Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [18F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.

Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

PURPOSE: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. METHODS: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. RESULTS: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (ß = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (ß = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (ß = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. CONCLUSION: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

Psychometric Evaluation of the A-NKS: A Diagnostic Instrument to Assess Impairment of Activities of Daily Living in Mild and Major Neurocognitive Disorder According to DSM-5.

BACKGROUND: Activities of daily living (ADL) functioning are important in the diagnosis of neurocognitive disorders (NCD), yet no standardized and validated instrument exist based on international classification systems. OBJECTIVE: We aimed to psychometrically evaluate the differentiated assessment of ADL and instrumental ADL (IADL) impairments due to NCD according to DSM-5 criteria (Instrument für die Erfassung von Alltagsbeeinträchtigungen bei Neurokognitiven Störungen; A-NKS). METHODS: We conducted a pilot study involving 92 participant-informant dyads of participants with mild or major NCDs, cognitively healthy individuals, and an informant, to test acceptability, internal consistency, and convergent validity with similar measures. RESULTS: Both A-NKS versions demonstrated excellent internal consistency (α= 0.95 -0.99) and correlate with other instrumental ADL instruments (participant [informant]: Barthel Index: rs = -0.26, p≤0.05 [rs = -0.30, p≤0.01]; Amsterdam IADL: rs = 0.59, p≤0.01 [rs = 0.48, p≤0.01]; SIDAM ADL: rs = 0.46, p≤0.001 [rs = 0.47, p≤0.001]). Additionally, there are correlations with the scale autonomy of the WHOQOL-OLD (rs = -0.50, p≤0.001 [rs = -0.37, p≤0.001]) and physical, as well as cognitive activities (rs = -0.39, p≤0.001 [rs = -0.50, p≤0.001]). They were well-accepted by participants and informants. CONCLUSIONS: The A-NKS is an instrument with acceptable psychometric properties to assess ADL due to neurodegenerative decline in healthy individuals, and those with mild or major NCD. Further research is needed to confirm reliability and validity and investigate the factor structure.

TMS over the pre-SMA enhances semantic cognition via remote network effects on task-based activity and connectivity.

BACKGROUND: The continuous decline of executive abilities with age is mirrored by increased neural activity of domain-general networks during task processing. So far, it remains unclear how much domain-general networks contribute to domain-specific processes such as language when cognitive demands increase. The current neuroimaging study explored the potential of intermittent theta-burst stimulation (iTBS) over a domain-general hub to enhance executive and semantic processing in healthy middle-aged to older adults. METHODS: We implemented a cross-over within-subject study design with three task-based neuroimaging sessions per participant. Using an individualized stimulation approach, each participant received once effective and once sham iTBS over the pre-supplementary motor area (pre-SMA), a region of domain-general control. Subsequently, task-specific stimulation effects were assessed in functional MRI using a semantic and a non-verbal executive task with varying cognitive demand. RESULTS: Effective stimulation increased activity only during semantic processing in visual and dorsal attention networks. Further, iTBS induced increased seed-based connectivity in task-specific networks for semantic and executive conditions with high cognitive load but overall reduced whole-brain coupling between domain-general networks. Notably, stimulation-induced changes in activity and connectivity related differently to behavior: While stronger activity of the parietal dorsal attention network was linked to poorer semantic performance, its enhanced coupling with the pre-SMA was associated with more efficient semantic processing. CONCLUSIONS: iTBS modulates networks in a task-dependent manner and generates effects at regions remote to the stimulation site. These neural changes are linked to more efficient semantic processing, which underlines the general potential of network stimulation approaches in cognitive aging.

Stroke-GFCN: ischemic stroke lesion prediction with a fully convolutional graph network.

Purpose: The interpretation of image data plays a critical role during acute brain stroke diagnosis, and promptly defining the requirement of a surgical intervention will drastically impact the patient's outcome. However, determining stroke lesions purely from images can be a daunting task. Many studies proposed automatic segmentation methods for brain stroke lesions from medical images in different modalities, though heretofore results do not satisfy the requirements to be clinically reliable. We investigate the segmentation of brain stroke lesions using a geometric deep learning model that takes advantage of the intrinsic interconnected diffusion features in a set of multi-modal inputs consisting of computer tomography (CT) perfusion parameters. Approach: We propose a geometric deep learning model for the segmentation of ischemic stroke brain lesions that employs spline convolutions and unpooling/pooling operators on graphs to excerpt graph-structured features in a fully convolutional network architecture. In addition, we seek to understand the underlying principles governing the different components of our model. Accordingly, we structure the experiments in two parts: an evaluation of different architecture hyperparameters and a comparison with state-of-the-art methods. Results: The ablation study shows that deeper layers obtain a higher Dice coefficient score (DCS) of up to 0.3654. Comparing different pooling and unpooling methods shows that the best performing unpooling method is the proportional approach, yet it often smooths the segmentation border. Unpooling achieves segmentation results more adapted to the lesion boundary corroborated with systematic lower values of Hausdorff distance. The model performs at the level of state-of-the-art models without optimized training methods, such as augmentation or patches, with a DCS of 0.4553±0.0031. Conclusions: We proposed and evaluated an end-to-end trainable fully convolutional graph network architecture using spline convolutional layers for the ischemic stroke lesion prediction. We propose a model that employs graph-based operations to predict acute stroke brain lesions from CT perfusion parameters. Our results prove the feasibility of using geometric deep learning to solve segmentation problems, and our model shows a better performance than other models evaluated. The proposed model achieves improved metric values for the DCS metric, ranging from 8.61% to 69.05%, compared with other models trained under the same conditions. Next, we compare different pooling and unpooling operations in relation to their segmentation results, and we show that the model can produce segmentation outputs that adapt to irregular segmentation boundaries when using simple heuristic unpooling operations.

Associations of lesion location, structural disconnection, and functional diaschisis with depressive symptoms post stroke.

Introduction: Post-stroke depressive symptoms (PSDS) are common and relevant for patient outcome, but their complex pathophysiology is ill understood. It likely involves social, psychological and biological factors. Lesion location is a readily available information in stroke patients, but it is unclear if the neurobiological substrates of PSDS are spatially localized. Building on previous analyses, we sought to determine if PSDS are associated with specific lesion locations, structural disconnection and/or localized functional diaschisis. Methods: In a prospective observational study, we examined 270 patients with first-ever stroke with the Hospital Anxiety and Depression Scale (HADS) around 6 months post-stroke. Based on individual lesion locations and the depression subscale of the HADS we performed support vector regression lesion-symptom mapping, structural-disconnection-symptom mapping and functional lesion network-symptom-mapping, in a reanalysis of this previously published cohort to infer structure-function relationships. Results: We found that depressive symptoms were associated with (i) lesions in the right insula, right putamen, inferior frontal gyrus and right amygdala and (ii) structural disconnection in the right temporal lobe. In contrast, we found no association with localized functional diaschisis. In addition, we were unable to confirm a previously described association between depressive symptom load and a network damage score derived from functional disconnection maps. Discussion: Based on our results, and other recent lesion studies, we see growing evidence for a prominent role of right frontostriatal brain circuits in PSDS.

Tissue Outcome Prediction in Patients with Proximal Vessel Occlusion and Mechanical Thrombectomy Using Logistic Models.

Perfusion CT is established to aid selection of patients with proximal intracranial vessel occlusion for thrombectomy in the extended time window. Selection is mostly based on simple thresholding of perfusion parameter maps, which, however, does not exploit the full information hidden in the high-dimensional perfusion data. We implemented a multiparametric mass-univariate logistic model to predict tissue outcome based on data from 405 stroke patients with acute proximal vessel occlusion in the anterior circulation who underwent mechanical thrombectomy. Input parameters were acute multimodal CT imaging (perfusion, angiography, and non-contrast) as well as basic demographic and clinical parameters. The model was trained with the knowledge of recanalization status and final infarct localization. We found that perfusion parameter maps (CBF, CBV, and Tmax) were sufficient for tissue outcome prediction. Compared with single-parameter thresholding-based models, our logistic model had comparable volumetric accuracy, but was superior with respect to topographical accuracy (AUC of receiver operating characteristic). We also found higher spatial accuracy (Dice index) in an independent internal but not external cross-validation. Our results highlight the value of perfusion data compared with non-contrast CT, CT angiography and clinical information for tissue outcome-prediction. Multiparametric logistic prediction has high potential to outperform the single-parameter thresholding-based approach. In the future, the combination of tissue and functional outcome prediction might provide an individual biomarker for the benefit from mechanical thrombectomy in acute stroke care.

Thalamocortical disconnection involved in pusher syndrome.

The presence of both isolated thalamic and isolated cortical lesions have been reported in the context of pusher syndrome-a disorder characterized by a disturbed perception of one's own upright body posture, following unilateral left- or right-sided stroke. In recent times, indirect quantification of functional and structural disconnection increases the knowledge derived from focal brain lesions by inferring subsequent brain network damage from the respective lesion. We applied both measures to a sample of 124 stroke patients to investigate brain disconnection in pusher syndrome. Our results suggest a hub-like function of the posterior and lateral portions of the thalamus in the perception of one's own postural upright. Lesion network symptom mapping investigating functional disconnection indicated cortical diaschisis in cerebellar, frontal, parietal and temporal areas in patients with thalamic lesions suffering from pusher syndrome, but there was no evidence for functional diaschisis in pusher patients with cortical stroke and no evidence for the convergence of thalamic and cortical lesions onto a common functional network. Structural disconnection mapping identified posterior thalamic disconnection to temporal, pre-, post- and paracentral regions. Fibre tracking between the thalamic and cortical pusher lesion hotspots indicated that in cortical lesions of patients with pusher syndrome, it is disconnectivity to the posterior thalamus caused by accompanying white matter damage, rather than the direct cortical lesions themselves, that lead to the emergence of pusher syndrome. Our analyses thus offer the first evidence for a direct thalamo-cortical (or cortico-thalamic) interconnection and, more importantly, shed light on the location of the respective thalamo-cortical disconnections. Pusher syndrome seems to be a consequence of direct damage or of disconnection of the posterior thalamus.

Involvement of Thalamocortical Networks in Patients With Poststroke Thalamic Aphasia.

BACKGROUND AND OBJECTIVE: Theories assume that thalamic stroke may cause aphasia because of dysfunction in connected cortical networks. This takes into account that brain functions are organized in distributed networks, and in turn, localized damage may result in a network disorder such as thalamic aphasia. With this study, we investigate whether the integration of the thalamus into specific thalamocortical networks underlies symptoms after thalamic stroke. We hypothesize that thalamic lesions in patients with language impairments are functionally connected to cortical networks for language and cognition. METHODS: We combined nonparametric lesion mapping methods in a retrospective cohort of patients with acute or subacute first-ever thalamic stroke. A relationship between lesion location and language impairments was assessed using nonparametric voxel-based lesion-symptom mapping. This method reveals regions more frequently damaged in patients with compared with those without a symptom of interest. To test whether these symptoms are linked to a common thalamocortical network, we additionally performed lesion-network-symptom mapping. This method uses normative connectome data from resting-state fMRI of healthy participants (n = 65) for functional connectivity analyses, with lesion sites serving as seeds. Resulting lesion-dependent network connectivity of patients with language impairments was compared with those with motor and sensory deficits as baseline. RESULTS: A total of 101 patients (mean [SD] age 64.1 [14.6] years, 57 left, 42 right, and 2 bilateral lesions) were included in the study. Voxel-based lesion-symptom mapping showed an association of language impairments with damage to left mediodorsal thalamic nucleus lesions. Lesion-network-symptom mapping revealed that language compared with sensory deficits were associated with higher normative lesion-dependent network connectivity to left frontotemporal language networks and bilateral prefrontal, insulo-opercular, midline cingular, and parietal domain-general networks. Lesions related to motor and sensory deficits showed higher lesion-dependent network connectivity within the sensorimotor network spanning prefrontal, precentral, and postcentral cortices. DISCUSSION: Thalamic aphasia relates to lesions in the left mediodorsal thalamic nucleus and to functionally connected left cortical language and bilateral cortical networks for cognitive control. This suggests that dysfunction in thalamocortical networks contributes to thalamic aphasia. We propose that inefficient integration between otherwise undamaged domain-general and language networks may cause thalamic aphasia.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Age-related reorganization of functional network architecture in semantic cognition.

Cognitive aging is associated with widespread neural reorganization processes in the human brain. However, the behavioral impact of such reorganization is not well understood. The current neuroimaging study investigated age differences in the functional network architecture during semantic word retrieval in young and older adults. Combining task-based functional connectivity, graph theory and cognitive measures of fluid and crystallized intelligence, our findings show age-accompanied large-scale network reorganization even when older adults have intact word retrieval abilities. In particular, functional networks of older adults were characterized by reduced decoupling between systems, reduced segregation and efficiency, and a larger number of hub regions relative to young adults. Exploring the predictive utility of these age-related changes in network topology revealed high, albeit less efficient, performance for older adults whose brain graphs showed stronger dedifferentiation and reduced distinctiveness. Our results extend theoretical accounts on neurocognitive aging by revealing the compensational potential of the commonly reported pattern of network dedifferentiation when older adults can rely on their prior knowledge for successful task processing. However, we also demonstrate the limitations of such compensatory reorganization and show that a youth-like network architecture in terms of balanced integration and segregation is associated with more economical processing.

Cardiac function in relation to functional status and fatigue in patients with post-COVID syndrome.

Patients with Post-COVID syndrome (PCS) are frequently referred for cardiologic evaluation. We assessed cardiac function and biomarkers in relation to functional status and fatigue in patients with PCS. This prospective single-center cohort study included 227 patients with persisting symptoms after COVID-19 infection. Most frequent complaints were fatigue (70%), dyspnea (56%), neurocognitive symptoms (34%) and chest pain (28%). Standardized questionnaires were used to assess Post-COVID-Functional-Scale (PCFS) and fatigue (MFI-20). The fatigue severity was inversely related to age and did not correlate with cardiovascular diseases, echocardiographic findings, or biomarkers. Similarly, mild to moderate functional impairment (PCFS 1-3) did not correlate with cardiovascular alterations. However, the subgroup of patients with significant functional impairment (PCFS = 4) had more frequent cardiovascular comorbidities, biomarkers and impaired global longitudinal strain (GLS). Patients with elevated troponin T showed abnormal GLS, reduced left ventricular ejection fraction and impaired tricuspid annular plane systolic excursion. The majority of patients with PCS shows a normal cardiac function. Only the small subgroup of patients with severe functional impairment and patients with elevated troponin T is at risk for impaired cardiac function and likely to benefit from specialized care by a cardiologist.

Neuropsychiatric phenotype of post COVID-19 syndrome in non-hospitalized patients.

The post COVID-19 syndrome (PCS) is an emerging phenomenon worldwide with enormous socioeconomic impact. While many patients describe neuropsychiatric deficits, the symptoms are yet to be assessed and defined systematically. In this prospective cohort study, we report on the results of a neuropsychiatric consultation implemented in May 2021. A cohort of 105 consecutive patients with merely mild acute course of disease was identified by its high symptom load 6 months post infection using a standardized neurocognitive and psychiatric-psychosomatic assessment. In this cohort, we found a strong correlation between higher scores in questionnaires for fatigue (MFI-20), somatization (PHQ15) and depression (PHQ9) and worse functional outcome as measured by the post COVID functional scale (PCFS). In contrast, neurocognitive scales correlated with age, but not with PCFS. Standard laboratory and cardiopulmonary biomarkers did not differ between the group of patients with predominant neuropsychiatric symptoms and a control group of neuropsychiatrically unaffected PCS patients. Our study delineates a phenotype of PCS dominated by symptoms of fatigue, somatisation and depression. The strong association of psychiatric and psychosomatic symptoms with the PCFS warrants a systematic evaluation of psychosocial side effects of the pandemic itself and psychiatric comorbidities on the long-term outcome of patients with SARS-CoV-2 infection.

Association of Lesion Location and Depressive Symptoms Poststroke.

BACKGROUND: Depressive symptoms are a common stroke sequela, yet their neurobiological substrates are still unclear. We sought to determine if they are associated with specific lesion locations. METHODS: In a prospective observational study, 270 patients with stroke were tested twice with the Hospital Anxiety and Depression Scale around day 6 and again 6 months poststroke and voxel-based lesion behavior mapping was performed. RESULTS: Frequency of depressive symptoms (depression subscale of the Hospital Anxiety and Depression Scale >7) after 6 months was 19.6 %. Higher Hospital Anxiety and Depression Scale scores for depression around day 6 were the only variable associated with depressive symptoms after 6 months in a multiple logistic regression. Lesions in the right putamen were significantly associated with depressive symptoms after 6 months in the voxel-based lesion behavior mapping. CONCLUSIONS: Lesions in the right basal ganglia might increase the risk of depressive symptoms 6 months poststroke.

The Supratrochlear Artery Sign-A New Piece in the Puzzle of Cerebral Vasospasm.

BACKGROUND: Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) has been extensively investigated, but the impact of collateralization remains unclear. We investigated the predictive value of collateral activation for delayed cerebral ischemia (DCI)-related infarctions and functional outcome. METHODS: Data from 43 patients with CVS (January 2014 to August 2021) were evaluated for the angiographic presence of leptomeningeal and ophthalmic collaterals (anterior falcine artery (AFA), supratrochlear artery (STA), dorsal nasal artery (DNA)) on internal carotid artery angiograms. Vasospasm-related infarction and the modified Rankin Scale (mRS) score after six months were chosen as the endpoints. RESULTS: 77% of the patients suffered from DCI-related infarctions. In 233 angiograms (at hospitalization, before spasmolysis, after six months), positive vessel signs were observed in 31 patients for STA, 35 for DNA, and 31 for AFA. The STA sign had the highest positive (84.6%) and negative (85.7%) predictive value for unfavorable outcome (mRS 4-6) in patients aged ≥50 years. DNA and AFA signs were not meaningful predictors for either endpoint. Leptomeningeal collaterals showed a positive Pearson's correlation with the STA sign in 87.5% (p = 0.038) without providing any prediction for either endpoint. CONCLUSIONS: The STA sign is associated with clinical outcome in patients with CVS after SAH aged ≥50 years, and was correlated with the occurrence of leptomeningeal collaterals.

Voxelwise structural disconnection mapping: Methodological validation and recommendations.

Voxelwise disconnection mapping is a novel approach to disclose lesion-symptom relationships for symptoms caused by white matter disconnection. It uses MRI-based fiber tracking in healthy subjects seeded from patient's focal brain lesions. Resulting individual disconnection maps can then be statistically associated with symptoms. Despite increasing use in the recent years, the validity of this approach remains to be investigated. In this study, we validated both, our own implementation and the implementation provided within BCBtoolkit. For technical validation, we used simulated symptoms based on overlap of 70 real stroke lesions with tracts from a white matter atlas. For clinical validation, paresis scores and lesions from 316 patients with stroke were used. We found that voxelwise disconnection mapping is technically valid and outperforms the standard voxel-based lesion-symptom mapping approach for symptoms caused by white matter disconnection. Supporting its clinical validity and utility, we were able to reproduce the known association between corticospinal tract damage and contralateral hemiparesis. In addition, we demonstrate that the validity can be substantially diminished by relatively minor methodological changes. Based on these results, we derive methodological recommendations for the future use of voxelwise disconnection mapping. Our study highlights the importance of validating novel methodological approaches in the rapidly evolving field of neuroimaging.

fMRI informed voxel-based lesion analysis to identify lesions associated with right-hemispheric activation in aphasia recovery.

Several mechanisms have been attributed to post-stroke loss and recovery of language functions. However, the significance and timing of domain-general and homotopic right-hemispheric activation is controversial. We aimed to examine the effect of left-hemispheric lesion location and time post-stroke on right-hemispheric activation. Voxel-based lesion analyses were informed by auditory language-related fMRI activation of 71 patients with left middle cerebral artery stroke examined longitudinally in the acute, subacute and early chronic phase. Language activation was determined in several right-hemispheric regions of interest and served as regressor of interest for voxel-based lesion analyses. We found that an acute to chronic increase of language activation in the right supplementary motor area was associated with lesions to the left extreme capsule as part of the ventral language pathway. Importantly, this activation increase correlated significantly with improvement of out-of-scanner comprehension abilities. We interpret our findings in terms of successful domain-general compensation in patients with critical left frontotemporal disconnection due to damage to the ventral language pathway but relatively spared cortical language areas.

Differential Diagnosis Between Alzheimer's Disease-Related Depression and Pseudo-Dementia in Depression: A New Indication for Amyloid-ß Imaging?

BACKGROUND: Alzheimer's disease and depression can start with combined cognitive and depressive symptoms [1, 2]. Accurate differential diagnosis is desired to initiate specific treatment. OBJECTIVE: We investigated whether amyloid-ß PET imaging can discriminate both entities. METHODS: This retrospective observational study included 39 patients (20 female, age = 70±11years) with both cognitive and depressive symptoms who underwent amyloid-ß PET imaging and in whom clinical follow-up data was available. Amyloid-ß PET was carried out applying [18F]Florbetaben or [11C]PiB. The PET images were analyzed by standardized visual and relative-quantitative evaluation. Based on clinical follow-up (median of 2.4 years [range 0.3 to 7.0 years, IQR = 3.7 years] after amyloid PET imaging which was not considered in obtaining a definite diagnosis), discrimination ability between AD-related depression and pseudo-dementia in depression/depression with other comorbidities was determined. RESULTS: Visually, all 10 patients with pseudo-dementia in depression and all 15 patients with other depression were rated as amyloid-ß-negative; 2 of 14 patients with AD-related depression were rated amyloid-ß-negative. ROC curve analysis of the unified composite standardized uptake value ratios (cSUVRs) was able to discriminate pseudo-dementia in depression from AD-related depression with high accuracy (AUC = 0.92). Optimal [18F]Florbetaben discrimination cSUVR threshold was 1.34. In congruence with the visual PET analysis, the resulting sensitivity of the relative-quantitative analysis was 86% with a specificity of 100%. CONCLUSION: Amyloid-ß PET can differentiate AD-related depression and pseudo-dementia in depression. Prospective clinical studies are warranted to confirm this result and to potentially broaden the spectrum of clinical applications for amyloid-ß PET imaging.