PET Imaging in Dementia: Mini-Review and Canadian Perspective for Clinical Use.

PET imaging is increasingly recognized as an important diagnostic tool to investigate patients with cognitive disturbances of possible neurodegenerative origin. PET with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), assessing glucose metabolism, provides a measure of neurodegeneration and allows a precise differential diagnosis among the most common neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia or dementia with Lewy bodies. PET tracers specific for the pathological deposits characteristic of different neurodegenerative processes, namely amyloid and tau deposits typical of Alzheimer's Disease, allow the visualization of these aggregates in vivo. [18F]FDG and amyloid PET imaging have reached a high level of clinical validity and are since 2022 investigations that can be offered to patients in standard clinical care in most of Canada.This article will briefly review and summarize the current knowledge on these diagnostic tools, their integration into diagnostic algorithms as well as perspectives for future developments.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Adjusting gait step-by-step: Brain activation during split-belt treadmill walking.

When walking on a split-belt treadmill, where each leg is driven at a different speed, a temporary change is made to the typical steady-state walking pattern. The exact ways in which the brain controls these temporary changes to walking are still unknown. Ten young adults (23±3y) walked on a split-belt treadmill for 30 min on 2 separate occasions: tied-belt control with both belts at comfortable walking speed, and continuous adjustment where speed ratio between belts changed every 15 seconds. 18F-fluorodeoxyglucose (18FDG) positron emission tomography (PET) imaging measured whole brain glucose metabolism distribution, or activation, during each treadmill walking condition. The continuous adjustment condition, compared to the tied-belt control, was associated with increased activity of supplementary motor areas (SMA), posterior parietal cortex (PPC), anterior cingulate cortex and anterior lateral cerebellum, and decreased activity of posterior cingulate and medial prefrontal cortex. In addition, peak activation of the PPC, SMA and PFC were correlated with cadence and temporal gait variability. We propose that a "fine-tuning" network for human locomotion exists which includes brain areas for sensorimotor integration, motor planning and goal directed attention. These findings suggest that distinct regions govern the inherent flexibility of the human locomotor plan to maintain a successful and adjustable walking pattern.

Association between carotid atheroma and cerebral cortex structure at age 73 years.

OBJECTIVE: To examine the relationship between carotid atherosclerosis and cerebral cortical thickness and investigate whether cortical thickness mediates the association between carotid atheroma and relative cognitive decline. METHODS: We assessed 554 community-dwelling subjects (male/female: 296/258) from the Lothian Birth Cohort 1936 who underwent brain magnetic resonance imaging and carotid Doppler ultrasound studies at age 73 years. The relationship between carotid atherosclerosis markers (internal carotid artery stenosis, intima-media thickness, velocity, pulsatility, and resistivity indexes) and vertex-wide cerebral cortical thickness was examined cross-sectionally, controlling for gender, extensive vascular risk factors (VRFs), and intelligence quotient at age 11 (IQ-11). We also determined the association between carotid stenosis and a composite measure of fluid intelligence at age 73 years. A mediation model was applied to examine whether cortical thickness mediated the relationship between carotid stenosis and cognitive function. RESULTS: A widespread negative association was identified between carotid stenosis (median = 15%) and cerebral cortical thickness at age 73 years, independent of the side of carotid stenosis, other carotid measures, VRFs, and IQ-11. This association increased in an almost dose-response relationship from mild to severe degrees of carotid stenosis, across the anterior and posterior circulation territories. A negative association was also noted between carotid stenosis and fluid intelligence (standardized beta coefficient = -0.151, p = 0.001), which appeared partly (approximately 22%) mediated by carotid stenosis-related thinning of the cerebral cortex. INTERPRETATION: The findings suggest that carotid stenosis represents a marker of processes that accelerate aging of the cerebral cortex and cognition that is in part independent of measurable VRFs. Cortical thinning within the anterior and posterior circulation territories partially mediated the relationship between carotid atheroma and fluid intelligence. Ann Neurol 2018;84:576-587.

Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. SIGNIFICANCE STATEMENT: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.

Assessing neuronal density in peri-infarct cortex with PET: Effects of cortical topology and partial volume correction.

The peri-infarct cortex (PIC) is the site of long-term physiologic changes after ischemic stroke. Traditional methods for delineating the peri-infarct gray matter (GM) have used a volumetric Euclidean distance metric to define its extent around the infarct. This metric has limitations in the case of cortical stroke, i.e., those where ischemia leads to infarction in the cortical GM, because the vascularization of the cerebral cortex follows the complex, folded topology of the cortical surface. Instead, we used a geodesic distance metric along the cortical surface to subdivide the PIC into equidistant rings emanating from the infarct border and compared this new approach to a Euclidean distance metric definition. This was done in 11 patients with [F-18]-Flumazenil ([18-F]-FMZ) positron emission tomography (PET) scans at 2 weeks post-stroke and at 6 month follow-up. FMZ is a PET radiotracer with specific binding to the alpha subunits of the type A γ-aminobutyric acid (GABAA) receptor. Additionally, we used partial-volume correction (PVC) of the PET images to compensate for potential cortical thinning and long-term neuronal loss in follow-up images. The difference in non-displaceable binding potential (BPND ) between the stroke unaffected and affected hemispheres was 35% larger in the geodesic versus the Euclidean peri-infarct models in initial PET images and 48% larger in follow-up PET images. The inter-hemispheric BPND difference was approximately 17-20% larger after PVC when compared to uncorrected PET images. PET studies of peri-infarct GM in cortical strokes should use a geodesic model and include PVC as a preprocessing step. Hum Brain Mapp 38:326-338, 2017. © 2016 Wiley Periodicals, Inc.

Post-stroke dementia - a comprehensive review.

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing.

Neuroimaging in vascular cognitive impairment: a state-of-the-art review.

Imaging is critical in the diagnosis and treatment of dementia, particularly in vascular cognitive impairment, due to the visualization of ischemic and hemorrhagic injury of gray and white matter. Magnetic resonance imaging (MRI) and positron emission tomography (PET) provide structural and functional information. Clinical MRI is both generally available and versatile - T2-weighted images show infarcts, FLAIR shows white matter changes and lacunar infarcts, and susceptibility-weighted images reveal microbleeds. Diffusion MRI adds another dimension by showing graded damage to white matter, making it more sensitive to white matter injury than FLAIR. Regions of neuroinflammatory disruption of the blood-brain barrier with increased permeability can be quantified and visualized with dynamic contrast-enhanced MRI. PET shows metabolism of glucose and accumulation of amyloid and tau, which is useful in showing abnormal metabolism in Alzheimer's disease. Combining MRI and PET allows identification of patients with mixed dementia, with MRI showing white matter injury and PET demonstrating regional impairment of glucose metabolism and deposition of amyloid. Excellent anatomical detail can be observed with 7.0-Tesla MRI. Imaging is the optimal method to follow the effect of treatments since changes in MRI scans are seen prior to those in cognition. This review describes the role of various imaging modalities in the diagnosis and treatment of vascular cognitive impairment.

Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1.

BACKGROUND: Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. METHODS: Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C]-flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F]-fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. RESULTS: CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [11C]FMZ-binding was within the control range at all time points. Significant [18F]FMISO-retention (1.16 ± 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct. CONCLUSION: ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology.

Add-on Effects of Repetitive Transcranial Magnetic Stimulation on Subacute Aphasia Therapy: Enhanced Improvement of Functional Communication and Basic Linguistic Skills. A Randomized Controlled Study.

OBJECTIVE: To determine to what extent repetitive transcranial magnetic stimulation (rTMS) combined with speech and language therapy improves functional communication and basic linguistic skills of individuals with subacute aphasia. DESIGN: Randomized, blinded, and sham-controlled study. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Participants (N=30) with subacute aphasia after stroke. INTERVENTIONS: During a 2-week treatment period, half of the participants received 10 sessions of 20-minute inhibitory 1-Hz rTMS over the right inferior frontal gyrus (Brodmann area 45), and the other half received sham stimulation. Directly thereafter, all the participants underwent 45 minutes of speech and language therapy. MAIN OUTCOME MEASURES: Aachen Aphasia Test, Amsterdam-Nijmegen Everyday Language Test (ANELT), a naming screening, and subscales of the FIM, all assessed the day before and the day after treatment period. RESULTS: The participants who received real rTMS significantly improved with respect to all 10 measures of basic linguistic skills and functional communication, whereas sham-treated participants significantly improved in only 6 of 10 measures (paired t tests, P<.05). There was a significant difference in the gains made by the 2 groups on 5 of 10 measures including functional communication (ANELT) (repeated-measures analysis of variance, P≤.05). CONCLUSIONS: For the first time, this study has demonstrated that basic linguistic skills as well as functional communication are bolstered by combining rTMS and behavioral language therapy in patients with subacute aphasia.

Non-invasive repeated therapeutic stimulation for aphasia recovery: a multilingual, multicenter aphasia trial.

Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used in case series and small randomized controlled trials to improve recovery from poststroke aphasia in combination with speech and language therapy. Results of these studies suggest possible clinical efficacy and an excellent safety profile. Therefore, a larger international multicenter proof-of-concept trial was launched, to directly compare the safety and efficacy of rTMS, tDCS, and sham stimulation as adjuvant therapy to speech and language therapy in subacute poststroke aphasia. In the 4 participating centers, subacute stroke patients with aphasia are randomized between 5 and 30 days after ischemic stroke to either receive rTMS, tDCS, or sham stimulation in combination with a daily 45 minutes speech and language therapy session for 10 days. Efficacy is evaluated at 1 and 30 days after the last of the 10 treatment sessions using 3 outcome measures, validated in all participating languages: Boston naming test, Token test, and verbal fluency test. Additionally, adverse events are recorded to prove safety. In this study, a total of 90 patients will be recruited, and data analysis will be completed in 2016. This is the first multilingual and multinational randomized and controlled trial in poststroke aphasia and if positive, will add an effective new strategy for early stage poststroke aphasia rehabilitation.

Surface-based partial-volume correction for high-resolution PET.

Tissue radioactivity concentrations, measured with positron emission tomography (PET) are subject to partial volume effects (PVE) due to the limited spatial resolution of the scanner. Last generation high-resolution PET cameras with a full width at half maximum (FWHM) of 2-4mm are less prone to PVEs than previous generations. Corrections for PVEs are still necessary, especially when studying small brain stem nuclei or small variations in cortical neuroreceptor concentrations which may be related to cytoarchitectonic differences. Although several partial-volume correction (PVC) algorithms exist, these are frequently based on a priori assumptions about tracer distribution or only yield corrected values of regional activity concentrations without providing PVE corrected images. We developed a new iterative deconvolution algorithm (idSURF) for PVC of PET images that aims to overcome these limitations by using two innovative techniques: 1) the incorporation of anatomic information from a cortical gray matter surface representation, extracted from magnetic resonance imaging (MRI) and 2) the use of anatomically constrained filtering to attenuate noise. PVE corrected images were generated with idSURF implemented into a non-interactive processing pipeline. idSURF was validated using simulated and clinical PET data sets and compared to a frequently used standard PVC method (Geometric Transfer Matrix: GTM). The results on simulated data sets show that idSURF consistently recovers accurate radiotracer concentrations within 1-5% of true values. Both radiotracer concentrations and non-displaceable binding potential (BPnd) values derived from clinical PET data sets with idSURF were highly correlated with those obtained with the standard PVC method (R(2) = 0.99, error = 0%-3.2%). These results suggest that idSURF is a valid and potentially clinically useful PVC method for automatic processing of large numbers of PET data sets.

The complementary role of the cerebral hemispheres in recovery from aphasia after stroke: a critical review of literature.

OBJECTIVES: To review the literature on the specific role of the right cerebral hemisphere during recovery from aphasia in order to address the lack of consensus among authors. To derive a theoretical model reconciling the controversial findings in the literature. METHODS: Initial PubMed, MEDLINE (1946 to 5 May 2012) and PsycINFO (1806 to first week June 2012) searches on recovery mechanisms from aphasia, whether treatment-related or not, retrieved a total of 35 English language articles. Articles, cross-referenced in this initial set were also reviewed if they met the inclusion criteria, thus resulting in a total of 42 articles included in this review. MAIN OUTCOMES: Recruitment of the right hemisphere during recovery from aphasia can be effective if it occurs during a critical time window post-stroke. The recruitment's effectiveness will depend on the lesion's location, extent and permanence. Preservation of core language processing areas will generate minimal right hemisphere recruitment and vice versa. Some experimental studies seem to suggest that the improvement linked to a particular hemisphere can be modulated by specific therapy methods. CONCLUSION: The specific conditions in which effective right recruitment takes place may have important implications for rehabilitation treatment. These findings could lead to improved recovery in people suffering from aphasia. However, more research with non-invasive brain stimulation is needed.

Predicting Language Function Post-Stroke: A Model-Based Structural Connectivity Approach.

BACKGROUND: The prediction of post-stroke language function is essential for the development of individualized treatment plans based on the personal recovery potential of aphasic stroke patients. OBJECTIVE: To establish a framework for integrating information on connectivity disruption of the language network based on routinely collected clinical magnetic resonance (MR) images into Random Forest modeling to predict post-stroke language function. METHODS: Language function was assessed in 76 stroke patients from the Non-Invasive Repeated Therapeutic Stimulation for Aphasia Recovery trial, using the Token Test (TT), Boston Naming Test (BNT), and Semantic Verbal Fluency (sVF) Test as primary outcome measures. Individual infarct masks were superimposed onto a diffusion tensor imaging tractogram reference set to calculate Change in Connectivity scores of language-relevant gray matter regions as estimates of structural connectivity disruption. Multivariable Random Forest models were derived to predict language function. RESULTS: Random Forest models explained moderate to high amount of variance at baseline and follow-up for the TT (62.7% and 76.2%), BNT (47.0% and 84.3%), and sVF (52.2% and 61.1%). Initial language function and non-verbal cognitive ability were the most important variables to predict language function. Connectivity disruption explained additional variance, resulting in a prediction error increase of up to 12.8% with variable omission. Left middle temporal gyrus (12.8%) and supramarginal gyrus (9.8%) were identified as among the most important network nodes. CONCLUSION: Connectivity disruption of the language network adds predictive value beyond lesion volume, initial language function, and non-verbal cognitive ability. Obtaining information on connectivity disruption based on routine clinical MR images constitutes a significant advancement toward practical clinical application.

Effects of noninvasive brain stimulation on language networks and recovery in early poststroke aphasia.

BACKGROUND AND PURPOSE: Modulation of activity in language networks using repetitive transcranial magnetic stimulation (rTMS) may possibly support recovery from poststroke aphasia. Case series and feasibility studies seem to indicate a therapeutic effect; however, randomized sham-controlled, proof-of-principle studies relating clinical effects to activation patterns are missing. METHODS: Twenty-four patients with subacute poststroke aphasia were randomized to a 10-day protocol of 20-minute inhibitory 1 Hz rTMS over the right triangular part of the posterior inferior frontal gyrus or sham stimulation, followed by 45 minutes of speech and language therapy. Activity in language networks was measured with O-15-water positron emission tomography during verb generation before and after treatment. Language performance was assessed using the Aachen Aphasia Test battery. RESULTS: The primary outcome measure, global Aachen Aphasia Test score change, was significantly higher in the rTMS group (t test, P=0.003). Increases were largest for subtest naming (P=0.002) and tended to be higher for comprehension, token test, and writing (P<0.1). Patients in the rTMS group activated proportionally more voxels in the left hemisphere after treatment than before (difference in activation volume index) compared with sham-treated patients (t test, P=0.002).There was a moderate but significant linear relationship between activation volume index change and global Aachen Aphasia Test score change (r2=0.25; P=0.015). CONCLUSIONS: Ten sessions of inhibitory rTMS over the right posterior inferior frontal gyrus, in combination with speech and language therapy, significantly improve language recovery in subacute ischemic stroke and favor recruitment of left-hemispheric language networks.

Noninvasive brain stimulation for treatment of right- and left-handed poststroke aphasics.

BACKGROUND: Accumulating evidence from single case studies, small case series and randomized controlled trials seems to suggest that inhibitory noninvasive brain stimulation (NIBS) over the contralesional inferior frontal gyrus (IFG) of right-handers in conjunction with speech and language therapy (SLT) improves recovery from poststroke aphasia. Application of inhibitory NIBS to improve recovery in left-handed patients has not yet been reported. METHODS: A total of 29 right-handed subacute poststroke aphasics were randomized to receive either 10 sessions of SLT following 20 min of inhibitory repetitive transcranial magnetic stimulation (rTMS) over the contralesional IFG or 10 sessions of SLT following sham stimulation; 2 left-handers were treated according to the same protocol with real rTMS. Language activation patterns were assessed with positron emission tomography prior to and after the treatment; 95% confidence intervals for changes in language performance scores and the activated brain volumes in both hemispheres were derived from TMS- and sham-treated right-handed patients and compared to the same parameters in left-handers. RESULTS: Right-handed patients treated with rTMS showed better recovery of language function in global aphasia test scores (t test, p < 0.002) as well as in picture-naming performance (ANOVA, p = 0.03) than sham-treated right-handers. In treated right-handers, a shift of activation to the ipsilesional hemisphere was observed, while sham-treated patients consolidated network activity in the contralesional hemisphere (repeated-measures ANOVA, p = 0.009). Both left-handed patients also improved, with 1 patient within the confidence limits of TMS-treated right-handers (23 points, 15.9-28.9) and the other patient within the limits of sham-treated subjects (8 points, 2.8-14.5). Both patients exhibited only a very small interhemispheric shift, much less than expected in TMS-treated right-handers, and more or less consolidated initially active networks in both hemispheres. CONCLUSION: Inhibitory rTMS over the nondominant IFG appears to be a safe and effective treatment for right-handed poststroke aphasics. In the 2 cases of left-handed aphasics no deterioration of language performance was observed with this protocol. However, therapeutic efficiency is less obvious and seems to be more related to the dominance pattern prior to the stroke than to the TMS intervention.

Towards tropomyosin-related kinase B (TrkB) receptor ligands for brain imaging with PET: radiosynthesis and evaluation of 2-(4-[(18)F]fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one and 2-(4-([N-methyl-(11)C]-dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-one.

The interaction of tropomyosin-related kinase B (TrkB) with the cognate ligand brain-derived neurotrophic factor (BDNF) mediates fundamental pathways in the development of the nervous system. TrkB signaling alterations are linked to numerous neurodegenerative diseases and conditions. Herein we report the synthesis, biological evaluation and radiosynthesis of the first TrkB radioligands based on the recently identified 7,8-dihydroxyflavone chemotype. 2-(4-[(18)F]fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one ([(18)F]10b) was synthesized in high radiochemical yields via an efficient SNAr radiofluorination involving a para-Michael acceptor substituted aryl followed by BBr3-promoted double demethylation. Selective N-[(11)C]methylation afforded 2-(4-([N-methyl-(11)C]-dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-one ([(11)C]10c) from the fully deprotected catechol-bearing normethyl precursor 13 with [(11)C]MeOTf. In vitro autoradiography of [(18)F]10b with transverse rat brain sections revealed high specific binding in the cortex, striatum, hippocampus and thalamus in accordance with expected TrkB distribution. Blockade experiments with both 7,8-dihydroxyflavone (1a) and TrkB cognate ligand, BDNF, led to decreases of 80% and 85% of radioligand binding strongly supporting the hypothesis that 7,8-dihydroxyflavones exert their effect on TrkB phosphorylation via direct TrkB extracellular domain (ECD) binding. Positron emission tomography (PET) studies revealed that [(18)F]10b and [(11)C]10c brain uptake is minimal and that they are rapidly eliminated from the plasma (effective plasma half-life 5-10 min) via hepatic secretion. Nevertheless, the high specific binding and TrkB specificity derived from in vitro experiments suggests that the 7,8-disubstituted flavone chemotype represents a promising scaffold for the development of TrkB radiotracers for PET.

Dosimetry of [18F]TRACK, the first PET tracer for imaging of TrkB/C receptors in humans.

BACKGROUND: Reduced expression or impaired signalling of tropomyosin receptor kinases (Trk receptors) are found in a vast spectrum of CNS disorders. [18F]TRACK is the first PET radioligand for TrkB/C with proven in vivo brain penetration and on-target specific signal. Here we report dosimetry data for [18F]TRACK in healthy humans. 6 healthy participants (age 22-61 y, 3 female) were scanned on a General Electric Discovery PET/CT 690 scanner. [18F]TRACK was synthesized with high molar activities (Am = 250 ± 75 GBq/µmol), and a dynamic series of 12 whole-body scans were acquired after injection of 129 to 147 MBq of the tracer. Images were reconstructed with standard corrections using the manufacturer's OSEM algorithm. Tracer concentration time-activity curves (TACs) were obtained using CT-derived volumes-of-interest. Organ-specific doses and the total effective dose were estimated using the Committee on Medical Internal Radiation Dose equation for adults and tabulated Source tissue values (S values). RESULTS: Average organ absorbed dose was highest for liver and gall bladder with 6.1E-2 (± 1.06E-2) mGy/MBq and 4.6 (± 1.18E-2) mGy/MBq, respectively. Total detriment weighted effective dose EDW was 1.63E-2 ± 1.68E-3 mSv/MBq. Organ-specific TACs indicated predominantly hepatic tracer elimination. CONCLUSION: Total and organ-specific effective doses for [18F]TRACK are low and the dosimetry profile is similar to other 18F-labelled radio tracers currently used in clinical settings.

Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease.

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aß-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aß-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aß-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aß-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aß-PET related more closely to higher cortical Aß (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aß-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.