Objective: People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha‐synuclein (α‐syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α‐syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD‐affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert.Methods: High‐performance liquid chromatography and novel enzyme‐linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α‐syn deposition) and six age‐matched controls were tested.Results: PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups.Interpretation: These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia.

Quiz Ref ID Individuals with Parkinson disease (PD) have an increased risk of dementia.^1,2 The 2 major correlates of dementia associated with PD are cortical synucleinopathy (α-synuclein aggregates in Lewy bodies or Lewy neurites) or pathologic changes frequently interpreted as Alzheimer disease (AD).^3-9 Studies^10-12 using the in vivo amyloid-imaging agent [¹¹C]–Pittsburgh Compound B (PiB) with positron emission tomography have reported elevated cortical PiB binding in patients with PD, supporting the notion that Aβ accumulation commonly accompanies dementia with PD. However, a recent pathologic study¹³ of PD patients with dementia who had received PiB scans suggests that Aβ accumulation is not necessarily accompanied by neocortical tauopathy in PD. Thus, the relative frequency and extent of tauopathy in the PD population remain unclear. Frequently used clinicopathologic diagnostic criteria (eg, National Institute on Aging and Reagan Institute [NIA-Reagan] criteria) require tauopathy (neocortical neurofibrillary tangles and neuritic plaques) and Aβ plaques to attribute cognitive impairment to dementia from AD.^14,15 Cerebrospinal fluid (CSF) biomarker data also support the hypothesis that both tauopathy (hyperphosphorylated tau) and reduced Aβ42 herald the onset of cognitive change in AD.¹⁶ Previous studies^3,9,17 relied on the occurrence of Aβ plaques to conclude that AD contributed to dementia in people with PD, but this finding would not meet the most widely used pathologic criteria for AD.

APOE genotype regulates disease development in mouse models of α-synucleinopathy and affects cognition in patients with Parkinson’s disease.

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.

Background: Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods: We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results: One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion: Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.