Abstract The value of iron-based MRI changes for the diagnosis and staging of Alzheimer’s disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. -weighted MRI was performed on post-mortem cortical tissue of controls, late-onset AD, and early-onset AD followed by histology and correlation analyses. Combining ex-vivo high-resolution MRI and histopathology revealed that: LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; (2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex-vivo. Abbreviations AD Alzheimer’s disease EOAD early-onset AD GM gray matter IRP iron regulating proteins LOAD late-onset AD MCI mild cognitive impairment PBS phosphate buffered saline QSM quantitative susceptibility mapping WM white matter
Multiplex Ligation-Dependent Probe Amplification (MLPA) is an application that can be used for the detection of multiple chromosomal aberrations in a single experiment. In one reaction, up to 50 different genomic sequences can be analysed. For a reliable work-flow, tools are needed for administrative support, data management, normalisation, visualisation, reporting and interpretation.Here, we developed a data management system, MLPAInter for MLPA interpretation, that is windows executable and has a stand-alone database for monitoring and interpreting the MLPA data stream that is generated from the experimental setup to analysis, quality control and visualisation. A statistical approach is applied for the normalisation and analysis of large series of MLPA traces, making use of multiple control samples and internal controls.MLPAinter visualises MLPA data in plots with information about sample replicates, normalisation settings, and sample characteristics. This integrated approach helps in the automated handling of large series of MLPA data and guarantees a quick and streamlined dataflow from the beginning of an experiment to an authorised report.
Objective: This study assessed the effects of the N-methyl-D-aspartate(NMDA) antagonist dextromethorphan (DM) on levodopa-induced dyskinesias in Parkinson9s disease (PD). Background: Recent experimental evidence suggests that increased synaptic efficacy of NMDA receptors expressed on basal ganglia neurons may play a role in the pathophysiology of levodopa-induced motor response complications. Methods: DM was given to six PD patients with motor fluctuations in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week study arm, patients received several brief IV levodopa infusions while parkinsonian symptoms and dyskinesias were frequently scored. Levodopa dose-response curves for antiparkinsonian and dyskinetic effects were then compared for each study arm. Results: With DM, average and maximum dyskinesia scores improved by >50%, without compromising the antiparkinsonian response magnitude or duration of levodopa, although in some subjects the levodopa threshold dose was slightly higher with DM than with placebo. Conclusions: These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptors can ameliorate levodopa-associated dyskinesias.
Background and Purpose —Microvascular changes such as microaneurysms and fibrinoid necrosis have been found in the presence of cerebral amyloid angiopathy (CAA). These CAA-associated microvasculopathies (CAA-AM) may contribute to the development of CAA-associated hemorrhages and/or infarcts, hereafter referred to as “cerebrovascular lesions.” Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) is an autosomal dominant form of CAA, in which the amyloid angiopathy is pathologically and biochemically similar to sporadic CAA associated with aging and Alzheimer disease. To determine the significance of CAA-AM for CAA-associated cerebrovascular complications, we investigated the association between CAA-AM and cerebrovascular lesions in HCHWA-D patients. Methods —In a previous autopsy study we semiquantitatively scored CAA-AM in 29 HCHWA-D patients. In the present study we reviewed clinical charts and autopsy protocols of these same patients. We investigated whether CAA-AM was associated with age at death, number of cerebrovascular lesions, duration of clinical illness, hypertension, and atherosclerosis. Results —An association was found between CAA-AM and the number of cerebrovascular lesions ( P =0.009). The presence of microaneurysmal degeneration was most strongly associated with the number of cerebrovascular lesions ( P <0.001). In addition, we found an association between atherosclerosis and the CAA-AM score ( P =0.047). Hypertension was not associated with CAA-AM. Conclusions —Our findings support previous reports suggesting an important role of secondary microvascular degenerative changes in CAA-associated cerebrovascular lesions and suggest an aggravating effect of systemic atherosclerosis, but not hypertension, on the evolution of CAA-AM. These findings may be of relevance to understanding cerebrovascular complications of sporadic or Alzheimer disease–associated CAA.
Multiplex ligation‐dependent probe amplification (MLPA) is a new assay for the detection of multiple chromosomal deletions in tumor tissue in a single experiment. Since genotyping of gliomas with oligodendroglial features by the detection of 1p/19q chromosomal deletions became essential for treatment decisions, we developed and validated an MLPA‐ based assay to determine these losses in formalin fixed and paraffin embedded oligodendroglial tumors (OG). Nineteen OGs, and 10 control samples were analyzed by MLPA and the results were correlated with those obtained by fluorescent in situ hybridization (FISH). The MLPA results were reproducible in all samples in which repeated experiments were performed. In 18 of 19 OGs, MLPA and FISH were concordant for presence or absence of 1p deletion. In 3 OGs, MLPA detected a 19q deletion not shown by FISH. For the other 15 OGs, MLPA and FISH were concordant. In one sample with 50% to 75% of tumor, MLPA failed to detect the 1p/19q deletions revealed by FISH (though with borderline values of significance). We conclude that MLPA is a valid and reproducible method for the detection of 1p/19q chromosomal deletions in OGs stored on formalin fixed, paraffin embedded tissue.
Abstract Background The clinical presentation of Alzheimer’s disease (AD) including age at onset, is remarkably heterogeneous. In previous research, we showed that inflammation is differently distributed between typical and atypical AD (Boon et al., 2018). In addition, distinct Aβ deposits in AD pathology are recognized. These deposits are called plaques when located in brain parenchyma or cerebral amyloid angiopathy (CAA) when located in the cerebral vessels. Recently, we described a novel Aβ plaque‐type, referred to as ‘the coarse‐grained plaque’. In this study, we evaluate its clinical relevance and perform in‐depth morphological characterization. Method The coarse‐grained plaque’s presence was investigated in the frontal cortex of Aβ‐pathology‐positive cases (N=74), including non‐demented controls (n=15), early‐onset (EO)AD (n=38), and late‐onset (LO)AD (n=21), using a semi‐quantitative approach. Main plaque characteristics were compared to other well‐defined Aβ deposits; the classic cored plaque, the cotton wool plaque, and CAA. In‐depth characterization was done by studying the coarse‐grained plaque’s Aβ isoform (Aβ 40 , Aβ 42 , Aβ N3pE , and pSer8Aβ) composition, neuroinflammatory component, and vascular association using immunohistochemistry and 3D confocal laser scanning microscopy imaging. Result The plaque was only observed in cases with clinical symptoms, it was more prominent in EOAD (95%) than in LOAD (66%) and was associated with a homozygous ApoE4 status (Figure 1). The coarse‐grained plaque showed a multi‐cored Aβ morphology and was seen in the proximity of CAA‐affected sulci. Its predominant Aβ 40 composition was distinct from other plaques, but showed similarities to that of CAA (Figure 2A). 3D imaging revealed a unique hollow Aβ 40 ‐shell structure (Figure 2B) with microglia in Aβ‐devoid holes (Figure 3). Furthermore, the plaque’s immunoreactivity for the CAA‐Type 1 specific marker norrin suggests – although having a different morphology ‐ a close etiological relation with CAA. Conclusion The coarse‐grained plaque is a clinically relevant Aβ deposit as it occurs only in clinical AD and is more frequent in early‐onset cases. The plaque is strongly associated with neuroinflammatory and vascular changes. Differences in presence of coarse‐grained plaque among AD subtypes, contributes to the compiling evidence that also pathophysiology in AD is heterogeneous.
