Thomas E. Cope

18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

The extent to which the tau tracer [18F]AV-1451 can differentiate between tauopathies is unknown. By comparing patients with Alzheimer’s disease and progressive supranuclear palsy (PSP), Passamonti et al. show that [18F]AV-1451 displays greater specificity for Alzheimer-related tau pathology than PSP-related pathology. A machine learning algorithm correctly diagnosed 94% of cases.

The basal ganglia in perceptual timing: Timing performance in Multiple System Atrophy and Huntington's disease

The timing of perceptual events depends on an anatomically and functionally connected network comprising basal ganglia, cerebellum, pre-frontal cortex and supplementary motor area. Recent studies demonstrate the cerebellum to be involved in absolute, duration-based timing, but not in relative timing based on a regular beat. Conversely, functional involvement of the striatum is observed in relative timing, but its role in absolute timing is unclear. This work tests the specific role of the basal ganglia in the perceptual timing of auditory events. It aims to distinguish the hypothesised unified model of time perception (Teki, Grube, & Griffiths, 2012), in which the striatum is a mandatory component for all timing tasks, from a modular system in which they subserve relative timing, with absolute timing processed by the cerebellum. Test groups comprised individuals with Multiple System Atrophy, a disorder in which similar pathology can produce clinical deficits associated with dysfunction of the cerebellum (MSA-C, n=8) or striatum (MSA-P, n=10), and early symptomatic Huntingtons disease (HD, n=14). Individuals with chronic autoimmune peripheral neuropathy (n=11) acted as controls. Six adaptive tasks were carried out to assess perceptual thresholds for absolute timing through duration discrimination for sub- and supra-second time intervals, and relative timing through the detection of beat-based regularity and irregularity, detection of a delay within an isochronous sequence, and the discrimination of sequences with metrical structure. All three patient groups exhibited impairments in performance in comparison with the control group for all tasks, and severity of impairment was significantly correlated with disease progression. No differences were demonstrated between MSA-C and MSA-P, and the most severe impairments were observed in those with HD. The data support an obligatory role for the basal ganglia in all tested timing tasks, both absolute and relative, as predicted by the unified model. The results are not compatible with models of a brain timing network based upon independent modules.

Is musical hallucination an otological phenomenon? a review of the literature

Background:  Musical hallucination is the subjective experience of hearing music, or aspects of music, when none is being played, and as such is a disorder of the processing of complex sounds.

The Brain Basis for Misophonia

Summary Misophonia is an affective sound-processing disorder characterized by the experience of strong negative emotions (anger and anxiety) in response to everyday sounds, such as those generated by other people eating, drinking, chewing, and breathing [1, 2, 3, 4, 5, 6, 7, 8]. The commonplace nature of these sounds (often referred to as “trigger sounds”) makes misophonia a devastating disorder for sufferers and their families, and yet nothing is known about the underlying mechanism. Using functional and structural MRI coupled with physiological measurements, we demonstrate that misophonic subjects show specific trigger-sound-related responses in brain and body. Specifically, fMRI showed that in misophonic subjects, trigger sounds elicit greatly exaggerated blood-oxygen-level-dependent (BOLD) responses in the anterior insular cortex (AIC), a core hub of the “salience network” that is critical for perception of interoceptive signals and emotion processing. Trigger sounds in misophonics were associated with abnormal functional connectivity between AIC and a network of regions responsible for the processing and regulation of emotions, including ventromedial prefrontal cortex (vmPFC), posteromedial cortex (PMC), hippocampus, and amygdala. Trigger sounds elicited heightened heart rate (HR) and galvanic skin response (GSR) in misophonic subjects, which were mediated by AIC activity. Questionnaire analysis showed that misophonic subjects perceived their bodies differently: they scored higher on interoceptive sensibility than controls, consistent with abnormal functioning of AIC. Finally, brain structural measurements implied greater myelination within vmPFC in misophonic individuals. Overall, our results show that misophonia is a disorder in which abnormal salience is attributed to particular sounds based on the abnormal activation and functional connectivity of AIC.

[18F]AV-1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation

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‐Alzheimers 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 techniques specificity.

Auditory temporal-envelope processing in high-functioning children with Autism Spectrum Disorder.

Individuals with Autism Spectrum Disorder (ASD) perform worse than controls when listening to speech in a temporally modulated noise (Alcántara, Weisblatt, Moore, & Bolton, 2004; Groen et al., 2009). The current study examined whether this is due to poor auditory temporal-envelope processing. Temporal modulation transfer functions were measured in 6 high-functioning children with ASD and 6 control listeners, using sinusoidal amplitude modulation of a broadband noise. Modulation-depth thresholds at low modulation rates were significantly higher for the ASD group than for the Control group, and generally higher at all modulation rates tested. Low-pass filter model estimates of temporal-envelope resolution and temporal-processing efficiency showed significant differences between the groups for modulation-depth threshold values at low modulation rates. Intensity increment-detection thresholds, measured on a subset of individuals in the ASD and Control groups, were not significantly different. The results are consistent with ASD individuals having reduced processing efficiency of temporal modulations. Possible neural mechanisms that might underlie these findings are discussed.

Rapid-onset, linezolid-induced lactic acidosis in MELAS.

Due to their prokaryotic origins, mitochondria are susceptible to a number of antibiotics that target the bacterial ribosome, and this vulnerability is exacerbated by certain mutations of the mitochondrial genome. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome is characterised by biochemical and structural abnormalities of the muscle mitochondria, in which episodes of lactic acidosis stem from dysfunction of assembled respiratory complex I. Linezolid is an oxazolidinone antibiotic that has been reported to induce lactic acidosis, especially after prolonged administration, through inhibition of the mitochondrially synthesised components of oxidative phosphorylation. We report a patient with longstanding MELAS who suffered a severe lactic acidosis of rapid onset, with associated features of mitochondrial failure, shortly after the commencement of linezolid therapy and in the context of an otherwise improving clinical picture. This case emphasises the importance of circumspection when utilising drugs known to be toxic to the mitochondrion in patients with mitochondrial disease. In particular, given the biochemically plausible interaction, it would seem prudent to avoid the use of linezolid in patients with MELAS whenever possible.

Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy

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 Alzheimers disease but not progressive supranuclear palsy. Tau distribution in the latter is better explained by metabolic demand and trophic support.

[18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia

Introduction Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which to test the specificity of in vivo binding of the putative tau ligand [18F]AV-1451, which is elevated in frontotemporal lobar degeneration tauopathies. Methods and results Seven patients (five with svPPA and two with ‘right’ semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with [18F]AV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BPND (non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BPND was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of [18F]AV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity. Conclusions [18F]AV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for [18F]AV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed ‘off target’ binding sites for [18F]AV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of [18F]AV-1451 to differentiate and track different types of frontotemporal lobar degeneration.

Tinnitus Loudness in Quiet and Noise After Resection of Vestibular Schwannoma

Objectives: (1) To use a loudness model to assess the influence of loudness recruitment on estimates of the loudness of tinnitus obtained by loudness matching; (2) To compare the effect of background noise on the loudness of tinnitus for individuals who are unilaterally deaf after resection of vestibular schwannoma (VS) and those with idiopathic tinnitus. Background: After translabyrinthine resection of VS, patients experience unilateral deafness and tinnitus in the operated ear. Most complain that their tinnitus is more bothersome in noisy environments, unlike those with idiopathic tinnitus. Participants: Unilaterally deaf individuals experiencing tinnitus as a consequence of VS surgery and a comparison group with idiopathic tinnitus. Methods: Participants adjusted the level of a probe tone at the frequency where their hearing was best to match the loudness of their tinnitus in quiet; for VS participants, matches were made using a probe in the unaffected ear. Matches were then obtained in the presence of threshold-equalizing noise. Results: For those with idiopathic tinnitus, the probe loudness level, calculated using a loudness model, was almost invariant with hearing loss at the probe frequency and was usually between 20 and 50 phons. For the VS group, the probe loudness level ranged from 6 to 51 phons. With increasing threshold-equalizing-noise level, the loudness match decreased slightly for the comparison group but increased significantly for the VS group. Conclusion: The tinnitus in quiet had a moderate loudness for both groups. Background noise slightly decreased tinnitus loudness for most participants with idiopathic tinnitus but increased tinnitus loudness for VS participants. We propose 2 possible mechanisms for the effect of noise in the VS group.