Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) represent challenging neurodegenerative disorders for clinicians and nonclinical scientists alike. Although initially lumped ...together as “Parkinson's‐Plus” syndromes, CBS and PSP are clinically and pathologically distinct from Parkinson's disease. It is now clear that behavioral and cognitive changes are common in both syndromes and affect impact quality of life and carer burden considerably. We briefly review the clinical, pathological, and neuroradiological features of each syndrome, followed by more detailed descriptions of the behavioral and cognitive deficits encountered in CBS and PSP. Clinically and pathologically heterogeneous, CBS is characterized by a wide range of cognitive and behavioral disturbances. impairments in executive function and memory are common, but nonspecific. In contrast, deficits in language and visuospatial abilities appear to be more distinctive features of CBS; the relevance of specific patterns of impairment to the underlying histopathology, or prognosis, remains to be fully elucidated. As in CBS, behavioral and cognitive changes are almost universal in PSP, with a wide range of reported deficits. Apathy is very common, often paradoxically accompanied by impulsivity. Executive dysfunction is prominent, but memory and visuospatial deficits also occur. An emerging field is the study of social cognition, which appears impaired in both syndromes. As therapeutic strategies for neurodegenerative pathologies emerge, more specific diagnostic tools in CBS and PSP will be required. Careful clinicopathological correlation, and the development of biomarkers for specific histopathologies, will be important milestones on the road to effective treatments.
Perception of temporal patterns is critical for speech, movement, and music. In the auditory domain, perception of a regular pulse, or beat, within a sequence of temporal intervals is associated with ...basal ganglia activity. Two alternative accounts of this striatal activity are possible: "searching" for temporal regularity in early stimulus processing stages or "prediction' of the timing of future tones after the beat is found (relying on continuation of an internally generated beat). To resolve between these accounts, we used functional magnetic resonance imaging (fMRI) to investigate different stages of beat perception. Participants heard a series of beat and nonbeat (irregular) monotone sequences. For each sequence, the preceding sequence provided a temporal beat context for the following sequence. Beat sequences were preceded by nonbeat sequences, requiring the beat to be found anew ("beat finding" condition), or by beat sequences with the same beat rate ("beat continuation"), or a different rate ("beat adjustment"). Detection of regularity is highest during beat finding, whereas generation and prediction are highest during beat continuation. We found the greatest striatal activity for beat continuation, less for beat adjustment, and the least for beat finding. Thus, the basal ganglia's response profile suggests a role in beat prediction, not in beat finding.
Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these ...projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer's disease, Parkinson's disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.
Murley and Rowe review the neurochemical changes arising from frontotemporal lobar degeneration, including the syndromes frontotemporal dementia, progressive supranuclear palsy and corticobasal ...degeneration. The evidence base from in vivo and post-mortem human studies, and preclinical models, suggests new strategies to facilitate the development of symptomatic pharmacological treatments, in stratified populations.
Abstract
Frontotemporal lobar degeneration causes a spectrum of complex degenerative disorders including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome, each of which is associated with changes in the principal neurotransmitter systems. We review the evidence for these neurochemical changes and propose that they contribute to symptomatology of frontotemporal lobar degeneration, over and above neuronal loss and atrophy. Despite the development of disease-modifying therapies, aiming to slow neuropathological progression, it remains important to advance symptomatic treatments to reduce the disease burden and improve patients' and carers' quality of life. We propose that targeting the selective deficiencies in neurotransmitter systems, including dopamine, noradrenaline, serotonin, acetylcholine, glutamate and gamma-aminobutyric acid is an important strategy towards this goal. We summarize the current evidence-base for pharmacological treatments and suggest strategies to improve the development of new, effective pharmacological treatments.
Abstract Background Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias. Methods Open-label, ...nonrandomized, multicenter, phase 3 study to validate the18 F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology. Results Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% 95% confidence interval or CI 93.8–100%, specificity 88.9% 95% CI 77.0–100%). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively. Conclusions Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD. Trial registration ClinicalTrials.gov NCT01020838.
•We performed meta-analyses on fMRI/PET studies of human intentional decision.•Intentional choices activate a brain network maximal in the medial frontal cortex.•Four types of intentional decision ...paradigms are identified in the literature.•Intentional decisions rely on regions with distinct cognitive and computational roles.
Brain-imaging research on intentional decision-making often employs a “free-choice” paradigm, in which participants choose among options with identical values or outcomes. Although the medial prefrontal cortex has commonly been associated with choices, there is no consensus on the wider network that underlies diverse intentional decisions and behaviours. Our systematic literature search identified 35 fMRI/PET experiments using various free-choice paradigms, with appropriate control conditions using external instructions. An Activation Likelihood Estimate (ALE) meta-analysis showed that, compared with external instructions, intentional decisions consistently activate the medial and dorsolateral prefrontal cortex, the left insula and the inferior parietal lobule. We then categorized the studies into four different types according to their experimental designs: reactive motor intention, perceptual intention, inhibitory intention, and cognitive intention. We conducted conjunction and contrast meta-analyses to identify consistent and selective spatial convergence of brain activation within each specific category of intentional decision. Finally, we used meta-analytic decoding to probe cognitive processes underlying free choices. Our findings suggest that the neurocognitive process underlying intentional decision incorporates anatomically separated components subserving distinct cognitive and computational roles.
Inflammation is increasingly implicated as a risk factor for dementia, stroke, and small vessel disease (SVD). However, the underlying mechanisms and causative pathways remain unclear. We ...systematically reviewed the existing literature on the associations between markers of inflammation and SVD (i.e., white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB)) in cohorts of older people with good health, cerebrovascular disease, or cognitive impairment. Based on distinctions made in the literature, markers of inflammation were classified as systemic inflammation (e.g. C-reactive protein, interleukin-6, fibrinogen) or vascular inflammation/endothelial dysfunction (e.g. homocysteine, von Willebrand factor, Lp-PLA2). Evidence from 82 articles revealed relatively robust associations between SVD and markers of vascular inflammation, especially amongst stroke patients, suggesting that alterations to the endothelium and blood-brain barrier may be a driving force behind SVD. Conversely, cross-sectional findings on systemic inflammation were mixed, although longitudinal investigations demonstrated that elevated levels of systemic inflammatory markers at baseline predicted subsequent SVD severity and progression. Importantly, regional analysis revealed that systemic and vascular inflammation were differentially related to two distinct forms of SVD. Specifically, markers of vascular inflammation tended to be associated with SVD in areas typical of hypertensive arteriopathy (e.g., basal ganglia), while systemic inflammation appeared to be involved in CAA-related vascular damage (e.g., centrum semiovale). Nonetheless, there is insufficient data to establish whether inflammation is causal of, or secondary to, SVD. Findings have important implications on interventions, suggesting the potential utility of treatments targeting the brain endothelium and blood brain barrier to combat SVD and associated neurodegenerative diseases.
Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain controversial. Using a ...stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree of modulation by the inferior frontal gyrus, predicted individual differences in participants' stopping performance (stop-signal reaction time). We then used diffusion-weighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures. Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control.
Prion-like, trans-neuronal spread of tau pathology in humans is controversial. By evaluating tau burden and functional connectivity in living patients, Cope et al. demonstrate relationships ...consistent with this in Alzheimer's disease but not progressive supranuclear palsy. Tau distribution in the latter is better explained by metabolic demand and trophic support.
Abstract
Alzheimer's disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer's disease, neuropathology and atrophy preferentially affect 'hub' brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer's disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer's disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer's disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker 'small-world' properties. Conversely, in PSP, unlike in Alzheimer's disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer's disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.
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