Objective
To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co‐occurring Alzheimer disease (AD) pathology impacts the ...anatomic distribution of α‐synuclein (SYN) pathology and that co‐occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD.
Methods
Fifty‐five autopsy‐confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN−AD = 35). Digital measures of tau, β‐amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing.
Results
SYN burden was higher in SYN + AD than SYN−AD in each neocortical region (F1, 54 = 5.6–6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43–49 = 0.7–1.7, p > 0.2). SYN + AD performed worse than SYN−AD on a temporal lobe–mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = −0.39 to −0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8–97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F1, 40–43 = 1.6–2.0, p > 0.1).
Interpretation
LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1–13 ANN NEUROL 2019;85:259–271.
Abstract Olfactory dysfunction has gained recognition as an early and nearly universal feature of Lewy body Parkinson's disease (PD). Recently, research efforts have focused on the use of early ...non-motor symptoms of PD as early biomarkers and have suggested that investigating neurodegeneration in the aspects of the nervous system subserving these symptoms may offer important insights into the pathophysiology of Lewy body PD. Therefore, there has been interest in characterizing the pathology observed in the olfactory bulb and system of patients with PD, dementia with Lewy bodies and perhaps more importantly, in subjects with incidental Lewy pathology, defined as people with Lewy pathology without evidence of Parkinsonism or dementia during life. The olfactory bulb may be ideally suited to investigations into the pathophysiology of the Lewy body disorders as it is one of the few areas of the brain wherein the entirety of neurons susceptible to Lewy neurodegeneration, including the dendritic arborization, cell soma, axon and synaptic terminals, can be examined in the same preparation. Interestingly, there is a lack of Lewy neurodegeneration in the dopaminergic neurons of the olfactory bulb and paradoxically, an apparent increase in dopaminergic neurons in some PD patients compared to controls. In this report, the known neuropathology of the olfactory system in PD will be reviewed and the advantages of investigating degeneration of the olfactory bulb as a model of Lewy neurodegeneration will be discussed.
Monitoring physical activity is important in Parkinson disease (PD), but patient recall may be unreliable. We examined relationships between self-reported activity, objective monitoring, and clinical ...characteristics.
Participants completed the self-reported Physical Activity Scale in the Elderly (PASE) to determine subjective minutes of moderate-vigorous physical activity (MVPA); a subset wore an Actigraph monitor capturing step count and objective MVPA using a PD-specific algorithm. Relationships between subjective and objective measurements were determined using partial correlations controlling for age and disease stage.
Sixty-six subjects completed subjective reporting; median age (interquartile range IQR) was 70 (69–74) years and median disease duration (IQR) was 4 (1.5–7.5) years. Age-adjusted median PASE was 135.3. Median daily step count was 3615 (IQR 1772–4870), which was moderately well-correlated with PASE (ρ = 0.56, p = 0.003). Median MVPA was 8.1 min/day (IQR 2.2–23.2), which was not correlated with PASE (ρ = -0.003, p = 0.98).
Physical activity in this cohort of Veterans with PD is low and consists mostly of low-intensity steps rather than MVPA. The symptomatic and disease-modifying potential of lower intensity activity is uncertain. These data emphasize the need for interventions to increase MVPA in PD and the importance of objective monitoring using wearable technology.
•Self-reported activity in PD is associated with total daily steps.•Self-reported activity in PD is not well-correlated with moderate-vigorous physical activity.•Objective assessment with wearables may improve assessment of activity levels in PD.
Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's ...disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients F(1, 110) = 9.72, P = 0.002, remarkably even in those with normal cognition at baseline F(1, 80) = 4.71, P = 0.03. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal-temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.
Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as ...amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.
To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD).
We examined the extent of nigral dysfunction and ...degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed.
Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD.
These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.
The crystal structure of the double-stranded DNA bacteriophage HK97 mature empty capsid was determined at 3.6 angstrom resolution. The 660 angstrom diameter icosahedral particle contains 420 subunits ...with a new fold. The final capsid maturation step is an autocatalytic reaction that creates 420 isopeptide bonds between proteins. Each subunit is joined to two of its neighbors by ligation of the side-chain lysine 169 to asparagine 356. This generates 12 pentameric and 60 hexameric rings of covalently joined subunits that loop through each other, creating protein chainmail: topologically linked protein catenanes arranged with icosahedral symmetry. Catenanes have not been previously observed in proteins and provide a stabilization mechanism for the very thin HK97 capsid.
Impulse control disorders (ICDs) in Parkinson disease (PD) are common and can be difficult to manage. The objective of this study was to determine the efficacy and tolerability of naltrexone, an ...opioid antagonist, for the treatment of ICDs in PD.
Patients with PD (n = 50) and an ICD were enrolled in an 8-week, randomized (1:1), double-blind, placebo-controlled study of naltrexone 50-100 mg/d (flexible dosing). The primary outcome measure was response based on the Clinical Global Impression-Change score, and the secondary outcome measure was change in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) ICD score.
Forty-five patients (90%) completed the study. The Clinical Global Impression-Change response rate difference favoring naltrexone in completers was 19.8% (95% confidence interval CI -8.7% to 44.2%). While this difference was not significant (odds ratio=1.6, 95% CI 0.5-5.2, Wald χ2 df=0.5 1, p=0.5), naltrexone treatment led to a significantly greater decrease in QUIP-RS ICD score over time compared with placebo (regression coefficient for interaction term in linear mixed-effects model=-7.37, Fdf=4.3 1, 49, p=0.04). The estimated changes in QUIP-RS ICD scores from baseline to week 8 were 14.9 points (95% CI 9.9-19.9) for naltrexone and 7.5 points (95% CI 2.5-12.6) for placebo.
Naltrexone treatment was not efficacious for the treatment of ICDs in PD using a global assessment of response, but findings using a PD-specific ICD rating scale support further evaluation of opioid antagonists for the treatment of ICD symptoms in PD.
This study provides Class I evidence that in patients with PD and an ICD, naltrexone does not significantly increase the probability of achieving response. However, the study lacked the precision to exclude an important difference in response rates.
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