International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson Patients: Potential Treatment to Improve Insulin-Like Growth Factor-1 Function.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) function is impaired in Parkinson disease. Cyclic glycine-proline (cGP), a metabolite of IGF-1, is neuroprotective through improving IGF-1 function. Parkinson disease patients score lower on Hospital-associated Anxiety and Depression Scale after supplementing blackcurrant anthocyanins (BCA), which may be associated with IGF-1 function. We evaluated the changes of cGP and IGF-1 before and after the supplementation. METHODS: Plasma and cerebrospinal fluid (CSF) were collected from 11 male patients before and after 28 day supplementation of BCA. The concentrations of IGF-1, IGF binding protein (IGFBP)-3, and cGP were measured using ELISA and HPLC-MS assays. The presence of cGP in the BCA was evaluated. RESULTS: cGP presented in the BCA. BCA supplementation increased the concentration of cGP (p < 0.01), but not IGF-1 and IGFBP-3 in the CSF. CSF concentration of cGP was correlated with plasma concentration of cGP (R = 0.68, p = 0.01) and cGP/IGF-1 molar ratio (R = 0.66, p = 0.01). The CSF/plasma ratio was high in cGP and low in IGF-1 and IGFBP-3. CONCLUSION: cGP is a natural nutrient to the BCA. The increased CSF cGP in Parkinson disease patients may result from the central uptake of plasma cGP. Given neurotrophic function, oral availability, and effective central uptake of cGP, the BCA has the potential to be developed to treat neurological conditions with IGF-1 deficiency.

Deep grey matter MRI abnormalities and cognitive function in relapsing-remitting multiple sclerosis.

Although deep grey matter (GM) involvement in multiple sclerosis (MS) is well documented, in-vivo multi-parameter magnetic resonance imaging (MRI) studies and association with detailed cognitive measures are limited. We investigated volumetric, diffusion and perfusion metrics in thalamus, hippocampus, putamen, caudate nucleus and globus pallidum, and neuropsychological measures, spanning 4 cognitive domains, in 60 relapsing-remitting MS patients (RRMS) (mean disease duration of 5.1 years, median EDSS of 1.5) and 30 healthy controls. There was significantly reduced volume of thalamus, hippocampus and putamen in the RRMS patients, but no diffusion or perfusion changes in these structures. Decreased volume in these deep GM volumes in RRMS patients was associated with a modest reduction in cognitive performance, particularly information processing speed, consistent with a subtle disruption of distributed networks, that subserve cognition, in these patients. Future longitudinal studies are needed to elucidate the influence of deep GM changes on the evolution of cognitive deficits in MS.

Differential effects of neuromuscular electrical stimulation parameters on submental motor-evoked potentials.

BACKGROUND: Neuromuscular electrical stimulation (NMES) of the muscles underlying the pharynx and faucial pillars affects the excitability of corticobulbar projections in a frequency- and duration-specific manner. The anterior hyomandibular (submental) muscles are primary targets for the clinical application of NMES to improve disordered swallowing, but the optimal NMES parameters for this application are unknown. OBJECTIVE: To determine the influence of NMES parameters on the excitability of corticobulbar projections to the submental musculature. METHODS: Transcranial magnetic stimulation (TMS) was used in event-related protocols, triggered by either volitional contraction of the submental muscles or pharyngeal swallowing, to assess corticobulbar excitability prior to, immediately following, and 30, 60, and 90 minutes post-NMES in 25 healthy volunteers. In the first 2 experiments, 4 stimulus frequencies (5, 20, 40, and 80 Hz) and 3 NMES dosages, manipulated through stimulus train durations or number of repetitions, were evaluated. The optimal excitatory NMES triggered by volitional swallowing (event-related NMES) was then replicated in a new sample and contrasted with non-event-related NMES (either discrete events or continuously for 1 hour). RESULTS: It was found that 80Hz NMES increased motor-evoked potential (MEP) amplitude at 30 minutes and 60 minutes poststimulation only after 60 repetitions of 4-s event-related NMES trains. Non-event-related and continuous NMES did not affect MEP amplitudes. No changes in MEP onset latencies were observed. CONCLUSIONS: Changes in corticobulbar excitability induced by NMES of the submental muscle group are frequency and dose dependent and only occur after NMES triggered by volitional swallowing. Underlying neural mechanisms are discussed.

Towards therapy to relieve memory impairment after anterior thalamic lesions: improved spatial working memory after immediate and delayed postoperative enrichment.

Injury to the anterior thalamic nuclei (ATN) is associated with severe amnesia in humans. To test the principle that these deficits may be amenable to intervention, the behavioural effects of postoperative housing in an enriched environment were examined in rats that received neurotoxic lesions of the ATN. As expected, rats with ATN lesions maintained in standard group-housing showed severe, and in this case long-term, deficits in a preoperatively trained non-matching-to-sample spatial working memory task. Thirty days of enriched housing, introduced either at 5 days (Experiment 1) or delayed until 40 days post-surgery (Experiment 2) markedly reduced this working memory impairment, including evidence of improved utilization of spatial cues. The treatment gains found in Experiment 2 were maintained at 4 months post-surgery despite no further enrichment. ATN lesions also retarded the postoperative acquisition of spatial discrimination problems in Experiment 1, irrespective of the separation between target arms, but this impairment was not ameliorated by the prior enrichment. This study provides the first evidence of substantial recovery of severe, and otherwise long-lasting, spatial working memory deficits after ATN brain injury and suggests that further investigation on the extent of possible recovery of function in animal models of diencephalic amnesia is warranted.

Odour-place paired-associate learning and limbic thalamus: comparison of anterior, lateral and medial thalamic lesions.

Several subregions in the limbic thalamus have been suggested as the key locus for diencephalic amnesia, including the anterior thalamic nuclei, intralaminar nuclei and mediodorsal nuclei. There is, however, no consensus as to a single critical site and recent research has suggested instead that different thalamic areas may contribute to diencephalic amnesia in subtly different ways. This study compared the effects of lesions to anterior (AT), lateral (LT) and posteromedial (MT) aggregates of thalamic nuclei on Gilbert and Kesner's [Gilbert, PE, Kesner, RP. Role of the rodent hippocampus in paired-associate learning involving associations between a stimulus and a spatial location. Behav Neurosci 2002;116(1):63-71; Gilbert, PE, Kesner, RP. Localization of function within the dorsal hippocampus: the role of the CA3 subregion in paired-associate learning. Behav Neurosci 2003;117(6):1385-94] paired-associate task, in which rats were postoperatively trained to form an arbitrary association between odours and spatial locations in a circular open field. Both AT and LT lesions, but not MT lesions, severely impaired odour-place paired-associate learning. Probe trials revealed that the rats were not using specific location information after acquisition training. All groups were able to learn non-associative odour and place discrimination tasks quickly, with only the AT group showing delayed acquisition. This study provides the first direct comparison of different thalamic lesions on paired-associate learning and new evidence on the importance of the LT region in learning and memory. The results support the notion that injury to both the AT and LT subregions of the thalamus may each be major contributors to diencephalic amnesia. There is need for traditional models of memory function to take greater account of the contributions of thalamic nuclei.

Dissociable memory effects after medial thalamus lesions in the rat.

Variable neuropathology in cases of diencephalic amnesia has led to uncertainty in identifying key thalamic nuclei and their potential role in learning and memory. Based on the principal neural connections of the medial thalamus, the current study tested the hypothesis that different aggregates of thalamic nuclei contribute to separate memory systems. Lesions of the anterior thalamic aggregate (AT), which comprises the anterodorsal, anteromedial and anteroventral nuclei produced substantial deficits in both working and reference spatial memory in a radial arm maze task in rats, supporting the view that the AT is an integral part of a hippocampal memory system. Lesions to the lateral thalamic aggregate (LT), which comprises the intralaminar nuclei (centrolateral, paracentral and rostral central medial nuclei) and lateral mediodorsal thalamic nuclei (lateral and paralamellar nuclei) produced a mild working memory impairment only, while lesions to the posteromedial thalamic aggregate (MT), which comprises the central and medial mediodorsal thalamic nuclei and the intermediodorsal nucleus had no effect on radial arm maze performance. In contrast, only MT lesions impaired learning associated with memory for reward value, consistent with the idea that the MT contributes to an amygdala memory system. Compared with chance discrimination, the control and AT groups, but not MT or LT groups, showed evidence for temporal order memory for two recently presented objects; all groups showed intact object recognition for novel vs. familiar objects. These new dissociations show that different medial thalamic aggregates participate in multiple memory systems and reinforce the idea that memory deficits in diencephalic amnesics may vary as a function of the relative involvement of different thalamic regions.

Spatial working memory and the brainstem cholinergic innervation to the anterior thalamus.

The anteroventral thalamic nucleus (AV) has a role in spatial memory, but the influence of the prominent brainstem cholinergic projection to this region is unknown. Here, spatial memory in a 12-arm radial maze was examined after 0.15 microl bilateral AV infusions of scopolamine. In part one, rats visited six arms singly (the phase 1 arms) and, after a 10 min delay, were allowed free choice to both phase 1 arms and the remaining six baited arms (phase 2 arms). Scopolamine (10 microg) administered during the delay increased errors to both phase 1 and phase 2 arms, whereas PBS infusions increased phase 1 arm errors only. The PBS effect was the result of inserting the internal cannulas alone and not the infusion. The same dose of scopolamine (10 microg) infused before maze testing (part two: no phase 1 arms, no delay) also impaired spatial memory over and above the effects of both PBS and no-infusion, which did not differ markedly. Part two also showed that choice latency and choice strategies were unaffected by PBS and scopolamine. Cannulation and infusion procedures in both parts one and two did not produce any negative carryover effects across multiple control (no internal cannula) sessions, and a trypan blue manipulation indicated that infusions were restricted to the AV region. This study provides the first direct evidence that the brainstem cholinergic innervation to the limbic thalamus influences learning and memory, which may have important implications for human neurological conditions such as alcohol-related disorders and schizophrenia.