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Winston, Alan; Henderson, Merle
doi: 10.1093/brain/awae310pmid: 39394804
This scientific commentary refers to ‘Serum and CSF biomarkers in asymptomatic patients during primary HIV infection: a randomized study’ by Calcagno et al. (https://doi.org/10.1093/brain/awae271).
doi: 10.1093/brain/awae307pmid: 39331738
This scientific commentary refers to ‘Direct current stimulation modulates prefrontal cell activity and behaviour without inducing seizure-like firing’ by Fehring et al. (https://doi.org/10.1093/brain/awae273).
Ballanger, Bénédicte; Boulinguez, Philippe
doi: 10.1093/brain/awae328pmid: 39414256
This scientific commentary refers to ‘Neurophysiological markers of motor compensatory mechanisms in early Parkinson’s disease’ by Passaretti et al. (https://doi.org/10.1093/brain/awae210).
Herz, Damian M; Frank, Michael J; Tan, Huiling; Groppa, Sergiu
doi: 10.1093/brain/awae184pmid: 38869168
Control of actions allows adaptive, goal-directed behaviour. The basal ganglia, including the subthalamic nucleus, are thought to play a central role in dynamically controlling actions through recurrent negative feedback loops with the cerebral cortex. Here, we summarize recent translational studies that used deep brain stimulation to record neural activity from and apply electrical stimulation to the subthalamic nucleus in people with Parkinson’s disease.These studies have elucidated spatial, spectral and temporal features of the neural mechanisms underlying the controlled delay of actions in cortico-subthalamic networks and demonstrated their causal effects on behaviour in distinct processing windows. While these mechanisms have been conceptualized as control signals for suppressing impulsive response tendencies in conflict tasks and as decision threshold adjustments in value-based and perceptual decisions, we propose a common framework linking decision-making, cognition and movement. Within this framework, subthalamic deep brain stimulation can lead to suboptimal choices by reducing the time that patients take for deliberation before committing to an action. However, clinical studies have consistently shown that the occurrence of impulse control disorders is reduced, not increased, after subthalamic deep brain stimulation surgery. This apparent contradiction can be reconciled when recognizing the multifaceted nature of impulsivity, its underlying mechanisms and modulation by treatment. While subthalamic deep brain stimulation renders patients susceptible to making decisions without proper forethought, this can be disentangled from effects related to dopamine comprising sensitivity to benefits versus costs, reward delay aversion and learning from outcomes.Alterations in these dopamine-mediated mechanisms are thought to underlie the development of impulse control disorders and can be relatively spared with reduced dopaminergic medication after subthalamic deep brain stimulation. Together, results from studies using deep brain stimulation as an experimental tool have improved our understanding of action control in the human brain and have important implications for treatment of patients with neurological disorders.
Filippi, Massimo; Preziosa, Paolo; Barkhof, Frederik; Ciccarelli, Olga; Cossarizza, Andrea; De Stefano, Nicola; Gasperini, Claudio; Geraldes, Ruth; Granziera, Cristina; Haider, Lukas; Lassmann, Hans; Margoni, Monica; Pontillo, Giuseppe; Ropele, Stefan; Rovira, Àlex; Sastre-Garriga, Jaume; Yousry, Tarek A; Rocca, Maria A
Benkirane, Mehdi; Bonhomme, Marion; Morsy, Heba; Safgren, Stephanie L; Marelli, Cecilia; Chaussenot, Annabelle; Smedley, Damian; Cipriani, Valentina; de Sainte-Agathe, Jean-Madeleine; Ding, Can; Larrieu, Lise; Vestito, Letizia; Margot, Henri; Lesca, Gaetan; Ramond, Francis;
Spitz, Gershon; Hicks, Amelia J; McDonald, Stuart J; Dore, Vincent; Krishnadas, Natasha; O’Brien, Terence J; O’Brien, William T; Vivash, Lucy; Law, Meng; Ponsford, Jennie L; Rowe, Christopher; Shultz, Sandy R
doi: 10.1093/brain/awae255pmid: 39315931
Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition.We recruited participants ≥40 years of age who had suffered a single moderate–severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory.A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10–33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = −2.17, SE = 1.06, P = 0.043, 95% CI [−4.28, −0.07]; long delay: bP-tau = −2.56, SE = 1.08, P = 0.020, 95% CI [−4.71, −0.41]}, tau {immediate memory: bTau = −6.22, SE = 2.47, P = 0.014, 95% CI [−11.14, −1.30]} and UCH-L1 {immediate memory: bUCH-L1 = −2.14, SE = 1.07, P = 0.048, 95% CI [−4.26, −0.01]}, but was not associated with functional outcome.Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate–severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI.
Sakato, Yusuke; Shima, Atsushi; Terada, Yuta; Takeda, Kiyoaki; Sakamaki-Tsukita, Haruhi; Nishida, Akira; Yoshimura, Kenji; Wada, Ikko; Furukawa, Koji; Kambe, Daisuke; Togo, Hiroki; Mukai, Yohei; Sawamura, Masanori; Nakanishi, Etsuro; Yamakado, Hodaka;
Passaretti, Massimiliano; Cilia, Roberto; Rinaldo, Sara; Rossi Sebastiano, Davide; Orunesu, Eva; Devigili, Grazia; Braccia, Arianna; Paparella, Giulia; De Riggi, Martina; van Eimeren, Thilo; Strafella, Antonio Paolo; Lanteri, Paola; Berardelli, Alfredo; Bologna, Matteo; Eleopra, Roberto
Showing 1 to 10 of 27 Articles
doi: 10.1093/brain/awae251pmid: 39045667
The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side effects, highlighting the importance of adjusted treatment considerations. MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immunopathological and MRI aspects of ageing in the CNS in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed.
doi: 10.1093/brain/awae193pmid: 38884572
Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts.By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2−576.7); P = 4.02 ×10−7].Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity.Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.
doi: 10.1093/brain/awae303pmid: 39445741
The clinical manifestation of Parkinson’s disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson’s disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration.We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer’s disease pathology was assessed by evaluating amyloid-β concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET.The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-β pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution.
Compensatory mechanisms in Parkinson’s disease are defined as the changes that the brain uses to adapt to neurodegeneration and progressive dopamine reduction. Motor compensation in early Parkinson’s disease could, in part, be responsible for a unilateral onset of clinical motor signs despite the presence of bilateral nigrostriatal degeneration. Although several mechanisms have been proposed for compensatory adaptations in Parkinson’s disease, the underlying pathophysiology is unclear.Here, we investigate motor compensation in Parkinson’s disease by investigating the relationship between clinical signs, dopamine transporter imaging data and neurophysiological measures of the primary motor cortex (M1), using transcranial magnetic stimulation in presymptomatic and symptomatic hemispheres of patients. In this cross-sectional, multicentre study, we screened 82 individuals with Parkinson’s disease. Patients were evaluated clinically in their medication OFF state using standardized scales. Sixteen Parkinson’s disease patients with bilateral dopamine transporter deficit in the putamina but unilateral symptoms were included. Twenty-eight sex- and age-matched healthy controls were also investigated. In all participants, we tested cortical excitability using single- and paired-pulse techniques, interhemispheric inhibition and cortical plasticity with paired associative stimulation. Data were analysed with ANOVAs, multiple linear regression and logistic regression models. Individual coefficients of motor compensation were defined in patients based on clinical and imaging data, i.e. the motor compensation coefficient. The motor compensation coefficient includes an asymmetry score to balance motor and dopamine transporter data between the two hemispheres, in addition to a hemispheric ratio accounting for the relative mismatch between the magnitude of motor signs and dopaminergic deficit.In patients, corticospinal excitability and plasticity were higher in the presymptomatic compared with the symptomatic M1. Also, interhemispheric inhibition from the presymptomatic to the symptomatic M1 was reduced. Lower putamen binding was associated with higher plasticity and reduced interhemispheric inhibition in the presymptomatic hemisphere. The motor compensation coefficient distinguished the presymptomatic from the symptomatic hemisphere. Finally, in the presymptomatic hemisphere, a higher motor compensation coefficient was associated with lower corticospinal excitability and interhemispheric inhibition and with higher plasticity.In conclusion, the present study suggests that motor compensation involves M1–striatal networks and intercortical connections becoming more effective with progressive loss of dopaminergic terminals in the putamen. The balance between these motor networks seems to be driven by cortical plasticity.