The Aortic Ductus Diverticulum-Innocent Bystander or Potential Source of Thromboembolic Stroke?

OBJECTIVE: Due to reversal blood flow in the diastolic phase, outpouchings at the aortic isthmus may carry the risk of thrombus formation and subsequent thromboembolism. The objective was to evaluate the association between aortic ductus diverticula (ADDs) and ischemic brain alterations in cerebral magnetic resonance imaging. METHODS: A retrospective analysis of 218 patients who received both a dedicated computed tomography angiography of the thoracic aorta and a brain magnetic resonance imaging was performed. Two radiologists independently reviewed all examinations for the presence of ADD as well as ischemic alterations of the brain. The association between this anatomical variant and ischemic brain alterations was evaluated by univariate and bivariate logistic regression analyses. RESULTS: ADDs were identified/present in 35 of 218 patients (16%). Ischemic brain alterations were found in 57% of patients (20/35) with an ADD and in 42% of the control group (77/183, P = 0.1). The presence of an ADD did not prove to be an independent risk factor for ischemic brain alterations after multivariate adjustment (odds ratio = 1.7, 95% confidence interval = 0.72-3.96, P = 0.225). CONCLUSIONS: In the present study, ADDs were not significantly associated with ischemic brain alterations. Therefore, ADDs seem to be an innocent bystander with respect to the pathogenesis of ischemic brain alterations.

The default mode network and cognition in Parkinson's disease: A multimodal resting-state network approach.

Involvement of the default mode network (DMN) in cognitive symptoms of Parkinson's disease (PD) has been reported by resting-state functional MRI (rsfMRI) studies. However, the relation to metabolic measures obtained by [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is largely unknown. We applied multimodal resting-state network analysis to clarify the association between intrinsic metabolic and functional connectivity abnormalities within the DMN and their significance for cognitive symptoms in PD. PD patients were classified into normal cognition (n = 36) and mild cognitive impairment (MCI; n = 12). The DMN was identified by applying an independent component analysis to FDG-PET and rsfMRI data of a matched subset (16 controls and 16 PD patients) of the total cohort. Besides metabolic activity, metabolic and functional connectivity within the DMN were compared between the patients' groups and healthy controls (n = 16). Glucose metabolism was significantly reduced in all DMN nodes in both patient groups compared to controls, with the lowest uptake in PD-MCI (p < .05). Increased metabolic and functional connectivity along fronto-parietal connections was identified in PD-MCI patients compared to controls and unimpaired patients. Functional connectivity negatively correlated with cognitive composite z-scores in patients (r = -.43, p = .005). The current study clarifies the commonalities of metabolic and hemodynamic measures of brain network activity and their individual significance for cognitive symptoms in PD, highlighting the added value of multimodal resting-state network approaches for identifying prospective biomarkers.

Feasibility of short imaging protocols for [18F]PI-2620 tau-PET in progressive supranuclear palsy.

PURPOSE: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [18F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [18F]PI-2620 tau-PET imaging of PSP. METHODS: Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [18F]PI-2620 PET was performed by a dynamic 60-min scan. Distribution volume ratios (DVRs) were calculated using full and truncated scan durations (0-60, 0-50, 0-40, 0-30, and 0-20 min p.i.). Standardized uptake value ratios (SUVrs) were obtained 20-40, 30-50, and 40-60 min p.i.. All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP-RS from HCs in predefined subcortical and cortical target regions (effect size, area under the curve (AUC), multi-region classifier). RESULTS: 0-50 and 0-40 DVR showed equivalent effect sizes as 0-60 DVR (averaged Cohen's d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0-30 or 0-20 DVR. The 20-40 SUVr indicated the best performance of all static acquisition windows (averaged Cohen's d: 0.99). The globus pallidus internus discriminated patients with PSP-RS and HCs at a similarly high level for 0-60 DVR (AUC: 0.96), 0-40 DVR (AUC: 0.96), and 20-40 SUVr (AUC: 0.94). The multi-region classifier sensitivity of these time windows was consistently 86%. CONCLUSION: Truncated and static imaging windows can be used for [18F]PI-2620 PET imaging of PSP. 0-40 min dynamic scanning offers the best balance between accuracy and economic scanning.

Network degeneration in Parkinson's disease: multimodal imaging of nigro-striato-cortical dysfunction.

The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson's disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson's disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson's disease. Forty-two patients with mild-to-moderate stage Parkinson's disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster ß-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson's disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson's disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson's disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson's disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism.

Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury.

PURPOSE: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several ß-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG). METHODS: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0-60 min p.i.) and static [18F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. RESULTS: Highest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers. CONCLUSION: Early-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control.

Impulsive-compulsive behaviours like pathological gambling or hypersexuality are a frequent side effect of dopamine replacement therapy in patients with Parkinson's disease. Multiple imaging studies suggest a significant reduction of presynaptic dopamine transporters in the nucleus accumbens to be a predisposing factor, reflecting either a reduction of mesolimbic projections or, alternatively, a lower presynaptic dopamine transporter expression per se. Here, we aimed to test the hypothesis of fewer mesolimbic projections as a risk factor by using dopamine synthesis capacity as a proxy of dopaminergic terminal density. Furthermore, previous studies have demonstrated a reduction of fronto-striatal connectivity to be associated with increased risk of impulsive-compulsive behaviour in Parkinson's disease. Therefore, another aim of this study was to investigate the relationship between severity of impulsive-compulsive behaviour, dopamine synthesis capacity and fronto-striatal connectivity. Eighty participants underwent resting state functional MRI and anatomical T1-weighted images [mean age: 68 ± 9.9 years, 67% male (patients)]. In 59 participants, 18F-DOPA-PET was obtained and voxel-wise Patlak slopes indicating dopamine synthesis capacity were calculated. All participants completed the QUIP-RS questionnaire, a well validated test to quantify severity of impulsive-compulsive behaviour in Parkinson's disease. A voxel-wise correlation analysis between dopamine synthesis capacity and QUIP-RS score was calculated for striatal regions. To investigate the relationship between symptom severity and functional connectivity, voxel-wise correlations were performed. A negative correlation was found between dopamine synthesis capacity and QUIP-RS score in the nucleus accumbens (r = -0.57, P = 0.001), a region functionally connected to the rostral anterior cingulate cortex. The connectivity strength was modulated by QUIP-RS, i.e. patients with more severe impulsive-compulsive behaviours had a weaker functional connectivity between rostral anterior cingulate cortex and the nucleus accumbens. In addition, cortical thickness and severity of impulsive-compulsive behaviour were positively correlated in the subgenual rostral anterior cingulate cortex. We found three factors to be associated with severity of impulsive-compulsive behaviour: (i) decreased dopamine synthesis capacity in the nucleus accumbens; (ii) decreased functional connectivity of the rostral anterior cingulate cortex with the nucleus accumbens; and (iii) increased cortical thickness of the subgenual rostral anterior cingulate cortex. Rather than a downregulation of dopamine transporters, a reduction of mesolimbic dopaminergic projections in conjunction with a dysfunctional rostral anterior cingulate cortex-a region known to play a key role in impulse control-could be the most crucial neurobiological risk factor for the development of impulsive-compulsive behaviours in patients with Parkinson's disease under dopamine replacement therapy.

Networks of tau distribution in Alzheimer's disease.

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.

The Role of Tau Imaging in Parkinsonian Disorders.

PURPOSE OF REVIEW: Differential diagnosis of atypical Parkinson syndromes (APS) is difficult as clinical presentations may vary and as there is a strong overlap between disease entities. Aggregations of misfolded and hyperphosphorylated tau proteins are the common denominator of many of these diseases. RECENT FINDINGS: Several tau targeting positron emission tomography (PET) tracers have been evaluated as possible biomarkers in APS in the recent years. For Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal degeneration, promising results have been reported with regard to the ability to detect the presence of disease and to discriminate patients from controls. However, the discussion about the specificity of the first-generation radiotracers and their value in the clinical context is ongoing. A combined interpretation of signal strength and distribution pattern in PET scans with first- and second-generation tracers may be helpful in clinical diagnosis and follow-up of patients with APS.

Multimodal correlation of dynamic [18F]-AV-1451 perfusion PET and neuronal hypometabolism in [18F]-FDG PET.

PURPOSE: Cerebral glucose metabolism measured with [18F]-FDG PET is a well established marker of neuronal dysfunction in neurodegeneration. The tau-protein tracer [18F]-AV-1451 PET is currently under evaluation and shows promising results. Here, we assess the feasibility of early perfusion imaging with AV-1451 as a substite for FDG PET in assessing neuronal injury. METHODS: Twenty patients with suspected neurodegeneration underwent FDG and early phase AV-1451 PET imaging. Ten one-minute timeframes were acquired after application of 200 MBq AV-1451. FDG images were acquired on a different date according to clinical protocol. Early AV-1451 timeframes were coregistered to individual FDG-scans and spatially normalized. Voxel-wise intermodal correlations were calculated on within-subject level for every possible time window. The window with highest pooled correlation was considered optimal. Z-transformed deviation maps (ZMs) were created from both FDG and early AV-1451 images, comparing against FDG images of healthy controls. RESULTS: Regional patterns and extent of perfusion deficits were highly comparable to metabolic deficits. Best results were observed in a time window from 60 to 360 s (r = 0.86). Correlation strength ranged from r = 0.96 (subcortical gray matter) to 0.83 (frontal lobe) in regional analysis. ZMs of early AV-1451 and FDG images were highly similar. CONCLUSION: Perfusion imaging with AV-1451 is a valid biomarker for assessment of neuronal dysfunction in neurodegenerative diseases. Radiation exposure and complexity of the diagnostic workup could be reduced significantly by routine acquisition of early AV-1451 images, sparing additional FDG PET.

Working Memory Training Responsiveness in Parkinson's Disease Is Not Determined by Cortical Thickness or White Matter Lesions.

Patients with Parkinson's disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson's disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness.

Treatment outcome and identification of factors influencing overall survival after Lu-177-PSMA-617 radioligand therapy in metastatic prostate cancer.

OBJECTIVE: To examine the clinical benefit of Lu-177-PSMA-617 radioligand therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Between November 2014 and December 2018, a total of 56 consecutive patients (median age 69.5 years; range 55-84 years) with mCRPC were included in this retrospective analysis. Patients received between 1 and 4 therapy cycles with a mean activity of 6.8 GBq per cycle. Biochemical response was evaluated using Prostate Cancer Working Group Criteria 3 (PCWG 3). Survival was assessed using Kaplan-Meier estimates and Cox proportional hazards regression analysis. This retrospective study was approved by the local ethics committee. RESULTS: A total of 139 treatment cycles with Lu-177-PSMA-617 were performed. A decline of 50% or more of prostate-specific antigen (PSA) level occurred in 54% and a PSA decline of any amount in 65% of patients. The estimated median overall survival (OS) was 16 months, in the chemotherapy subgroup 14 months. A longer OS was associated with a PSA-decline ≥50%, more than 2 cycles of therapy, cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l]. These identified predictors remained significant on uni- and multivariate Cox regression analysis. Moreover, 40% of the patients who were non-responders after the first therapy cycle turned into responders after the second one. CONCLUSION: PSA-decline ≥50%, a cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l] were identified as key predictors of prolonged OS in patients with mCRPC. In contrast rapid clinical deterioration mostly due to skeletal carcinomatosis resulted in early treatment failure.

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson's disease.

The prevailing network perspective of Parkinson's disease (PD) emerges not least from the ascending neuropathology traceable in histological studies. However, whether longitudinal in vivo correlates of network degeneration in PD can be observed remains unresolved. Here, we applied a trimodal imaging protocol combining 18F-fluorodeoxyglucose (FDG)- and 18F-fluoro-L-Dopa- (FDOPA)-PET with resting-state functional MRI to assess longitudinal changes in midbrain metabolism, striatal dopamine depletion and striatocortical dysconnectivity in 17 well-characterized PD patients. Whole-brain (un)paired-t-tests with focus on midbrain or striatum were performed between visits and in relation to 14 healthy controls (HC) in PET modalities. Resulting clusters of FDOPA-PET comparisons provided volumes for seed-based functional connectivity (FC) analyses between visits and in relation to HC. FDG metabolism in the left midbrain decreased compared to baseline along with caudatal FDOPA-uptake. This caudate cluster exhibited a longitudinal FC decrease to sensorimotor and frontal areas. Compared to healthy subjects, dopamine-depleted putamina indicated stronger decline in striatocortical FC at follow-up with respect to baseline. Increasing nigrostriatal deficits and striatocortical decoupling were associated with deterioration in motor scores between visits in repeated-measures correlations. In summary, our results demonstrate the feasibility of in-vivo tracking of progressive network degeneration using a multimodal imaging approach. Specifically, our data suggest advancing striatal and widespread striatocortical dysfunction via an anterior-posterior gradient originating from a hypometabolic midbrain cluster within a well-characterized and only mild to moderately affected PD cohort during a relatively short period.

Dopaminergic pathways and resting-state functional connectivity in Parkinson's disease with freezing of gait.

Freezing of gait is a common phenomenon of advanced Parkinson's disease. Besides locomotor function per se, a role of cognitive deficits has been suggested. Limited evidence of associated dopaminergic deficits points to caudatal denervation. Further, altered functional connectivity within resting-state networks with importance for cognitive functions has been described in freezers. A potential pathophysiological link between both imaging findings has not yet been addressed. The current study sought to investigate the association between dopaminergic pathway dysintegrity and functional dysconnectivity in relation to FOG severity and cognitive performance in a well-characterized PD cohort undergoing high-resolution 6-[18F]fluoro-L-Dopa PET and functional MRI. The freezing of gait questionnaire was applied to categorize patients (n = 59) into freezers and non-freezers. A voxel-wise group comparison of 6-[18F]fluoro-L-Dopa PET scans with focus on striatum was performed between both well-matched and neuropsychologically characterized patient groups. Seed-to-voxel resting-state functional connectivity maps of the resulting dopamine depleted structures and dopaminergic midbrain regions were created and compared between both groups. For a direct between-group comparison of dopaminergic pathway integrity, a molecular connectivity approach was conducted on 6-[18F]fluoro-L-Dopa scans. With respect to striatal regions, freezers showed significant dopaminergic deficits in the left caudate nucleus, which exhibited altered functional connectivity with regions of the visual network. Regarding midbrain structures, the bilateral ventral tegmental area showed altered functional coupling to regions of the default mode network. An explorative examination of the integrity of dopaminergic pathways by molecular connectivity analysis revealed freezing-associated impairments in mesolimbic and mesocortical pathways. This study represents the first characterization of a link between dopaminergic pathway dysintegrity and altered functional connectivity in Parkinson's disease with freezing of gait and hints at a specific involvement of striatocortical and mesocorticolimbic pathways in freezers.

One-Stop Shop: 18F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases.

Tau protein aggregations are a hallmark of amyloid-associated Alzheimer disease and some forms of non-amyloid-associated frontotemporal lobar degeneration. In recent years, several tracers for in vivo tau imaging have been under evaluation. This study investigated the ability of 18F-flortaucipir PET not only to assess tau positivity but also to differentiate between amyloid-positive and -negative forms of neurodegeneration on the basis of different 18F-flortaucipir PET signatures. Methods: The 18F-flortaucipir PET data of 35 patients with amyloid-positive neurodegeneration, 19 patients with amyloid-negative neurodegeneration, and 17 healthy controls were included in a data-driven scaled subprofile model (SSM)/principal-component analysis (PCA) identifying spatial covariance patterns. SSM/PCA pattern expression strengths were tested for their ability to predict amyloid status in a receiver-operating-characteristic analysis and validated with a leave-one-out approach. Results: Pattern expression strengths predicted amyloid status with a sensitivity of 0.94 and a specificity of 0.83. A support vector machine classification based on pattern expression strengths in 2 different SSM/PCA components yielded a prediction accuracy of 98%. Anatomically, prediction performance was driven by parietooccipital gray matter in amyloid-positive patients versus predominant white matter binding in amyloid-negative patients. Conclusion: SSM/PCA-derived binding patterns of 18F-flortaucipir differentiate between amyloid-positive and -negative neurodegenerative diseases with high accuracy. 18F-flortaucipir PET alone may convey additional information equivalent to that from amyloid PET. Together with a perfusion-weighted early-phase acquisition (18F-FDG PET-equivalent), a single scan potentially contains comprehensive information on amyloid (A), tau (T), and neurodegeneration (N) status as required by recent biomarker classification algorithms (A/T/N).

Toward a Universal Readout for 18F-Labeled Amyloid Tracers: The CAPTAINs Study.

To date, 3 18F-labeled PET tracers have been approved for assessing cerebral amyloid plaque pathology in the diagnostic workup of suspected Alzheimer disease (AD). Although scanning protocols are relatively similar across tracers, U.S. Food and Drug Administration- and the European Medicines Agency-approved visual rating protocols differ among the 3 tracers. This proof-of-concept study assessed the comparability of the 3 approved visual rating protocols to classify a scan as amyloid-positive or -negative, when applied by groups of experts and nonexperts to all 3 amyloid tracers. Methods: In an international multicenter approach, both expert (n = 4) and nonexpert raters (n = 3) rated scans acquired with 18F-florbetaben, 18F-florbetapir and 18F-flutemetamol. Scans obtained with each tracer were presented for reading according to all 3 approved visual rating protocols. In a randomized order, every single scan was rated by each reader according to all 3 protocols. Raters were blinded for the amyloid tracer used and asked to rate each scan as positive or negative, giving a confidence judgment after each response. Percentage of visual reader agreement, interrater reliability, and agreement of each visual read with binary quantitative measures (fixed SUV ratio threshold for positive or negative scans) were computed. These metrics were analyzed separately for expert and nonexpert groups. Results: No significant differences in using the different approved visual rating protocols were observed across the different metrics of agreement in the group of experts. Nominal differences suggested that the 18F-florbetaben visual rating protocol achieved the highest interrater reliability and accuracy especially under low confidence conditions. For the group of nonexpert raters, significant differences between the different visual rating protocols were observed with overall moderate-to-fair accuracy and with the highest reliability for the 18F-florbetapir visual rating protocol. Conclusion: We observed high interrater agreement despite applying different visual rating protocols for all 18F-labeled amyloid tracers. This implies that the results of the visual interpretation of amyloid imaging can be well standardized and do not depend on the rating protocol in experts. Consequently, the creation of a universal visual assessment protocol for all amyloid imaging tracers appears feasible, which could benefit especially the less-experienced readers.

Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET.

The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer's disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

Working memory training increases neural efficiency in Parkinson's disease: a randomized controlled trial.

Impairment of working memory and executive functions is already frequently observed in early stages of Parkinson's disease. Improvements in working memory performance in this cohort could potentially be achieved via working memory training. However, the specific neural mechanisms underlying different working memory processes such as maintenance as opposed to manipulation are largely under-investigated in Parkinson's disease. Moreover, the plasticity of these correlates as a function of working memory training is currently unknown in this population. Thus, the working memory subprocesses of maintenance and manipulation were assessed in 41 cognitively healthy patients with Parkinson's disease using a newly developed working memory paradigm and functional MRI. Nineteen patients were randomized to a 5-week home-based digital working memory training intervention while the remaining patients entered a control, wait list condition. Working memory task-related activation patterns and context-dependent functional connectivity, as well as the change of these neural correlates as a function of training, were assessed. While both working memory processes activated an extended frontoparietal-cerebellar network, only the manipulation of items within working memory also recruited the anterior striatum. The intervention effect on the neural correlates was small, but decreased activation in areas relevant for working memory could be observed, with activation changes correlating with behavioural change. Moreover, training seemed to result in decreased functional connectivity when pure maintenance was required, and in a reorganization of functional connectivity when items had to be manipulated. In accordance with the neural efficacy hypothesis, training resulted in overall reduced activation and reorganized functional connectivity, with a differential effect on the different working memory processes under investigation. Now, larger trials including follow-up examinations are needed to further explore the long-term effects of such interventions on a neural level and to estimate the clinical relevance to potentially delay cognitive decline in cognitively healthy patients with Parkinson's disease.

Are left atrial diverticula and left-sided septal pouches relevant additional findings in cardiac CT? Correlation between left atrial outpouching structures and ischemic brain alterations.

PURPOSE: To evaluate the correlation between left atrial diverticula (LAD) and left-sided septal pouches (LSSP) with ischemic brain alterations in MRI. METHODS: A retrospective analysis of 174 patients who received both, a dedicated cardiac CT angiography (CCTA) and a brain MRI examination was performed. Two radiologists independently reviewed all examinations for the presence of LAD and LSSP as well as ischemic alterations of the brain. Subsequently, the correlation between these cardiac and cerebral findings as well as to other potentially related risk factors was assessed. RESULTS: 71 LAD (total prevalence 41%) and 65 LSSP (total prevalence 37%) were identified in 174 patients. Combined prevalence was 10%. Ischemic brain alterations were found in patients with a LAD in 42.3% (30/71) and with a LSSP in 64.6% (42/65). Patients without any anatomical variant in the left atrium showed ischemic brain alterations in 39.4% (26/66). The presence of a LSSP was associated with an increased risk for ischemic brain alterations in multivariate logistic regression analysis after adjusting for other risk factors (OR = 3.57, 95% CI = 0.51-2.09, p <  .01). CONCLUSION: In our study cohort LAD and LSSP are highly prevalent anatomical structures within the left atrium. Patients with LSSP showed an approximated 3.5-fold higher probability for ischemic brain alterations. Therefore, LSSP should be considered as a potential risk factor for cardioembolic strokes and its presence should be stated in cardiac CT reports.

Effects of Home-Based Working Memory Training on Visuo-Spatial Working Memory in Parkinson's Disease: A Randomized Controlled Trial.

BACKGROUND: Cognitive impairment is a very frequent and severe nonmotor symptom of Parkinson's disease (PD). Early intervention in this at-risk group for cognitive decline may be crucial for long-term preservation of cognitive functions. Computerized working memory training (WMT) has been proven beneficial in non-PD patient populations, but such evidence is still needed for patients with PD. OBJECTIVE: This study aimed to evaluate the effect of WMT on visuo-spatial working memory (WM) in cognitively unimpaired patients with PD. METHODS: A single-blind randomized controlled trial encompassing 76 patients with PD but no cognitive impairment according to level II diagnostic criteria was conducted. Thirty-seven patients engaged in home-based adaptive WMT 5 times per week for a period of 5 weeks, whereas the remaining patients were in the waiting list arm of the study (control group [CG]). Working memory performance was evaluated using a computerized task before and after intervention and at 14-week follow-up, allowing to quantify the precision of WM on a continuous scale, ie, to test not only if an item was remembered but also how well the location of this item was retained. RESULTS: Coincidently, the WMT group showed slightly worse WM performance compared with the CG at baseline, which was ameliorated after WMT. This training-induced effect remained stable until follow-up. CONCLUSION: Patients showing relatively low WM performance, despite not formally diagnosable as Parkinson's disease with mild cognitive impairment (PD-MCI), seem to benefit from home-based WMT. Thus, WMT could potentially be implemented in future trials as a time- and cost-efficient route to counteract subtle cognitive changes in early disease stages. TRIAL REGISTRATION: German Clinical Trial Register (drks.de, DRKS00009379).