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OBJECTIVES: Progressive supranuclear palsy (PSP) is characterized by deposition of straight filament tau aggregates in the grey matter (GM) of deep nuclei and cerebellum. We examined the relationship between tau pathology (assessed via 18F-AV1451 PET) and multimodal MRI imaging using GM volume, cortical thickness (CTh), and diffusion tensor imaging (DTI). METHODS: Twenty-three people with clinically probable PSP-Richardson's syndrome (age 68.8 ± 5.8 years, 39% female) and 23 controls underwent structural 3 T brain MRI including DTI. Twenty-one patients also had 18F-AV1451 PET imaging. Voxelwise volume-based morphometry, surface-based morphometry, and DTI correlations were performed with 18F-AV1451 binding in typical PSP regions of interest (putamen, thalamus and dentate cerebellum). Clinical impairment was also assessed in relation to the different imaging modalities. RESULTS: PSP subjects showed GM volume loss in frontotemporal regions, basal ganglia, midbrain, and cerebellum (FDR-corrected p < 0.05), reduced CTh in the left entorhinal and fusiform gyrus (p < 0.001) as well as DTI changes in the corpus callosum, internal capsule, and superior longitudinal fasciculus (FWE-corrected p < 0.05). In PSP, higher 18F-AV1451 binding correlated with GM volume loss in frontal regions, DTI changes in motor tracts, and cortical thinning in parietooccipital areas. Cognitive impairment was related to decreased GM volume in frontotemporal regions, thalamus and pallidum, as well as DTI alteration in corpus callosum and cingulum. CONCLUSION: This cross-sectional study demonstrates an association between in vivo proxy measures of tau pathology and grey and white matter degeneration in PSP. This adds to the present literature about the complex interplay between structural changes and protein deposition.

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Modern ischaemic stroke management involves intravenous thrombolysis followed by mechanical thrombectomy, which allows markedly higher rates of recanalization and penumbral salvage than thrombolysis alone. However, <50% of treated patients eventually enjoy independent life. It is therefore important to identify complementary therapeutic targets. In rodent models, the salvaged penumbra is consistently affected by selective neuronal loss, which may hinder recovery by interfering with plastic processes, as well as by microglial activation, which may exacerbate neuronal death. However, whether the salvaged penumbra in man is similarly affected is still unclear. Here we determined whether these two processes affect the non-infarcted penumbra in man and, if so, whether they are inter-related. We prospectively recruited patients with (i) acute middle-cerebral artery stroke; (ii) penumbra present on CT perfusion obtained <4.5 h of stroke onset; and (iii) early neurological recovery as a marker of penumbral salvage. PET with 11C-flumazenil and 11C-PK11195, as well as MRI to map the final infarct, were obtained at predefined follow-up times. The presence of selective neuronal loss and microglial activation was determined voxel-wise within the MRI normal-appearing ipsilateral non-infarcted zone and surviving penumbra masks, and their inter-relationship was assessed both across and within patients. Dilated infarct contours were consistently excluded to control for partial volume effects. Across the 16 recruited patients, there was reduced 11C-flumazenil and increased 11C-PK11195 binding in the whole ipsilateral non-infarcted zone (P = 0.04 and 0.02, respectively). Within the non-infarcted penumbra, 11C-flumazenil was also reduced (P = 0.001), but without clear increase in 11C-PK11195 (P = 0.18). There was no significant correlation between 11C-flumazenil and 11C-PK11195 in either compartment. This mechanistic study provides direct evidence for the presence of both neuronal loss and microglial activation in the ipsilateral non-infarcted zone. Further, we demonstrate the presence of neuronal loss affecting the surviving penumbra, with no or only mild microglial activation, and no significant relationship between these two processes. Thus, microglial activation may not contribute to penumbral neuronal loss in man, and its presence in the ipsilateral hemisphere may merely reflect secondary remote degeneration. Selective neuronal loss in the surviving penumbra may represent a novel therapeutic target as an adjunct to penumbral salvage to further improve functional outcome. However, microglial activation may not stand as the primary therapeutic approach. Protecting the penumbra by acutely improving perfusion and oxygenation in conjunction with thrombectomy for example, may be a better approach. 11C-flumazenil PET would be useful to monitor the effects of such therapies.

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The validation of tau radioligands could improve the diagnosis of frontotemporal lobar degeneration and the assessment of disease-modifying therapies. Here, we demonstrate that binding of the tau radioligand [18F]AV-1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT 10 + 16C>T gene mutation, recapitulating the pattern of neuropathology seen in her father. Given the genetic diagnosis and the non-Alzheimer's pathology, these findings suggest that [18F]AV-1451 might be a useful biomarker in primary tauopathies. Largerscale in vivo and post-mortem studies will be needed to assess the technique's specificity.

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Though stimulant drugs such as cocaine are considered highly addictive, some individuals report recreational use over long periods without developing dependence. Difficulties in response inhibition have been hypothesized to contribute to dependence, but previous studies investigating response inhibition in recreational cocaine users have reported conflicting results. Performance on a stop-signal task was examined in 24 recreational cocaine users and 32 healthy non-drug using control participants matched for age, gender and verbal intelligence during functional magnetic resonance imaging scanning. The two groups were further matched on traumatic childhood histories and the absence of family histories of addiction. Results revealed that recreational cocaine users did not significantly differ from controls on any index of task performance, including response execution and stop-signal reaction time, with the latter averaging 198 ms in both groups. Functional magnetic resonance imaging analyses indicated that, compared with controls, stopping in the recreational users was associated with increased activation in the pre-supplementary motor area but not the right inferior frontal cortex. Thus, findings imply intact response inhibition abilities in recreational cocaine users, though the distinct pattern of accompanying activation suggests increased recruitment of brain areas implicated in response inhibition. This increased recruitment could be attributed to compensatory mechanisms that enable preserved cognitive control in this group, possibly relating to their hypothetical resilience to stimulant drug dependence. Such overactivation, alternatively, may be attributable to prolonged cocaine use leading to neuroplastic adaptations.

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BACKGROUND: Although cocaine is known to be a highly addictive drug, there appears to be a select subset of individuals who are able to use the substance recreationally without developing dependence. These individuals do not report experiencing feelings of craving for cocaine, an important distinction from dependent users. However, no prior studies have compared attentional bias with cocaine cues between these groups to confirm this difference. Additionally, previous investigations into cognitive abilities in these individuals have been conflicting, and no research has been conducted on the neurobiological processes underlying cognitive functioning in this group. METHODS: This study administered the emotional cocaine-word Stroop to 27 recreational cocaine users, 50 stimulant-dependent individuals, and 52 healthy control participants during functional magnetic resonance imaging scanning. Behavioral and functional imaging results were compared between groups to assess attentional bias and cognitive effort to resist salient cocaine stimuli. RESULTS: Recreational users did not exhibit attentional bias to the cocaine words and did not differ from control subjects on task performance. Conversely, stimulant-dependent individuals were significantly more impaired on the task. Recreational participants also displayed a unique pattern of activation during performance, with significant underactivation in the orbitofrontal and anterior cingulate cortices compared with both dependent users and control subjects. CONCLUSIONS: The absence of bias to cocaine-related stimuli in recreational users indicates they do not share attentional preference for these words with dependent users. Their distinct pattern of activation suggests a decreased need for cognitive control due to diminished desire for the drug, potentially serving as a resilience factor against dependence.

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A neurocognitive endophenotype has been proposed for stimulant dependence, based on behavioral measures of inhibitory response control associated with white matter changes in the frontal cortex. This study investigated the functional neuroimaging correlates of inhibitory response control, as functional activity serves as a more dynamic measure than brain structure, allowing refinement of the suggested endophenotype. Stimulant-dependent individuals (SDIs), their unaffected siblings (SIBs), and healthy controls (CTs) performed the stop-signal task, including stop-signal reaction time (SSRT) as a measure of response inhibition, while undergoing functional magnetic resonance imaging. SDIs had impaired response inhibition accompanied by hypoactivation in the ventrolateral prefrontal cortex (PFC). In addition, they demonstrated hypoactivation in the anterior cingulate when failing to stop. In contrast, no hypoactivations were noted in their unaffected SIBs. Rather, they exhibited increased activation in the dorsomedial PFC relative to controls, together with inhibitory performance that was intermediate between that of the stimulant group and the healthy CT group. Such hyperactivations within the neurocircuitry underlying response inhibition and control are suggestive of compensatory mechanisms that could be protective in nature or could reflect coping with a pre-existing vulnerability, thus expressing potential aspects of resilience. The functional activation associated with response inhibition and error monitoring showed differential patterns of results between SDIs and their unaffected first-degree relatives, suggesting that the proposed endophenotype does not generalize to functional brain activity.

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