An evidence-base for noradrenergic deficits in Parkinson’s disease

Editorial comment for MDS-12-0410.R1 Pifl et al - Thalamic noradrenaline in Parkinson’s disease: deficits suggest role in motor and non-motor symptom

Apolipoprotein-E forms dimers in human frontal cortex and hippocampus

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippocampus from control and AD post-mortem samples were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions.</p> <p>Results</p> <p>In apoE3 homozygous samples, ~12% of apoE was present as a homodimer and ~2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD samples were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous samples but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous samples. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain sample homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts.</p> <p>Conclusion</p> <p>The identification of disulphide-linked apoE dimers in human cortical and hippocampal tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences.</p

Terra incognita—cerebellar contributions to neuropsychiatric and cognitive dysfunction in behavioral variant frontotemporal dementia

Although converging evidence has positioned the human cerebellum as an important relay for intact cognitive and neuropsychiatric processing, changes in this large structure remain mostly overlooked in behavioral variant frontotemporal dementia (bvFTD), a disease which is characterized by cognitive and neuropsychiatric deficits. The present study assessed whether degeneration in specific cerebellar subregions associate with indices of cognition and neuropsychiatric performance in bvFTD. Our results demonstrate a relationship between cognitive and neuropsychiatric decline across various domains of memory, language, emotion, executive, visuospatial function, and motivation and the degree of gray matter degeneration in cerebellar lobules V–VII. Most notably, bilateral cerebellar lobule VII and the posterior vermis emerged as distinct for memory processes, the right cerebellar hemisphere underpinned emotion, and the posterior vermis was highlighted in language dysfunction in bvFTD. Based on cortico-cerebellar connectivity maps, these findings in the cerebellum are consistent with the neural connections with the cortices involved in these domains in patients with bvFTD. Overall, the present study underscores the significance of cortical-cerebellar networks associated with cognition and neuropsychiatric dysfunction in bvFTD

Can we clinically diagnose dementia with Lewy bodies yet?

Dementia with Lewy Bodies (DLB) was initially identified and confirmed primarily by pathology, but is soon to be incorporated into the Diagnostic and Statistical Manual criteria as a clinical disease entity. Despite these advances over more than 20 years, current data suggest that the sensitivity of accurate clinical diagnosis of DLB is still very low, although there is mounting evidence that supportive features may increase diagnostic accuracy. Although DLB remains easy to identify pathologically with different cellular pathologies differentiating it from other dementia syndromes, pathological identification using only Lewy body pathology has been shown to be inaccurate due to overlap with patients without dementia symptoms. A number of studies now suggest that a combination of cellular pathologies, which include α-synuclein and β-amyloid deposition as well as dopamine denervation, assist with differentiating this dementia syndrome from others. The clinical and pathological overlap with the tauopathy of Alzheimer’s disease still remains to be clarified. To determine more robust and independent clinicopathological correlates from Alzheimer’s disease, longitudinal prospective studies, using specific clinical batteries on dementia patients reaching the proposed criteria for DLB, with post-mortem assessment of the multiple pathologies associated with dementia, are required. Identifying genetic causes for DLB is another approach to investigate the pathogenesis of DLB. However this approach has been hindered to date by difficulties with identifying DLB clinically. The use of novel techniques is likely to advance knowledge on the pathogenesis of DLB and assist with redefining clinical and pathologic diagnostic criteria. To achieve the goal of more accurate clinical diagnosis of DLB, breakthroughs are necessary on the pathogenesis of DLB

Aspects of innate immunity and Parkinson’s disease

Genetic studies on PARK genes have identified dysfunction in proteasomal, lysosomal, and mitochondrial enzymes as pathogenic for Parkinson’s disease(PD). We review the role of these and similar enzymes in mediating innate immunesignaling. In particular, we have identified that a number of PARK gene products as well as other enzymes have roles in innate immunesignaling as well as DNA repair and regulation biquitination, mitochondrial functioning, and synaptic trafficking. PD enzymatic dysfunction is likely to contribute to inadequate innate immune responses to a variety of extra-and intracellular stimuli, with a number of the innate immunity related enzymes found in the characteristic Lewy body pathology of PD. The decrease in innate immunity in PD is associated with an increase in markers of adaptive immunity, and recent GWAS studies have identified variants in human leukocyte antigen region asassociated with late-onset sporadicPD(Hamzaetal.,2010;Hill-Burnsetal.,2011). Intriguing newdata also suggest that peripheral immune responses maybe involved, giving some potential to alleviate such peripheral dysfunction more directly in patients with PD. It is now important to identify the cell type specific immune responses contributing to the initial changes that occur in PD, as well as to the propagating immune responses important for the progression of PD pathology between cells and within the brain. Overall, a complex interplay between different types of immunity appear to be involved in the underlying pathology of PD

Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson’s disease:A task-based fMRI study

Background: The neural substrates of visual hallucinations remain an enigma, due primarily to the difficulties associated with directly interrogating the brain during hallucinatory episodes. Aims: To delineate the functional patterns of brain network activity and connectivity underlying visual hallucinations in Parkinson’s disease. Methods: In this study, we combined functional magnetic resonance imaging (MRI) with a behavioral task capable of eliciting visual misperceptions, a confirmed surrogate for visual hallucinations, in 35 patients with idiopathic Parkinson’s disease. We then applied an independent component analysis to extract time series information for large-scale neuronal networks that have been previously implicated in the pathophysiology of visual hallucinations. These data were subjected to a task-based functional connectivity analysis, thus providing the first objective description of the neural activity and connectivity during visual hallucinations in patients with Parkinson’s disease. Results: Correct performance of the task was associated with increased activity in primary visual regions; however, during visual misperceptions, this same visual network became actively coupled with the default mode network (DMN). Further, the frequency of misperception errors on the task was positively correlated with the strength of connectivity between these two systems, as well as with decreased activity in the dorsal attention network (DAN), and with impaired connectivity between the DAN and the DMNs, and ventral attention networks. Finally, each of the network abnormalities identified in our analysis were significantly correlated with two independent clinical measures of hallucination severity. Conclusions: Together, these results provide evidence that visual hallucinations are due to increased engagement of the DMN with the primary visual system, and emphasize the role of dysfunctional engagement of attentional networks in the pathophysiology of hallucinations

Is Seladin-1 really a selective Alzheimer\u27s disease indicator?

Selective Alzheimer\u27s Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer\u27s disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD

Macroautophagy in sporadic and the genetic form of Parkinson’s disease with the A53T a-synuclein mutation

The A53T mutation in the a-synuclein gene causes autosomal-dominant Lewy body Parkinson’s disease (PD). Cultured cell models have linked this mutation to increased cell macroautophagy, although evidence of enhanced macroautophagy in patients with this mutation has not been assessed. Objective: To determine whether macroautophagy is increased by the A53T a-synuclein gene mutation in PD patients and cell models. Methods: Formalin-fixed paraffin-embedded 10 μm-thick tissue sections from the substantia nigra and anterior cingulate cortex of two PD patients with the A53T a-synuclein gene mutation were compared with four sporadic PD cases and four controls obtained from the Sydney Brain Bank. Lewy bodies were isolated from frontal cortex of a case with late stage PD (recruited from South Australian Brain Bank). Immunohistochemistry was performed for a-synuclein and the macroautophagy markers autophagy-specific gene (ATG) 5, ATG6/Beclin1 and ATG8/LC3. SHSY5Y cells were transfected with wild type or A53T mutant a-synuclein plasmids and observable changes in macroautophagy marker protein levels assessed using Western blotting. Results: a-Synuclein immunoreactive neurites and dots were more numerous in patients with A53T mutations compared with late stage sporadic PD patients, and perinuclear cytoplasmic a-synuclein aggregates were observed in the a-synuclein A53T gene transfected SH-SY5Y cells compared to wild type transfections. All PD patients (with or without A53T mutations) had increased immunohistochemical evidence for macroautophagy compared with controls, and the levels of the ATG5 complex were equally increased in wild type and A53T a-synuclein gene transfected cells compared to controls. Conclusion: Despite increased a-synuclein accumulation with A53T mutations, macroautophagy is not increased above that observed in sporadic patients with PD or in cells transfected with wild type a-synuclein, suggesting that mutated a-synuclein protein is not removed by macroautophagy

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