex correction on the diagnostic performance of dopamine transporter SPECT.

PURPOSE: The specific binding ratio (SBR) of 123I-FP-CIT (FP-CIT) in the putamen decreases with age by about 5% per decade and most likely is about 10% higher in females. However, the clinical utility of age and sex correction of the SBR is still a matter of debate. This study tested the impact of age and sex correction on the diagnostic performance of the putamen SBR in three independent patient samples. METHODS: Research sample: 207 healthy controls (HC) and 438 Parkinson's disease (PD) patients. Clinical sample A: 183 patients with neurodegenerative parkinsonian syndrome (PS) and 183 patients with non-neurodegenerative PS from one site. Clinical sample B: 84 patients with neurodegenerative PS and 38 patients with non-neurodegenerative PS from another site. Correction for age and sex of the putamen SBR was based on linear regression in the HC or non-neurodegenerative PS, separately in each sample. The area under the ROC curve (AUC) was used as performance measure. RESULTS: The putamen SBR was higher in females compared to males (PPMI: 14%, p < 0.0005; clinical sample A: 7%, p < 0.0005; clinical sample B: 6%, p = 0.361). Age-related decline of the putamen SBR ranged between 3.3 and 10.4% (p ≤ 0.019). In subjects ≥ 50 years, age and sex explained < 10% of SBR between-subjects variance. Correction of the putamen SBR for age and sex resulted in slightly decreased AUC in the PPMI sample (0.9955 versus 0.9969, p = 0.025) and in clinical sample A (0.9448 versus 0.9519, p = 0.057). There was a small, non-significant AUC increase in clinical sample B (0.9828 versus 0.9743, p = 0.232). CONCLUSION: These findings do not support age and sex correction of the putaminal FP-CIT SBR in the diagnostic workup of parkinsonian syndromes. This most likely is explained by the fact that the proportion of between-subjects variance caused by age and sex is considerably below the symptom threshold of about 50% reduction in neurodegenerative PS.

A convolutional neural network for fully automated blood SUV determination to facilitate SUR computation in oncological FDG-PET.

PURPOSE: The standardized uptake value (SUV) is widely used for quantitative evaluation in oncological FDG-PET but has well-known shortcomings as a measure of the tumor's glucose consumption. The standard uptake ratio (SUR) of tumor SUV and arterial blood SUV (BSUV) possesses an increased prognostic value but requires image-based BSUV determination, typically in the aortic lumen. However, accurate manual ROI delineation requires care and imposes an additional workload, which makes the SUR approach less attractive for clinical routine. The goal of the present work was the development of a fully automated method for BSUV determination in whole-body PET/CT. METHODS: Automatic delineation of the aortic lumen was performed with a convolutional neural network (CNN), using the U-Net architecture. A total of 946 FDG PET/CT scans from several sites were used for network training (N = 366) and testing (N = 580). For all scans, the aortic lumen was manually delineated, avoiding areas affected by motion-induced attenuation artifacts or potential spillover from adjacent FDG-avid regions. Performance of the network was assessed using the fractional deviations of automatically and manually derived BSUVs in the test data. RESULTS: The trained U-Net yields BSUVs in close agreement with those obtained from manual delineation. Comparison of manually and automatically derived BSUVs shows excellent concordance: the mean relative BSUV difference was (mean ± SD) = (- 0.5 ± 2.2)% with a 95% confidence interval of [- 5.1,3.8]% and a total range of [- 10.0, 12.0]%. For four test cases, the derived ROIs were unusable (< 1 ml). CONCLUSION: CNNs are capable of performing robust automatic image-based BSUV determination. Integrating automatic BSUV derivation into PET data processing workflows will significantly facilitate SUR computation without increasing the workload in the clinical setting.

Automatic classification of dopamine transporter SPECT: deep convolutional neural networks can be trained to be robust with respect to variable image characteristics.

PURPOSE: This study investigated the potential of deep convolutional neural networks (CNN) for automatic classification of FP-CIT SPECT in multi-site or multi-camera settings with variable image characteristics. METHODS: The study included FP-CIT SPECT of 645 subjects from the Parkinson's Progression Marker Initiative (PPMI), 207 healthy controls, and 438 Parkinson's disease patients. SPECT images were smoothed with an isotropic 18-mm Gaussian kernel resulting in 3 different PPMI settings: (i) original (unsmoothed), (ii) smoothed, and (iii) mixed setting comprising all original and all smoothed images. A deep CNN with 2,872,642 parameters was trained, validated, and tested separately for each setting using 10 random splits with 60/20/20% allocation to training/validation/test sample. The putaminal specific binding ratio (SBR) was computed using a standard anatomical ROI predefined in MNI space (AAL atlas) or using the hottest voxels (HV) analysis. Both SBR measures were trained (ROC analysis, Youden criterion) using the same random splits as for the CNN. CNN and SBR trained in the mixed PPMI setting were also tested in an independent sample from clinical routine patient care (149 with non-neurodegenerative and 149 with neurodegenerative parkinsonian syndrome). RESULTS: Both SBR measures performed worse in the mixed PPMI setting compared to the pure PPMI settings (e.g., AAL-SBR accuracy = 0.900 ± 0.029 in the mixed setting versus 0.957 ± 0.017 and 0.952 ± 0.015 in original and smoothed setting, both p < 0.01). In contrast, the CNN showed similar accuracy in all PPMI settings (0.967 ± 0.018, 0.972 ± 0.014, and 0.955 ± 0.009 in mixed, original, and smoothed setting). Similar results were obtained in the clinical sample. After training in the mixed PPMI setting, only the CNN provided acceptable performance in the clinical sample. CONCLUSIONS: These findings provide proof of concept that a deep CNN can be trained to be robust with respect to variable site-, camera-, or scan-specific image characteristics without a large loss of diagnostic accuracy compared with mono-site/mono-camera settings. We hypothesize that a single CNN can be used to support the interpretation of FP-CIT SPECT at many different sites using different acquisition hardware and/or reconstruction software with only minor harmonization of acquisition and reconstruction protocols.

Impact of plasma glucose level on the pattern of brain FDG uptake and the predictive power of FDG PET in mild cognitive impairment.

PURPOSE: Increased blood glucose level (BGL) has been reported to cause alterations of FDG uptake in the brain that mimic Alzheimer's disease (AD), even within the "acceptable" range ≤ 160 mg/dl. The aim of this study was (i) to confirm this in a large sample of well-characterized normal control (NC) subjects, and (ii) to analyze its impact on the prediction of AD dementia (ADD) in mild cognitive impairment (MCI). METHODS: The study included NCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) that were cognitively stable for ≥36 months after PET (n = 87, 74.2 ± 5.3 y), and ADNI MCIs with ≥36 months follow-up if not progressed to ADD earlier (n = 323, 71.1 ± 7.1 y). Seventy-three of the MCIs had progressed to ADD within 36 months. In the NCs, parenchyma-scaled FDG uptake was tested for clusters of correlation with BGL on the family-wise, error-corrected 5% level. In the MCIs, ROC analysis was used to assess the power of FDG uptake in a predefined AD-typical region for prediction of ADD. ROC analysis was repeated after correcting mean FDG uptake in the AD-typical region for BGL based on linear regression in the NCs. RESULTS: In the NCs, BGL (59-149 mg/dl) was negatively correlated with FDG uptake in a cluster comprising the occipital cortex and precuneus but sparing the posterior cingulate, independent of amyloid-ß and ApoE4 status. In the MCIs, FDG uptake in the AD-typical region provided an area of 0.804 under the ROC curve for prediction of ADD. Correcting FDG uptake in the AD-typical region for BGL (55-189 mg/dl) did not change predictive performance (area = 0.808, p = 0.311). CONCLUSIONS: Increasing BGL is associated with relative reduction of FDG uptake in the posterior cortex even in the "acceptable" range ≤ 160 mg/dl. The BGL-associated pattern is similar to the typical AD pattern, but not identical. BGL-associated variability of regional FDG uptake has no relevant impact on the power of FDG PET for prediction of MCI-to-ADD progression.

PETPVE12: an SPM toolbox for Partial Volume Effects correction in brain PET - Application to amyloid imaging with AV45-PET.

Positron emission tomography (PET) allows detecting molecular brain changes in vivo. However, the accuracy of PET is limited by partial volume effects (PVE) that affects quantitative analysis and visual interpretation of the images. Although PVE-correction methods have been shown to effectively increase the correspondence of the measured signal with the true regional tracer uptake, these procedures are still not commonly applied, neither in clinical nor in research settings. Here, we present an implementation of well validated PVE-correction procedures as a SPM toolbox, PETPVE12, for automated processing. We demonstrate its utility by a comprehensive analysis of the effects of PVE-correction on amyloid-sensitive AV45-PET data from 85 patients with Alzheimer's disease (AD) and 179 cognitively normal (CN) elderly. Effects of PVE-correction on global cortical standard uptake value ratios (SUVR) and the power of diagnostic group separation were assessed for the region-wise geometric transfer matrix method (PVEc-GTM), as well as for the 3-compartmental voxel-wise "Müller-Gärtner" method (PVEc-MG). Both PVE-correction methods resulted in decreased global cortical SUVRs in the low to middle range of SUVR values, and in increased global cortical SUVRs at the high values. As a consequence, average SUVR of the CN group was reduced, whereas average SUVR of the AD group was increased by PVE-correction. These effects were also reflected in increased accuracies of group discrimination after PVEc-GTM (AUC=0.86) and PVEc-MG (AUC=0.89) compared to standard non-corrected SUVR (AUC=0.84). Voxel-wise analyses of PVEc-MG corrected data also demonstrated improved detection of regionally increased AV45 SUVR values in AD patients. These findings complement the growing evidence for a beneficial effect of PVE-correction in quantitative analysis of amyloid-sensitive PET data. The novel PETPVE12 toolbox significantly facilitates the application of PVE-correction, particularly within SPM-based processing pipelines. This is expected to foster the use of PVE-correction in brain PET for more widespread use. The toolbox is freely available at http://www.fil.ion.ucl.ac.uk/spm/ext/#PETPVE12.

Reduction in camera-specific variability in [(123)I]FP-CIT SPECT outcome measures by image reconstruction optimized for multisite settings: impact on age-dependence of the specific binding ratio in the ENC-DAT database of healthy controls.

PURPOSE: Quantitative estimates of dopamine transporter availability, determined with [(123)I]FP-CIT SPECT, depend on the SPECT equipment, including both hardware and (reconstruction) software, which limits their use in multicentre research and clinical routine. This study tested a dedicated reconstruction algorithm for its ability to reduce camera-specific intersubject variability in [(123)I]FP-CIT SPECT. The secondary aim was to evaluate binding in whole brain (excluding striatum) as a reference for quantitative analysis. METHODS: Of 73 healthy subjects from the European Normal Control Database of [(123)I]FP-CIT recruited at six centres, 70 aged between 20 and 82 years were included. SPECT images were reconstructed using the QSPECT software package which provides fully automated detection of the outer contour of the head, camera-specific correction for scatter and septal penetration by transmission-dependent convolution subtraction, iterative OSEM reconstruction including attenuation correction, and camera-specific "to kBq/ml" calibration. LINK and HERMES reconstruction were used for head-to-head comparison. The specific striatal [(123)I]FP-CIT binding ratio (SBR) was computed using the Southampton method with binding in the whole brain, occipital cortex or cerebellum as the reference. The correlation between SBR and age was used as the primary quality measure. RESULTS: The fraction of SBR variability explained by age was highest (1) with QSPECT, independently of the reference region, and (2) with whole brain as the reference, independently of the reconstruction algorithm. CONCLUSION: QSPECT reconstruction appears to be useful for reduction of camera-specific intersubject variability of [(123)I]FP-CIT SPECT in multisite and single-site multicamera settings. Whole brain excluding striatal binding as the reference provides more stable quantitative estimates than occipital or cerebellar binding.

Preserved brain metabolic activity at the age of 96 years.

Loss of brain tissue becomes notable to cerebral magnetic resonance imaging (MRI) at age 30 years, and progresses more rapidly from mid 60s. The incidence of dementia increases exponentially with age, and is all too frequent in the oldest old (≥ 90 years of age), the fastest growing age group in many countries. However, brain pathology and cognitive decline are not inevitable, even at extremely old age (den Dunnen et al., 2008).

Robust, fully automatic delineation of the head contour by stereotactical normalization for attenuation correction according to Chang in dopamine transporter scintigraphy.

OBJECTIVES: Chang's method, the most widely used attenuation correction (AC) in brain single-photon emission computed tomography (SPECT), requires delineation of the outer contour of the head. Manual and automatic threshold-based methods are prone to errors due to variability of tracer uptake in the scalp. The present study proposes a new method for fully automated delineation of the head based on stereotactical normalization. The method was validated for SPECT with I-123-ioflupane. METHODS: The new method was compared to threshold-based delineation in 62 unselected patients who had received I-123-ioflupane SPECT at one of 3 centres. The impact on diagnostic power was tested for semi-quantitative analysis and visual reading of the SPECT images (six independent readers). RESULTS: The two delineation methods produced highly consistent semi-quantitative results. This was confirmed by receiver operating characteristic analyses in which the putamen specific-to-background ratio achieved highest area under the curve with negligible effect of the delineation method: 0.935 versus 0.938 for stereotactical normalization and threshold-based delineation, respectively. Visual interpretation of DVR images was also not affected by the delineation method. CONCLUSIONS: Delineation of the head contour by stereotactical normalization appears useful for Chang AC in I-123-ioflupane SPECT. It is robust and does not require user interaction. KEY POINTS: •Chang attenuation correction in brain SPECT requires delineation of the head contour. •Manual and threshold-based methods are prone to errors. •The study proposes a fully-automated method for delineation based on stereotactical normalization. •The method is shown to work reliably in I-123-ioflupane SPECT. •It might improve the workflow of I-123-ioflupane SPECT in everyday patient care.

ArcheD, a residual neural network for prediction of cerebrospinal fluid amyloid-beta from amyloid PET images.

Detection and measurement of amyloid-beta (Aß) aggregation in the brain is a key factor for early identification and diagnosis of Alzheimer's disease (AD). We aimed to develop a deep learning model to predict Aß cerebrospinal fluid (CSF) concentration directly from amyloid PET images, independent of tracers, brain reference regions or preselected regions of interest. We used 1870 Aß PET images and CSF measurements to train and validate a convolutional neural network ("ArcheD"). We evaluated the ArcheD performance in relation to episodic memory and the standardized uptake value ratio (SUVR) of cortical Aß. We also compared the brain region's relevance for the model's CSF prediction within clinical-based and biological-based classifications. ArcheD-predicted Aß CSF values correlated strongly with measured Aß CSF values ( r =0.81; p <0.001) and showed correlations with SUVR and episodic memory measures in all participants except in those with AD. For both clinical and biological classifications, cerebral white matter significantly contributed to CSF prediction ( q <0.01), specifically in non-symptomatic and early stages of AD. However, in late-stage disease, brain stem, subcortical areas, cortical lobes, limbic lobe, and basal forebrain made more significant contributions (q<0.01). Considering cortical gray matter separately, the parietal lobe was the strongest predictor of CSF amyloid levels in those with prodromal or early AD, while the temporal lobe played a more crucial role for those with AD. In summary, ArcheD reliably predicted Aß CSF concentration from Aß PET scans, offering potential clinical utility for Aß level determination and early AD detection.

The effect of plasma cortisol on hippocampal atrophy and clinical progression in mild cognitive impairment.

Introduction: Both elevated cortisol and hippocampal volume have been linked to an increased risk for the development of Alzheimer's disease (AD). This longitudinal study assessed the effects of plasma cortisol on hippocampal atrophy and clinical progression rates in patients with mild cognitive impairment (MCI). Methods: Patients with amnestic MCI (n = 304) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on availability of baseline plasma cortisol and hippocampal volume measures, assessed at baseline and during follow-ups. We investigated associations between plasma cortisol, hippocampal volume, and risk of clinical progression to AD over a study period of up to 100 months (mean follow-up time 36.8 months) using linear mixed models, Cox proportional hazards models, and Kaplan-Meier estimators. Results: Plasma cortisol predicted greater hippocampal atrophy, such that participants with higher cortisol showed faster decline in hippocampal volume over time (interaction: ß = -0.15, p = 0.004). Small hippocampal volume predicted a higher risk of clinical progression to AD (haard ratio [HR] = 2.15; confidence in terval [CI], 1.64-2.80; p < 0.001). A similar effect was not found for cortisol (HR = 1.206; CI, 0.82-1.37; p = 0.670) and there was no statistical evidence for an interaction between hippocampal volume and cortisol on clinical progression (HR = 0.81; CI, 0.57-0.17; p = 0.260). Discussion: Our findings suggest that higher cortisol predicts higher hippocampal atrophy, which in turn is a risk factor for progression to AD. Regulation of the hypothalamic-pituitary-adrenal axis through stress-reducing lifestyle interventions might be a protective factor against hippocampal degeneration at the prodromal stage of AD.

Individualized Summary Assessment of Detailed Neuropsychological Testing for the Etiological Diagnosis of Newly Detected Cognitive Impairment in Hospitalized Geriatric Patients.

BACKGROUND: Neuropsychological testing (NPT) of geriatric inpatients can be affected by the acute illness and/or the hospitalization. OBJECTIVE: To test individualized interpretation of detailed NPT for the differentiation between primary 'neurodegenerative' etiologies (predominantly Alzheimer's disease) and 'other' etiologies (including cerebrovascular disease) of newly detected cognitive impairment in geriatric inpatients without and with delirium in remission. METHODS: 96 geriatric inpatients (81.9±5.6 years, 64.6% females) with clinically uncertain cognitive impairment were included. 31.3% had delirium in remission that was not considered the primary cause of the cognitive impairment. Categorization of the most likely etiology as 'neurodegenerative' or 'other' was established retrospectively by a study neuropsychologist based on individualized summary assessment of detailed NPT compiled in a standardized vignette. The etiological diagnosis based on FDG-PET served as gold standard (54.2% 'neurodegenerative', 45.8% 'other'). RESULTS: Individualized summary assessment by the study neuropsychologist was correct in 80 patients (83.3%, 8 false positive, 8 false negative). The impact of delirium in remission was not significant (p = 0.237). Individualized summary assessment by an independent neuropsychologist resulted in more false positive cases (n = 22) at the same rate of false negative cases (n = 8). Automatic categorization with a decision tree model based on the most discriminative NPT scores was correct in 68 patients (70.8%, 14 false positive, 14 false negative). CONCLUSION: Individualized summary assessment of detailed NPT in the context of relevant clinical information might be useful for the etiological diagnosis of newly detected cognitive impairment in hospitalized geriatric patients, also in patients with delirium in remission, but requires task-specific expertise.

Stereotactical normalization with multiple templates representative of normal and Parkinson-typical reduction of striatal uptake improves the discriminative power of automatic semi-quantitative analysis in dopamine transporter SPECT.

BACKGROUND: The specific binding ratio (SBR) of 123I-FP-CIT in the putamen is widely used to support the interpretation of dopamine transporter (DAT) SPECT. Automatic methods for computation of the putamen SBR often include stereotactical normalization of the individual DAT-SPECT image to an anatomical standard space. This study compared using a single 123I-FP-CIT template image as target for stereotactical normalization versus multiple templates representative of normal and different levels of Parkinson-typical reduction of striatal 123I-FP-CIT uptake. METHODS: 1702 clinical 123I-FP-CIT SPECT images were stereotactically normalized (affine) to the anatomical space of the Montreal Neurological Institute (MNI) with SPM12 either using a single custom-made 123I-FP-CIT template representative of normal striatal uptake or using eight different templates representative of normal and different levels of Parkinson-typical reduction of striatal FP-CIT uptake with and without attenuation and scatter correction. In the latter case, SPM finds the linear combination of the multiple templates that best matches the patient's image. The putamen SBR was obtained using hottest voxels analysis in large unilateral regions-of-interest predefined in MNI space. The histogram of the putamen SBR in the whole sample was fitted by the sum of two Gaussians. The power to differentiate between reduced and normal SBR was estimated by the effect size of the distance between the two Gaussians computed as the differences between their mean values scaled to their pooled standard deviation. RESULTS: The effect size of the distance between the two Gaussians was 3.83 with the single template versus 3.96 with multiple templates for stereotactical normalization. CONCLUSIONS: Multiple templates representative of normal and different levels of Parkinson-typical reduction for stereotactical normalization of DAT-SPECT might provide improved separation between normal and reduced putamen SBR that could result in slightly improved power for the detection of nigrostriatal degeneration.

Same same but different: dopamine transporter SPECT on scanners with CZT vs. NaI detectors.

BACKGROUND: The aims of this study were to establish a normal database (NDB) for semiquantification of dopamine transporter (DAT) single-photon emission computed tomography (SPECT) with [123I]FP-CIT on a cadmium zinc telluride (CZT) camera, test the preexisting NaI-derived NDB for use in CZT scans, and compare the diagnostic findings in subjects imaged with a CZT scanner with either the preexisting NaI-based NDB or our newly defined CZT NDB. METHODS: The sample comprised 73 subjects with clinically uncertain parkinsonian syndrome (PS) who prospectively underwent [123I]FP-CIT SPECT on a CZT camera according to standard guidelines with identical acquisition and reconstruction protocols (DaTQUANT). Two experienced readers visually assessed the images and binarized the subjects into "non-neurodegenerative PS" and "neurodegenerative PS". Twenty-five subjects from the "non-neurodegenerative PS" subgroup were randomly selected to establish a CZT NDB. The remaining 48 subjects were defined as "test group". DaTQUANT was used to determine the specific binding ratio (SBR). For the test group, SBR values were transformed to z-scores for the putamen utilizing both the CZT NDB and the manufacturer-provided NaI-based NDB (GE NDB). A predefined fixed cut-off of -2 was used for dichotomization of z-scores to classify neurodegenerative and non-neurodegenerative PS. Performance of semiquantification using the two NDB to identify subjects with neurodegenerative PS was assessed in comparison with the visual rating. Furthermore, a randomized head-to-head comparison of both detector systems was performed semiquantitatively in a subset of 32 out of all 73 subjects. RESULTS: Compared to the visual rating as reference, semiquantification based on the dedicated CZT NDB led to fewer discordant ratings than the GE NDB in CZT scans (3 vs. 8 out of 48 subjects). This can be attributed to the putaminal z-scores being consistently higher with the GE NDB on a CZT camera (median absolute difference of 1.68), suggesting an optimal cut-off of -0.5 for the GE NDB instead of -2.0. Average binding ratios and z-scores were significantly lower in CZT compared to NaI data. CONCLUSIONS: Use of a dedicated, CZT-derived NDB is recommended in [123I]FP-CIT SPECT with a CZT camera since it improves agreement between semiquantification and visual assessment.

Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline.

BACKGROUND: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer's disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. OBJECTIVE: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. METHODS: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. RESULTS: Group differences approached significance for BF total volume (p = 0.061) and the Ch4 subregion (p = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. CONCLUSIONS: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at "grey zone" levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings.

Brain FDG PET for Short- to Medium-Term Prediction of Further Cognitive Decline and Need for Assisted Living in Acutely Hospitalized Geriatric Patients With Newly Detected Clinically Uncertain Cognitive Impairment.

PURPOSE: The aim of this study was to evaluate brain FDG PET for short- to medium-term prediction of cognitive decline, need for assisted living, and survival in acutely hospitalized geriatric patients with newly detected clinically uncertain cognitive impairment (CUCI). MATERIALS AND METHODS: The study included 96 patients (62 females, 81.4 ± 5.4 years) hospitalized due to (sub)acute admission indications with newly detected CUCI (German Clinical Trials Register DRKS00005041). FDG PET was categorized as "neurodegenerative" (DEG+) or "nonneurodegenerative" (DEG-) based on visual inspection by 2 independent readers. In addition, each individual PET was tested voxel-wise against healthy controls (P < 0.001 uncorrected). The resulting total hypometabolic volume (THV) served as reader-independent measure of the spatial extent of neuronal dysfunction/degeneration. FDG PET findings at baseline were tested for association with the change in living situation and change in vital status 12 to 24 months after PET. The association with the annual change of the CDR-SB (Clinical Dementia Rating Sum of Boxes) after PET was tested in a subsample of 72 patients. RESULTS: The mean time between PET and follow-up did not differ between DEG+ and DEG- patients (1.37 ± 0.27 vs 1.41 ± 0.27 years, P = 0.539). Annual change of CDR-SB was higher in DEG+ compared with DEG- patients (2.78 ± 2.44 vs 0.99 ± 1.81, P = 0.001), and it was positively correlated with THV (age-corrected Spearman ρ = 0.392, P = 0.001). DEG+ patients moved from at home to assisted living significantly earlier than DEG- patients (P = 0.050). Survival was not associated with DEG status or with THV. CONCLUSIONS: In acutely hospitalized geriatric patients with newly detected CUCI, the brain FDG PET can contribute to the prediction of further cognitive/functional decline and the need for assisted living within 1 to 2 years.

Vascular Health Is Associated With Functional Connectivity Decline in Higher-Order Networks of Older Adults.

Background: Poor vascular health may impede brain functioning in older adults, thus possibly increasing the risk of cognitive decline and Alzheimer's disease (AD). The emerging link between vascular risk factors (VRF) and longitudinal decline in resting-state functional connectivity (RSFC) within functional brain networks needs replication and further research in independent cohorts. Method: We examined 95 non-demented older adults using the IMAP+ cohort (Caen, France). VRF were assessed at baseline through systolic and diastolic blood pressure, body-mass-index, and glycated hemoglobin (HbA1c) levels. Brain pathological burden was measured using white matter hyperintensity (WMH) volumes, derived from FLAIR images, and cortical ß-Amyloid (Aß) deposition, derived from florbetapir-PET imaging. RSFC was estimated from functional MRI scans within canonical brain networks at baseline and up to 3 years of follow-up. Linear mixed-effects models evaluated the independent predictive value of VRF on longitudinal changes in network-specific and global RSFC as well as a potential association between these RSFC changes and cognitive decline. Results: We replicate that RSFC increased over time in global RSFC and in the default-mode, salience/ventral-attention and fronto-parietal networks. In contrast, higher diastolic blood pressure levels were independently associated with a decrease of RSFC over time in the default-mode, salience/ventral-attention, and fronto-parietal networks. Moreover, higher HbA1c levels were independently associated with a reduction of the observed RSFC increase over time in the salience/ventral-attention network. Both of these associations were independent of brain pathology related to Aß load and WMH volumes. The VRF-related changes in RSFC over time were not significantly associated with longitudinal changes in cognitive performance. Conclusion: Our longitudinal findings corroborate that VRF promote RSFC alterations over time within higher-order brain networks, irrespective of pathological brain burden. Altered RSFC in large-scale cognitive networks may eventually increase the vulnerability to aging and AD.