Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease.

BACKGROUND: Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end-organ damage. OBJECTIVE: To identify a biomarker for neurological involvement in WD. METHODS: Neuronal and glial-specific proteins were measured in plasma samples from 40 patients and 38 age-matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non-adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded. RESULTS: Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients. CONCLUSION: NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort.

OBJECTIVE: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI). METHODS: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception. RESULTS: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum. CONCLUSION: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.

Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: Initial application to the GENFI cohort.

Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Artificial grammar learning in vascular and progressive non-fluent aphasias.

Patients with non-fluent aphasias display impairments of expressive and receptive grammar. This has been attributed to deficits in processing configurational and hierarchical sequencing relationships. This hypothesis had not been formally tested. It was also controversial whether impairments are specific to language, or reflect domain general deficits in processing structured auditory sequences. Here we used an artificial grammar learning paradigm to compare the abilities of controls to participants with agrammatic aphasia of two different aetiologies: stroke and frontotemporal dementia. Ten patients with non-fluent variant primary progressive aphasia (nfvPPA), 12 with non-fluent aphasia due to stroke, and 11 controls implicitly learned a novel mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships. We compared response profiles for otherwise identical sequences of speech tokens (nonsense words) and tone sweeps. In all three groups the ability to detect grammatical violations varied with sequence complexity, with performance improving over time and being better for adjacent than non-adjacent relationships. Patients performed less well than controls overall, and this was related more strongly to aphasia severity than to aetiology. All groups improved with practice and performed well at a control task of detecting oddball nonwords. Crucially, group differences did not interact with sequence complexity, demonstrating that aphasic patients were not disproportionately impaired on complex structures. Hierarchical cluster analysis revealed that response patterns were very similar across all three groups, but very different between the nonsense word and tone tasks, despite identical artificial grammar structures. Overall, we demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently. The similarity of profiles of discriminatory abilities and rule learning across groups suggests that insights from previous studies of implicit sequence learning in vascular aphasia are likely to prove applicable in nfvPPA.

The role of high-field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward.

Historically, magnetic resonance imaging (MRI) has contributed little to the study of Parkinson's disease (PD), but modern MRI approaches have unveiled several complementary markers that are useful for research and clinical applications. Iron- and neuromelanin-sensitive MRI detect qualitative changes in the substantia nigra. Quantitative MRI markers can be derived from diffusion weighted and iron-sensitive imaging or volumetry. Functional brain alterations at rest or during task performance have been captured with functional and arterial spin labeling perfusion MRI. These markers are useful for the diagnosis of PD and atypical parkinsonism, to track disease progression from the premotor stages of these diseases and to better understand the neurobiological basis of clinical deficits. A current research goal using MRI is to generate time-dependent models of the evolution of PD biomarkers that can help understand neurodegeneration and provide reliable markers for therapeutic trials. This article reviews recent advances in MRI biomarker research at high-field (3T) and ultra high field-imaging (7T) in PD and atypical parkinsonism. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease.

BACKGROUND: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group. METHODS: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays. RESULTS: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. CONCLUSION: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Hierarchical Organization of Frontotemporal Networks for the Prediction of Stimuli across Multiple Dimensions.

Brain function can be conceived as a hierarchy of generative models that optimizes predictions of sensory inputs and minimizes "surprise." Each level of the hierarchy makes predictions of neural events at a lower level in the hierarchy, which returns a prediction error when these expectations are violated. We tested the generalization of this hypothesis to multiple sequential deviations, and we identified the most likely organization of the network that accommodates deviations in temporal structure of stimuli. Magnetoencephalography of healthy human participants during an auditory paradigm identified prediction error responses in bilateral primary auditory cortex, superior temporal gyrus, and lateral prefrontal cortex for deviation by frequency, intensity, location, duration, and silent gap. We examined the connectivity between cortical sources using a set of 21 generative models that embedded alternate hypotheses of frontotemporal network dynamics. Bayesian model selection provided evidence for two new features of functional network organization. First, an expectancy signal provided input to the prefrontal cortex bilaterally, related to the temporal structure of stimuli. Second, there are functionally significant lateral connections between superior temporal and/or prefrontal cortex. The results support a predictive coding hypothesis but go beyond previous work in demonstrating the generalization to multiple concurrent stimulus dimensions and the evidence for a temporal expectancy input at the higher level of the frontotemporal hierarchy. We propose that this framework for studying the brain's response to unexpected events is not limited to simple sensory tasks but may also apply to the neurocognitive mechanisms of higher cognitive functions and their disorders.

The impact of neurodegeneration on network connectivity: a study of change detection in frontotemporal dementia.

The neural response to unpredictable auditory events is suggested to depend on frontotemporal interactions. We used magnetoencephalography in patients with behavioral variant frontotemporal dementia to study change detection and to examine the impact of disease on macroscopic network connectivity underlying this core cognitive function. In patients, the amplitudes of auditory cortical responses to predictable standard tones were normal but were reduced for unpredictable deviant tones. Network connectivity, in terms of coherence among frontal, temporal, and parietal sources, was also abnormal in patients. In the beta frequency range, left frontotemporal coherence was reduced. In the gamma frequency range, frontal interhemispheric coherence was reduced whereas parietal interhemispheric coherence was enhanced. These results suggest impaired change detection resulting from dysfunctional frontotemporal interactions. They also provide evidence of a rostro-caudal reorganization of brain networks in disease. The sensitivity of magnetoencephalography to cortical network changes in behavioral variant frontotemporal dementia enriches the understanding of neurocognitive systems as well as showing potential for studies of experimental therapies for neurodegenerative disease.

Finding and feeling the musical beat: striatal dissociations between detection and prediction of regularity.

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.

Motor imagery after stroke: relating outcome to motor network connectivity.

OBJECTIVE: Neuroplasticity is essential for recovery after stroke and is the target for new stroke therapies. During recovery from subcortical motor stroke, brain activations associated with movement may appear normal despite residual functional impairment. This raises an important question: how far does recovery of motor performance depend on the processes that precede movement execution involving the premotor and prefrontal cortex, rather than recovery of the corticospinal system alone? METHODS: We examined stroke patients with functional magnetic resonance imaging while they either imagined or executed a finger-thumb opposition sequence. In addition to classical analyses of regional activations, we studied neuroplasticity in terms of differential network connectivity using structural equation modeling. The study included 8 right-handed patients who had suffered a left-hemisphere subcortical ischemic stroke with paresis, and 13 age-matched healthy controls. RESULTS: With good functional recovery, the regional activations had returned to normal in patients. However, connectivity within the extended motor network remained abnormal. These abnormalities were seen predominantly during motor imagery and correlated with motor performance. INTERPRETATION: Our results indicate that neuroplasticity can manifest itself as differences in connectivity among cortical areas remote from the infarct, rather than in the degree of regional activation. Connection strengths between nodes of the cortical motor network correlate with motor outcome. The altered organization of connectivity of the prefrontal areas may reflect the role of the prefrontal cortex in higher order planning of movement. Our results are relevant to the assessment and understanding of emerging physical and neurophysiological therapies for stroke rehabilitation.

Feeling the beat: premotor and striatal interactions in musicians and nonmusicians during beat perception.

Little is known about the underlying neurobiology of rhythm and beat perception, despite its universal cultural importance. Here we used functional magnetic resonance imaging to study rhythm perception in musicians and nonmusicians. Three conditions varied in the degree to which external reinforcement versus internal generation of the beat was required. The "volume" condition strongly externally marked the beat with volume changes, the "duration" condition marked the beat with weaker accents arising from duration changes, and the "unaccented" condition required the beat to be entirely internally generated. In all conditions, beat rhythms compared with nonbeat control rhythms revealed putamen activity. The presence of a beat was also associated with greater connectivity between the putamen and the supplementary motor area (SMA), the premotor cortex (PMC), and auditory cortex. In contrast, the type of accent within the beat conditions modulated the coupling between premotor and auditory cortex, with greater modulation for musicians than nonmusicians. Importantly, the response of the putamen to beat conditions was not attributable to differences in temporal complexity between the three rhythm conditions. We propose that a cortico-subcortical network including the putamen, SMA, and PMC is engaged for the analysis of temporal sequences and prediction or generation of putative beats, especially under conditions that may require internal generation of the beat. The importance of this system for auditory-motor interaction and development of precisely timed movement is suggested here by its facilitation in musicians.