Biology subjects

Mailman, R. B.

Publications and source records attributed to Mailman, R. B..

2 recordsLinked to original sources

bioRxiv2021

Decoupling of global brain activity and cerebrospinal fluid flow in Parkinson's cognitive decline

BackgroundDeposition and spreading of misfolded proteins (-synuclein and tau) have been linked to Parkinsons cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow that may reflect glymphatic function. ObjectiveTo determine if the decoupling of brain activity-CSF flow is linked to Parkinsons cognitive dysfunction. MethodsFunctional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment, MoCA) scores were collected from 60 Parkinsons and 58 control subjects. Parkinsons patients were subgrouped into those with (MoCA < 26; N = 29) and without (MoCA [≥] 26; N = 31) mild cognitive impairment (MCI). The coupling strength between the resting-state global blood-oxygen-level-dependent signal (gBOLD) and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. ResultsgBOLD-CSF coupling decreased significantly (p < 0.006) in Parkinsons patients showing MCI, compared to those without MCI and controls. Reduced gBOLD-CSF coupling was associated with decreased MoCA scores that was present in Parkinsons patients (p = 0.005) but not in controls (p = 0.65). Weaker gBOLD-CSF coupling in Parkinsons patients also was associated with a thinner right entorhinal cortex (Spearmans correlation = - 0.36; p = 0.012), an early structural change often seen in Alzheimers. ConclusionsThe decoupling between global brain activity and associated CSF flow is related to Parkinsons cognitive impairment.

neuroscience↗

bioRxiv2020

D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

AO_SCPLOWBSTRACTC_SCPLOWLevodopa is the Parkinsons disease standard-of-care, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral "dopamine agonist" matches the efficacy of levodopa. Although there are consistent data in both primate models and in Parkinsons disease showing that selective high intrinsic activity D1 agonists can equal levodopa, there are no data on whether such compounds would be effective in severe disease when levodopa efficacy is lower or even absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernable improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinsons patients.

neuroscience↗