To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type ...copathology.
We selected 57 patients with LBD (dementia with Lewy bodies DLB, n = 38; Parkinson disease dementia PDD, n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid
(Aβ
), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ
ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test BNT), executive abilities (letter fluency LF, reverse digit span RDS), and global cognition (Mini-Mental State Examination MMSE), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.
Patients with LBD + AD performed worse on BNT than patients with LBD - AD (
= 4.80,
= 0.03); both groups performed similarly on LF, RDS, and MMSE (all
> 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all
> 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28,
< 0.05) and p-tau (ρ = -0.26,
= 0.05) but not Aβ
(
> 0.1).
Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.
Physical activity is critical in Parkinson disease (PD) management, but barriers and motivators of activity in Veterans with PD may be unique. We examined activity habits, including barriers and ...motivators, in this population.
Participants completed the Physical Activity Scale in the Elderly (PASE). Compliance with American Heart Association (AHA) recommendations was assessed. Veterans also completed the Exercise Perceptions Questionnaire (EPQ), assessing knowledge, barriers, and motivators of activity. Free-text barriers/motivators were analyzed by the overlapping clusters method.
Seventy-five Veterans were recruited; mean age (standard deviation SD) was 70.5 (8.2) years and mean disease duration (SD) was 5.4 (5.2) years. Raw median PASE was 120.4 (interquartile range IQR 68.8–165.7); age-adjusted median PASE was 135.3. Only 9 Veterans (14.3%) were AHA-compliant. There were trends toward negative association between PASE and UPDRS-3 (r = −0.24, p = 0.06) and between PASE and PDQ-8 (r = −0.23, p = 0.08). Sixty-three subjects (84%) completed the EPQ; 27 (42.9%) preferred scheduled exercise, and only 33 (53.2%) reported that they preferred to exercise with others. Common themes of 46 free-text responses included desire to improve PD symptoms (n = 15, 32.6%) and social engagement (n = 12, 26.1%).
Self-reported activity in Veterans with PD is low, with less than 15% of subjects meeting recommended activity targets. Qualitative analysis of barriers and motivators revealed that although many Veterans enjoy the social aspects of group exercise, they may not feel comfortable in general exercise classes aimed at younger participants without chronic illnesses. These data will be useful in designing Veteran- and/or PD-specific interventions to increase activity levels.
•Veterans with Parkinson disease (PD) are largely sedentary and do not meet recommended physical activity thresholds.•Unlike the general population, many Veterans with PD dislike scheduled or group exercise.•Social engagement and exercise variety are strong motivators to exercise in this patient population.
Background
The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, ...evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse.
Methods
Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge‐like alcohol consumption, as measured by the “drinking in the dark” (DID) model in C57BL/6J mice.
Results
We found that 2 potent and selective NOP agonists AT‐202 (0, 0.3, 1, 3 mg/kg) and AT‐312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT‐202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol‐containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB‐612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB‐612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB‐612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB‐612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2‐bottle choice DID model that can assess moderate alcohol intake.
Conclusions
The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking.
Binge drinking represents an enormous public health concern in the United States and worldwide. We report experiments showing that treatment with antagonists of the receptor of the Nociceptin Orphanin FQ Peptide (NOP receptor) decreases excessive alcohol consumption in mouse models of binge‐like alcohol drinking. These experiments demonstrate that NOP receptor inhibition rather than activation represents a valuable approach for treatment of alcohol use disorders characterized by excessive alcohol consumption in humans.
Abstract Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 ( LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. ...With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.
Lambda-like double-stranded (ds) DNA bacteriophage undergo massive conformational changes in their capsid shell during the packaging of their viral genomes. Capsid shells are complex organizations of ...hundreds of protein subunits that assemble into intricate quaternary complexes that ultimately are able to withstand over 50 atm of pressure during genome packaging. The extensive integration between subunits in capsids requires the formation of an intermediate complex, termed a procapsid, from which individual subunits can undergo the necessary refolding and structural rearrangements needed to transition to the more stable capsid. Although various mature capsids have been characterized at atomic resolution, no such procapsid structure is available for a dsDNA virus or bacteriophage. Here we present a procapsid X-ray structure at 3.65 Å resolution, termed prohead II, of the lambda-like bacteriophage HK97, the mature capsid structure of which was previously solved to 3.44 Å (ref. 2). A comparison of the two largely different capsid forms has unveiled an unprecedented expansion mechanism that describes the transition. Crystallographic and hydrogen/deuterium exchange data presented here demonstrate that the subunit tertiary structures are significantly different between the two states, with twisting and bending motions occurring in both helical and -sheet regions. We also identified subunit interactions at each three-fold axis of the capsid that are maintained throughout maturation. The interactions sustain capsid integrity during subunit refolding and provide a fixed hinge from which subunits undergo rotational and translational motions during maturation. Previously published calorimetric data of a closely related bacteriophage, P22, showed that capsid maturation was an exothermic process that resulted in a release of 90 kJ mol-1 of energy. We propose that the major tertiary changes presented in this study reveal a structural basis for an exothermic maturation process probably present in many dsDNA bacteriophage and possibly viruses such as herpesvirus, which share the HK97 subunit fold.
Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long‐term neurological dysfunction. The mechanical forces that are caused by TBI ...propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed the tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1‐year post‐injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect the changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1‐year post‐injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.
In this study, pigs were subjected to mild TBI by rapid head rotation and neuropathologically assessed for axonal pathology, microglial morphological changes, and astrocyte reactivity out to one year post injury. We detected acute changes in axonal pathology, particularly in the periventricular white matter and fimbria/fornix, as well as changes to microglia morphology in the periventricular white matter and hippocampal subfields out to one year post injury. These ongoing morphological alterations suggest persistent changes in neuroimmune homeostasis after a single mild TBI.
α-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence ...suggests that α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human α-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, α-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal α-synuclein inclusions paralleling disease onset, and the α-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the α-synuclein inclusions contained 10–16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T α-synuclein leads to the formation of toxic filamentous α-synuclein neuronal inclusions that cause neurodegeneration.
Parkinson’s disease is a neurodegenerative disease affecting around 10 million people worldwide. The death of dopaminergic neurons in the substantia nigra and the axonal fibers that constitute the ...nigrostriatal pathway leads to a loss of dopamine in the striatum that causes the motor symptoms of this disease. Traditional treatments have focused on reducing symptoms, while therapies with human fetal or stem cell-derived neurons have centered on implanting these cells in the striatum to restore its innervation. An alternative approach is pathway reconstruction, which aims to rebuild the entire structure of neurons and axonal fibers of the nigrostriatal pathway in a way that matches its anatomy and physiology. This type of repair could be more capable of reestablishing the signaling mechanisms that ensure proper dopamine release in the striatum and regulation of other motor circuit regions in the brain. In this manuscript, we conduct a review of the literature related to pathway reconstruction as a treatment for Parkinson’s disease, delve into the limitations of these studies, and propose the requisite design criteria to achieve this goal at a human scale. We then present our tissue engineering-based platform to fabricate hydrogel-encased dopaminergic axon tracts in vitro for later implantation into the brain to replace and reconstruct the pathway. These tissue-engineered nigrostriatal pathways (TE-NSPs) can be characterized and optimized for cell number and phenotype, axon growth lengths and rates, and the capacity for synaptic connectivity and dopamine release. We then show original data of advances in creating these constructs matching clinical design criteria using human iPSC-derived dopaminergic neurons and a hyaluronic acid hydrogel. We conclude with a discussion of future steps that are needed to further optimize human-scale TE-NSPs and translate them into clinical products.
OBJECTIVES: To examine Montreal Cognitive Assessment (MoCA) performance in patients with Parkinson's disease (PD) with “normal” global cognition according to Mini‐Mental State Examination (MMSE) ...score.
DESIGN: A cross‐sectional comparison of the MoCA and the MMSE.
SETTING: Two movement disorders centers at the University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center.
PARTICIPANTS: A convenience sample of 131 patients with idiopathic PD who were screened for cognitive and psychiatric complications.
MEASUREMENTS: Subjects were administered the MoCA and MMSE, and only subjects defined as having a normal age‐ and education‐adjusted MMSE score were included in the analyses (N=100). As previously recommended in patients without PD, a MoCA score less than 26 was used to indicate the presence of at least mild cognitive impairment (MCI).
RESULTS: Mean MMSE and MoCA scores±standard deviation were 28.8±1.1 and 24.9±3.1, respectively. More than half (52.0%) of subjects with normal MMSE scores had cognitive impairment according to their MoCA score. Impairments were seen in numerous cognitive domains, including memory, visuospatial and executive abilities, attention, and language. Predictors of cognitive impairment on the MoCA using univariate analyses were male sex, older age, lower educational level, and greater disease severity; older age was the only predictor in a multivariate model.
CONCLUSION: Approximately half of patients with PD with a normal MMSE score have cognitive impairment based on the recommended MoCA cutoff score. These results suggest that MCI is common in PD and that the MoCA is a more sensitive instrument than the MMSE for its detection.
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