Lysosomal‐associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease

Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α‐synuclein‐positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone‐mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal‐associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD‐related increases in α‐synuclein in autopsy samples from subjects in the early pathological stage of PD (n = 9), compared to age‐ and postmortem delay‐matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α‐synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD samples, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α‐synuclein, and suggests that dysregulation of CMA‐mediated protein degradation occurs before substantial α‐synuclein aggregation in PD. © 2015 International Parkinson and Movement Disorder Society.     

Hippocampal volume and asymmetry in mild cognitive impairment and Alzheimer's disease: Meta‐analyses of MRI studies

Numerous studies have reported a smaller hippocampal volume in Alzheimer's disease (AD) patients than in aging controls. However, in mild cognitive impairment (MCI), the results are inconsistent. Moreover, the left‐right asymmetry of the hippocampus receives less research attention. In this article, meta‐analyses are designed to determine the extent of hippocampal atrophy in MCI and AD, and to evaluate the asymmetry pattern of the hippocampal volume in control, MCI, and AD groups. From 14 studies including 365 MCI patients and 382 controls, significant atrophy is found in both the left [Effect size (ES), 0.92; 95% confidence interval (CI), 0.72–1.11] and right (ES, 0.78; 95% CI, 0.57–0.98) hippocampus, which is lower than that in AD (ES, 1.60, 95% CI, 1.37–1.84, in left; ES, 1.52, 95% CI, 1.31–1.72, in right). Comparing with aging controls, the average volume reduction weighted by sample size is 12.9% and 11.1% in left and right hippocampus in MCI, and 24.2% and 23.1% in left and right hippocampus in AD, respectively. The findings show a bilateral hippocampal volume loss in MCI and the extent of atrophy is less than that in AD. By comparing the left and right hippocampal volume, a consistent left‐less‐than‐right asymmetry pattern is found, but with different extents in control (ES, 0.39), MCI (ES, 0.56), and AD (ES, 0.30) group. © 2009 Wiley‐Liss, Inc.     

Brain responses to social norms: Meta‐analyses of fMRI studies

Social norms have a critical role in everyday decision‐making, as frequent interaction with others regulates our behavior. Neuroimaging studies show that social‐based and fairness‐related decision‐making activates an inconsistent set of areas, which sometimes includes the anterior insula, anterior cingulate cortex, and others lateral prefrontal cortices. Social‐based decision‐making is complex and variability in findings may be driven by socio‐cognitive activities related to social norms. To distinguish among social‐cognitive activities related to social norms, we identified 36 eligible articles in the functional magnetic resonance imaging (fMRI) literature, which we separate into two categories (a) social norm representation and (b) norm violations. The majority of original articles (>60%) used tasks associated with fairness norms and decision‐making, such as ultimatum game, dictator game, or prisoner's dilemma; the rest used tasks associated to violation of moral norms, such as scenarios and sentences of moral depravity ratings. Using quantitative meta‐analyses, we report common and distinct brain areas that show concordance as a function of category. Specifically, concordance in ventromedial prefrontal regions is distinct to social norm representation processing, whereas concordance in right insula, dorsolateral prefrontal, and dorsal cingulate cortices is distinct to norm violation processing. We propose a neurocognitive model of social norms for healthy adults, which could help guide future research in social norm compliance and mechanisms of its enforcement.     

A differential display protocol to identify differentially expressed mRNAs in potassium-deprived cerebellar granule cells

Differential display (DD) has become a popular technique for the identification of differentially expressed genes. Here we present a DD protocol for studying mRNA expression changes during neuronal apoptosis. Neuronal apoptosis is typically dependent on macromolecular synthesis, thus suggesting that regulation of gene expression is involved in control of the activation of the cell-death machinery. In order to identify some of the genes involved, we employed the widely used cell culture model in which apoptosis is induced in rat cerebellar granule cells (CGCs) using potassium deprivation. Although DD has been applied productively in the study of various biological phenomena, the method has its drawbacks. In particular, the cloning and verification of cDNA fragments is frequently described as problematic or laborious, and often produces many "false positives". Here we report the successful use of DD including an efficient protocol for cDNA clone screening and verification. This protocol avoids some of the problems presented by heterogeneous DD bands, which may be a major cause of false-positive results. To identify the desired clones, we apply single-stranded conformational polymorphism (SSCP) and slot blot techniques.     

Frequency‐dependent neural activity in Parkinson's disease

The brainstem and basal ganglia are important in the pathophysiology of Parkinson's disease (PD). Reliable and sensitive detection of neural activity changes in these regions should be helpful in scientific and clinical research on PD. In this study, we used resting state functional MRI and amplitude of low frequency fluctuation (ALFF) methods to examine spontaneous neural activity in 109 patients with PD. We examined activity in two frequency bands, slow‐4 (between 0.027 and 0.073 Hz) and slow‐5 (0.010–0.027 Hz). Patients had decreased ALFF in the striatum and increased ALFF in the midbrain, and changes were more significant in slow‐4. Additionally, changes in slow‐4 in both basal ganglia and midbrain correlated with the severity of the parkinsonism. The ALFF in the caudate nucleus positively correlated with the dose of levodopa, while the ALFF in the putamen negatively correlated with the disease duration in both slow‐4 and slow‐5 bands. In addition, the ALFF in the rostral supplementary motor area negatively correlated with bradykinesia subscale scores. Our findings show that with a large cohort of patients and distinguishing frequency bands, neural modulations in the brainstem and striatum in PD can be detected and may have clinical relevance. The physiological interpretation of these changes needs to be determined. Hum Brain Mapp 35:5815–5833, 2014. © 2014 Wiley Periodicals, Inc.     

Dopamine agonist‐induced antecollis in Parkinson's disease

Few cases of dopamine agonist‐induced antecollis in Parkinson's disease (PD) have been reported. Literature review of 16 PD patients including our 3 cases with dopamine agonist‐induced antecollis showed predominance of (1) Japanese, (2) women, and (3) Hoehn‐Yahr stage of ≥3. We experienced three Japanese PD patients who subacutely exhibited antecollis following increased dopamine agonist dose that improved just after withdrawal of the agonist. One patient developed antecollis during increasing pramipexole dose in combination with cabergoline. Antecollis in another patient appeared during increasing pramipexole dose; it worsened after substituting pergolide for pramipexole, but improved after withdrawal of pergolide. Our cases indicate that there is no specific dopamine agonist causing antecollis, and it is possibly caused by a number of single dopamine agonists or a combination of them. Dopamine agonist‐induced antecollis should be considered when encountering antecollis in PD patients being treated with dopamine agonists and withdrawal of the agonist can improve symptoms. © 2009 Movement Disorder Society     

Age and sex differentially shape brain networks in Parkinson's disease

Aims

Age and sex are important individual factors modifying the clinical symptoms of patients with Parkinson's disease (PD). Our goal is to evaluate the effects of age and sex on brain networks and clinical manifestations of PD patients.

Methods

Parkinson's disease participants (n = 198) receiving functional magnetic resonance imaging from Parkinson's Progression Markers Initiative database were investigated. Participants were classified into lower quartile group (age rank: 0%~25%), interquartile group (age rank: 26%~75%), and upper quartile group (age rank: 76%~100%) according to their age quartiles to examine how age shapes brain network topology. The differences of brain network topological properties between male and female participants were also investigated.

Results

Parkinson's disease patients in the upper quartile age group exhibited disrupted network topology of white matter networks and impaired integrity of white matter fibers compared to lower quartile age group. In contrast, sex preferentially shaped the small-world topology of gray matter covariance network. Differential network metrics mediated the effects of age and sex on cognitive function of PD patients.

Conclusion

Age and sex have diverse effects on brain structural networks and cognitive function of PD patients, highlighting their roles in the clinical management of PD.