One of the pathological hallmarks of Alzheimer’s and related diseases is the increased accumulation of protein amyloid-β in the brain parenchyma. As such, recent studies have focused on characterizing protein and related clearance pathways involving perivascular flow of neurofluids, but human studies of these pathways are limited owing to limited methods for evaluating neurofluid circulation non-invasively in vivo. Here, we utilize non-invasive MRI methods to explore surrogate measures of CSF production, bulk flow, and egress in the context of independent PET measures of amyloid-β accumulation in older adults. Participants (N = 23) were scanned at 3.0T with 3D T₂-weighted turbo spin echo, 2D perfusion-weighted pseudo-continuous arterial spin labeling, and phase contrast angiography to quantify parasagittal dural space volume, choroid plexus perfusion, and net CSF flow through the aqueduct of Sylvius respectively. All participants also underwent dynamic PET imaging with amyloid-β tracer ¹¹C-Pittsburgh Compound B to quantify global cerebral amyloid-β accumulation. Spearman’s correlation analyses revealed a significant relationship between global amyloid-β accumulation and parasagittal dural space volume (rho = 0.529, p = 0.010), specifically in the frontal (rho = 0.527, p = 0.010), and parietal (rho = 0.616, p = 0.002) subsegments. No relationships were observed between amyloid-β and choroid plexus perfusion nor net CSF flow. Findings suggest that parasagittal dural space hypertrophy, and its possible role in CSF-mediated clearance, may be closely related to global amyloid-β accumulation. These findings are discussed in the context of our growing understanding of the physiological mechanisms of amyloid-β aggregation and clearance via neurofluids.

Background and Objectives Individuals with cerebellar ataxia (CA) can develop impulsive behavioral symptoms, often resulting in negative interpersonal consequences, detrimentally affecting their quality of life. Limited evidence exists concerning impulsivity in CA and its associated behavioral changes. We assessed impulsive traits in CA using the Barratt Impulsivity Scale (BIS-11) and compared them with those of Parkinson disease (PD) to investigate the differences in the impulsive trait profiles between CA and PD. Methods We conducted a dual-center cross-sectional study with individuals with CA and PD enrolled through consecutive sampling from movement disorders clinics at Columbia University Medical Center and Vanderbilt University Medical Center, respectively. Age-matched controls were recruited at the respective institutions. Participants were excluded if they had prior or comorbid neurologic and psychiatric diseases known to be associated with impulsivity. All participants completed the BIS-11 questionnaire as a measure of impulsive traits. We used a general linear model and a least absolute shrinkage and selection operation regression to compare the total, subscale, and individual items of the BIS-11 scores between groups. Subgroup analyses were performed to isolate cerebellar contributions to impulsivity from potential effects of extracerebellar pathology and dopaminergic dysfunction or medications. Results A total of 190 participants—90 age-matched controls, 50 participants with CA, and 50 with PD—completed the assessments. Persons with CA reported 9.7% higher BIS-11 scores than controls (p < 0.001), while persons with PD reported 24.9% higher scores than controls (p < 0.001). In CA, the most affected domain of impulsivity was nonplanning. In contrast, persons with PD noted greater impulsivity across the nonplanning, attentional, and motor domains. Discussion Impulsivity in CA is uniquely driven by the nonplanning trait, unlike in PD. This suggests that the cerebellum and basal ganglia may differentially govern impulsive behaviors with the cerebellum contributing to the brain circuitry of impulsivity in a domain-specific manner.

Impulsivity is inherent to behavioral disorders such as substance abuse and binge eating. While the role of dopamine in impulse behavior is well established, γ-aminobutyric acid (GABA) therapies have promise for the treatment of maladaptive behaviors. In Parkinson disease (PD), dopaminergic therapies can result in the development of impulsive and compulsive behaviors, and this clinical syndrome shares similar pathophysiology to that seen in addiction, substance abuse, and binge-eating disorders. We hypothesized that impulsive PD patients have a reduced thalamic GABAergic response to dopamine therapy. To test this hypothesis, we employed GABA magnetic resonance spectroscopy, D2-like receptor PET imaging, and clinical and quantitative measures of impulsivity in PD patients (n = 33), before and after dopamine agonist administration. We find a blunted thalamic GABA response to dopamine agonists in patients with elevated impulsivity (p = 0.027). These results emphasize how dopamine treatment differentially augments thalamic GABA concentrations, which may modify behavioral impulsivity.

Dysregulated dopamine (DA) release in the mesocorticolimbic circuit is noted in Parkinson’s disease (PD) patients with impulsive and compulsive behaviors (ICBs). However, the effect of acute DA release on mood, the localization of this process, and the phenotypic differences in patients with ICB remain unknown. We applied a placebo-controlled dextro-amphetamine (dAMPH) study in 20 PD patients: 10 with ICBs (PD-ICB) and 10 without (PD-C). Subjective mood experiences were measured with well-described self-reported measures including the Positive and Negative Affect Scale (PANAS), Drug Effects Questionnaire (DEQ), and Amphetamine Interview Rating Scale (AIRS). D2-like receptor availability was measured as non-displaceable binding potential (BP_ND) using PET imaging with the high-affinity D2/3 receptor ligand [¹⁸F]-fallypride. Among all the subjects, dAMPH increased the PANAS positive, DEQ feel, DEQ high, and AIRS total scores. Increases in the PANAS positive and AIRS total scores were greater in the PD-ICB cohort. A mixed-effects model correlated these questionnaire changes with dAMPH-induced reductions in BP_ND in the ventral striatum (VS), caudate, amygdala, and caudo-medial orbitofrontal cortex. The baseline caudate, VS, and amygdala BP_ND positively correlated with lower on-dAMPH PANAS positive scores. Elevated mood symptoms of acute dAMPH administration in PD are linked to DA release in the mesocorticolimbic regions. Distinctions in behavioral effects among PD-ICB subjects emphasize that dysregulated striatal and extra-striatal DA-ergic networks alter mood responses to stimulated DA release and may also contribute to behavioral changes resulting from DA-targeting therapies in PD.