LATE-NC aggravates GVD-mediated necroptosis in Alzheimer's disease

It has become evident that Alzheimer's Disease (AD) is not only linked to its hallmark lesions-amyloid plaques and neurofibrillary tangles (NFTs)-but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in neuronal death. One of these co-pathologies is the accumulation of phosphorylated transactive-response DNA binding protein 43 (pTDP-43) as neuronal cytoplasmic inclusions, currently considered to represent limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), in up to 70% of symptomatic AD cases. Granulovacuolar degeneration (GVD) is another AD co-pathology, which also contains TDP-43 and other AD-related proteins. Recently, we found that all proteins required for necroptosis execution, a previously defined programmed form of neuronal cell death, are present in GVD, such as the phosphorylated necroptosis executioner mixed-lineage kinase domain-like protein (pMLKL). Accordingly, this protein is a reliable marker for GVD lesions, similar to other known GVD proteins. Importantly, it is not yet known whether the presence of LATE-NC in symptomatic AD cases is associated with necroptosis pathway activation, presumably contributing to neuron loss by cell death execution. In this study, we investigated the impact of LATE-NC on the severity of necroptosis-associated GVD lesions, phosphorylated tau (pTau) pathology and neuronal density. First, we used 230 human post-mortem cases, including 82 controls without AD neuropathological changes (non-ADNC), 81 non-demented cases with ADNC, i.e.: pathologically-defined preclinical AD (p-preAD) and 67 demented cases with ADNC. We found that Braak NFT stage and LATE-NC stage were good predictors for GVD expansion and neuronal loss in the hippocampal CA1 region. Further, we compared the impact of TDP-43 accumulation on hippocampal expression of pMLKL-positive GVD, pTau as well as on neuronal density in a subset of nine non-ADNC controls, ten symptomatic AD cases with (ADTDP+) and eight without LATE-NC (ADTDP-). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in ADTDP+ cases, compared to ADTDP- and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in ADTDP+ compared to ADTDP- cases. These data suggest that co-morbid LATE-NC in AD impacts not only pTau pathology but also GVD-mediated necroptosis pathway activation, which results in an accelerated neuronal demise. This further highlights the cumulative and synergistic effects of comorbid pathologies leading to neuronal loss in AD. Accordingly, protection against necroptotic neuronal death appears to be a promising therapeutic option for AD and LATE

Primary Progressive Aphasia: a language disorder studied at the behavioral, structural and molecular imaging level

Following the first description of a case series of patients with a ’languagepredominant’ dementia syndrome by Marsel Mesulam in 1982, the term primary progressive aphasia (PPA) was coined. The primary symptom of PPA is the loss of language, which is progressive in nature. As of 2011, three clinical subtypes within the spectrum of PPA are internationally recognized: a nonfluent/agrammatic (NFV), a semantic (SV) and a logopenic variant (LV). Of the LV cases, 50-60% have underlying Alzheimer’s disease (AD) pathology. In 50-88% of NFV cases the underlying cause is frontotemporal lobar degeneration (FTLD)-tauopathy (i.e. corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) or Pick’s disease pathology) and 69-83% of SV cases have FTLD-Transactive response DNA binding Protein 43 kDa (TDP-43) type C pathology as underlying cause. Despite gradually increasing knowledge, the pathophysiology of PPA remains still poorly understood. The general aim of this thesis was to study pathophysiological mechanisms underlying PPA at a behavioral, structural and molecular imaging level. Using non-linguistic, acoustic stimuli devoid of meaning, we demonstrated that a subset of PPA patients were impaired in key domains of nonverbal core auditory processing. Patients with NFV PPA had the most marked deficits within the time/rhythm domain for the processing of short sequences of up to seven tones. A subset of the SV patients were also impaired, though less severely. Patients with LV PPA did not show any significant individual impairments. Our sound perception data allowed reliable discrimination of NFV from LV cases even though these contained no language stimuli and were purely based on perceptual judgment of pitch and rhythm in tone sequences. We also demonstrated that performance on a subset of the psychoacoustic tests correlated with conventional verbal repetition tests. Rhythm and time processing deficits in NFV PPA relied on right-hemispheric brain structures including the frontal operculum and posterior insula. We postulate that auditory timing pathways are altered in NFV PPA, which are used in common for processing acoustic sequence structure in both speech output and acoustic input. The perceptual timing deficits may contribute to the speech apraxia in NFV which is characterized by abnormal duration of inter-segmental time intervals of speech among other features. A subset of NFV PPA patients have single-word comprehension problems besides motor speech problems and/or agrammatism. These patients are considered as the fourth ’mixed’ variant (MV) of PPA. Based on imaging results reported in the current thesis, MV PPA showed a tau PET pattern, measured by [18F]-THK5351, which is highly similar to that observed in patients with NFV without single-word comprehension deficits (NFV-pure), namely increased [18F]-THK5351 binding in the premotor cortex and supplementary motor area. The topography of [18F]-THK5351 binding, but not the degree of atrophy was correlated with core clinical features of MV PPA. In MV, the atrophy pattern was more widespread and patients had a higher likelihood of underlying Alzheimer’s disease pathology compared to NFV-pure PPA. Next, we investigated in a series of PPA patients whether basal forebrain (BF) volume loss relates to cholinergic depletion and how this depends on the PPA variant. The BF is reportedly atrophic in SV and in NFV PPA, which might indicate a cholinergic deficit. Acetylcholinesterase (AChE) activity, a cholinergic system marker, was quantitatively measured in the neo- and allocortex using N-[11C]-Methylpiperidin-4-yl propionate (PMP)-PET with arterial sampling and metabolite correction. In the PPA group, only LV cases showed decreases in AChE activity levels compared to controls. Surprisingly, a substantial number of SV cases showed significant AChE activity increases compared to controls. We concluded that based on our findings, BF atrophy in SV PPA does not imply cholinergic depletion. In summary, the findings reported in this thesis shed light on the non-linguistic, acoustic processing deficits and the underlying neuronanatomical, and molecular imaging correlates which contribute to the clinical phenotype of PPA. Despite increasing knowledge, truly disease-modifying therapies are currently not available in PPA. Based on our findings, tau PET provides a direct measure of the topographic distribution of the underlying brain changes and could be of value in future trials in clinical drug development. A subset of LV cases could potentially benefit from treatment with cholinomimetic medication.nrpages: 234status: publishe

Reproducibility of graph measures at the subject level using resting-state fMRI

INTRODUCTION: Graph metrics have been proposed as potential biomarkers for diagnosis in clinical work. However, before it can be applied in a clinical setting, their reproducibility should be evaluated. METHODS: This study systematically investigated the effect of two denoising pipelines and different whole-brain network constructions on reproducibility of subject-specific graph measures. We used the multi-session fMRI dataset from the Brain Genomics Superstruct Project consisting of 69 healthy young adults. RESULTS: In binary networks, the test-retest variability for global measures was large at low density irrespective of the denoising strategy or the type of correlation. Weighted networks showed very low test-retest values (and thus a good reproducibility) for global graph measures irrespective of the strategy used. Comparing the test-retest values for different strategies, there were significant main effects of the type of correlation (Pearson correlation vs. partial correlation), the (partial) correlation value (absolute vs. positive vs. negative), and weight calculation (based on the raw (partial) correlation values vs. based on transformed Z-values). There was also a significant interaction effect between type of correlation and weight calculation. Similarly as for the binary networks, there was no main effect of the denoising pipeline. CONCLUSION: Our results demonstrated that normalized global graph measures based on a weighted network using the absolute (partial) correlation as weight were reproducible. The denoising pipeline and the granularity of the whole-brain parcellation used to define the nodes were not critical for the reproducibility of normalized graph measures.status: publishe

3D-shape perception in the clinical spectrum of Alzheimers disease

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3D-shape perception in amnestic MCI

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Comparison of [18F]-Flutemetamol uptake and CSF measurements in cognitively intact older individuals

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In vivo characterization of basal forebrain atrophy and cholinergic denervation in primary progressive aphasia

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Optimization of Wind Farm Configuration

Abstract: With the increasing popularity of wind farms, the question of what is the optimum turbine placement has arisen. This study aims at determining the minimum wind turbine spacing while maintaining maximum power generation. Performance will be judged by percentage of free stream velocity recovery as well as by the average turbine power coefficient (Cp). A model will be generated within Star CCM+ using Large Eddy Simulation (LES) and validated by wind tunnel testing. Historically, experiments have concluded that a spacing of 8 rotor diameters in an in-line configuration yields a free stream velocity recovery of 88%. This study will test staggered configurations which should increase the free stream velocity recovery, while allowing for smaller turbine spacing. The results will serve as a guide for designing future wind farms and predicting power output

Synaptic markers in liquor inversely correlate with gray matter volume in cognitively healthy individuals

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