Brain最新文献

Lewy body (LB) pathology is present as a co-pathology in approximately 50% of Alzheimer's disease (AD) dementia patients and may even represent the main neuropathologic substrate in a subset of patients with amnestic impairments. However, the degree to which LB pathology affects the neurodegenerative course and clinical phenotype in amnestic patients is not well understood. Recently developed α-synuclein seed amplification assays (αSyn-SAAs) provide a unique opportunity for further investigating the complex interplay between AD and LB pathology in shaping heterogeneous regional neurodegeneration patterns and clinical trajectories among amnestic patients. We studied 865 patients from the ADNI cohort with clinical diagnoses of aMCI (N=661) or AD dementia (N=211), who had CSF and FDG-PET data available. CSF samples were analyzed for peptide levels of Aβ1-42 and p-tau181, and αSyn positivity was evaluated using a novel αSyn-SAA. Based on positive/negative results on the different biomarkers, subjects were classified as "AD-LB-" (N=304), "AD+LB-" (N=335), "AD+LB+" (N=158) and "AD-LB+" (N=68). We analyzed group differences in regional FDG-PET patterns, demographics, APOE4 genotype, baseline and longitudinal domain-specific cognitive profiles (memory vs executive function/visuospatial performance), as well as risk for developing hallucinations. AD+LB+ showed worse global cognition (MMSE: p=0.005) and declined faster (p<0.001) than AD+LB-, but both groups exhibited similar memory-predominant cognitive profiles. In FDG-PET, AD+LB+ showed more severe hypometabolism compared to AD+LB-, but both groups were characterized by largely identical patterns of temporo-parietal hypometabolism. By contrast, AD-LB+ were less globally impaired (p<0.001) but characterized by a markedly more dysexecutive and visuospatial profile (p<0.003) and a strikingly different posterior-occipital pattern of hypometabolism. APOE4 positivity was similar between AD+LB+ and AD+LB- (72% vs. 75%, p=0.28) but lower in AD-LB+ (28%, p<0.001). On a group level, AD+LB+, AD+LB-, and AD-LB+ showed similar risks of developing hallucinations, but patients with a LB-like posterior-occipital hypometabolism pattern had a significantly higher risk compared to those showing an AD-typical temporo-parietal pattern (HR=2.58, p=0.004). In conclusion, LB co-pathology in AD was associated with more severe hypometabolism and faster cognitive decline, but did not affect the regional hypometabolic pattern or cognitive profile. By contrast, patients with relatively pure LB pathology showed a more executive/visuospatial-predominant cognitive profile and a distinct posterior-occipital hypometabolism pattern characteristic for LB disease. These findings indicate that the presence of LB pathology may have different consequences for the clinical phenotype depending on AD co-morbidity, which may have critical implications for accurate diagnosis and prognosis of patients presenting with amnestic syndromes.

Computational neuropsychiatry is a leading discipline to explain psychopathology in terms of neuronal message passing, distributed processing, and belief propagation in neuronal networks. Active Inference (AI) has been one of the ways of representing this dysfunctional signal processing. It involves that all neuronal processing and action selection can be explained by maximizing Bayesian model evidence, or minimizing variational free energy. Following these principles, it has been suggest that dysconnection in neuronal network results in aberrant belief updating and erroneous inference, leading to psychiatric and neurologic symptoms. However, there is a classic distinction between disorders of inference (or synaptopathy - including the majority of psychiatric disorders), and disorders of brain function (including vascular neurological pathologies and severe forms of tauopathy and synucleinopathies). This distinction is generally based on the idea that synaptopathies impair neuromodulatory precision weighting, leading to rigid inferences or heightened sensitivity to noise, while disorders of brain function are linked to damage in the nervous system (disconnection). This makes it challenging to apply the logic of the free energy principle. We suggest that this distinction will enable future models of neuropsychiatric symptoms to be improved by considering more than neuronal message passing.

Although the pathophysiology of migraine involves a complex ensemble of peripheral and central nervous system changes that remain incompletely understood, the activation and sensitization of the trigeminovascular system is believed to play a major role. However, non-invasive, in vivo neuroimaging studies investigating the underlying neural mechanisms of trigeminal system abnormalities in human migraine patients are limited. Here, we studied 60 patients with migraine (55 females, mean age ± SD: 36.28 ± 11.95 years) and 20 age-/sex-matched healthy controls (19 females, mean age ± SD: 35.45 ± 13.30 years) using ultra-high field 7 Tesla diffusion tensor imaging and functional MRI, as well as PET with the translocator protein ligand [11C]-PBR28. We evaluated MRI diffusivity measures and PET signal at the trigeminal nerve root, as well as brainstem functional MRI response to innocuous, ophthalmic trigeminal nerve territory stimulation. Patients with migraine demonstrated altered white matter microstructure at the trigeminal nerve root (n=53), including reduced fractional anisotropy, compared to healthy controls (n=18). Furthermore, in patients, lower fractional anisotropy was accompanied by 1) higher neuroinflammation (i.e. elevated [11C]-PBR28 PET signal) at the nerve root (n=36) and 2) lower functional MRI activation in an ipsilateral pontine cluster consistent with spinal trigeminal nucleus (n=51). These findings were more robust on the right side, which was consistent with the observation that right headache dominant patients demonstrated higher migraine severity compared to left headache dominant patients in our cohort. Multimodal imaging of the integrated neural mechanisms that characterize migraine underscores the importance of trigeminal system remodeling as both a key aspect of the dynamics underlying migraine pathophysiology and a target for therapeutic interventions.