Plasma and CSF concentrations of N-terminal tau fragments associate with in vivo neurofibrillary tangle burden.

INTRODUCTION: Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed. METHODS: We measured cerebrospinal fluid (CSF) and plasma concentrations of N-terminal tau fragments (NTA-tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aß) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments. RESULTS: CSF and plasma NTA-tau concentrations were specifically increased in cognitively impaired Aß-positive groups. CSF and plasma NTA-tau concentrations displayed stronger correlations with tau PET than with Aß PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA-tau are preferentially associated with tau pathology. Moreover, plasma NTA-tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum. DISCUSSION: NTA-tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials. HIGHLIGHTS: An assay for detecting N-terminal tau fragments (NTA-tau) in plasma and CSF was evaluated. NTA-tau is more closely associated with tau PET than amyloid PET or neurodegeneration. NTA-tau can successfully track in vivo tau deposition across the AD continuum. Plasma NTA-tau increased over time only in cognitively impaired amyloid-ß positive individuals.

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template.

Brain registration to a stereotaxic atlas is an effective way to report anatomic locations of interest and to perform anatomic quantification. However, existing stereotaxic atlases lack comprehensive coordinate information about white matter structures. In this paper, white matter-specific atlases in stereotaxic coordinates are introduced. As a reference template, the widely used ICBM-152 was used. The atlas contains fiber orientation maps and hand-segmented white matter parcellation maps based on diffusion tensor imaging (DTI). Registration accuracy by linear and non-linear transformation was measured, and automated template-based white matter parcellation was tested. The results showed a high correlation between the manual ROI-based and the automated approaches for normal adult populations. The atlases are freely available and believed to be a useful resource as a target template and for automated parcellation methods.