Background and purpose
Clinical diagnostic criteria for neurodegenerative diseases have been framed based on clinical phenomenology. However, systematic knowledge about the first reported clinical ...symptoms in neurodegenerative diseases is lacking. Therefore, the aim was to determine the prevalence and clinical implications of the first clinical symptom (FS) as assessed by medical history in neuropathologically proven neurodegenerative diseases.
Methods
Neuropathological diagnoses from the Neurobiobank Munich, Germany, were matched with clinical records for analyses of the diagnostic and prognostic values of FSs.
Results
In all, 301 patients with the neuropathological diagnoses Alzheimer disease (AD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD) including the neuropathologically indistinguishable clinical phenotypes Parkinson disease and dementia with Lewy bodies, multiple system atrophy (MSA) and corticobasal degeneration (CBD) were studied. Memory disturbance was the most common FS in AD (34%), FTLD (19%) and LBD (26%), gait disturbance in PSP (35%) and MSA (27%) and aphasia and personality changes in CBD (20%, respectively). In a model adjusting for prevalence in the general population, AD was predicted by memory disturbance in 79.0%, aphasia in 97.2%, personality changes in 96.0% and by cognitive disturbance in 99.0%. Gait disturbance and tremor predicted LBD in 54.6% and 97.3%, coordination disturbance MSA in 59.4% and dysarthria FTLD in 73.0%. Cognitive FSs were associated with longer survival in AD (12.0 vs. 5.3 years; p < 0.001) and FTLD (8.2 vs. 4.1 years; p = 0.005) and motor FSs with shorter survival in PSP (7.2 vs. 9.7; p = 0.048).
Conclusions
Assessing FSs in neurodegenerative diseases may be beneficial for accuracy of diagnosis and prognosis and thereby may improve clinical care and precision of study recruitment.
In this work, the distribution of first clinical symptoms in neurodegenerative diseases is provided together with a prevalence adjusted model that depicts the probabilities for each neurodegenerative diagnosis if a distinct first symptom occurs in a patient. For clinicians that hover between two neurodegenerative diagnoses, a scheme is given that may facilitate diagnosis using the first clinical symptom. Further, the prognostic value of the first clinical symptom regarding survival in neurodegenerative diseases is analyzed.
Background and purpose
Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to ...investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND.
Methods
Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared amongst ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined.
Results
In all, 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n = 144; LBD, n = 103; PSP, n = 93; FTLD, n = 53; MSA, n = 36; CBD, n = 25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p = 0.005), LBD (p = 0.001), MSA (p = 0.005) and PSP (p < 0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p = 0.017).
Conclusions
Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk.
The current clinical neuropathological correlation study reveals high seizure prevalences in neurodegenerative diseases, particularly in Alzheimer disease. Additionally, this work shows associations between cognitive first symptoms and an increased seizure risk and between motor first symptoms and a decreased seizure risk in neurodegenerative diseases.
Implementing and maintaining the information technology (IT) infrastructure of a brain bank can be a daunting task for any brain bank coordinator, particularly when access to both funds and IT ...professionals is limited. Many questions arise when attempting to determine which IT products are most suitable for a brain bank. The requirements of each brain bank must be assessed carefully to ensure that the chosen IT infrastructure will be able to meet those requirements successfully and will be able to expand and adapt as the size of the brain bank increases. This chapter provides some valuable insights to be considered when implementing the IT infrastructure for a brain bank and discusses the pros and cons of various approaches and products.
Background
In the neurodegenerative conditions Alzheimer disease (AD), Lewy body disease (LBD) including the neuropathologically indistinguishable Parkinson disease and dementia with Lewy bodies, ...frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) figures for seizure risk are inconsistent, rare or lacking. This is particular true if neuropathologically confirmed diagnoses are stipulated. Therefore, our goal was to determine the lifetime risk for epileptic seizures and to investigate associated clinical parameters in neuropathologically diagnosed neurodegenerative diseases.
Method
Cases from the Neurobiobank Munich, Germany, were matched with information from clinical files regarding the occurrence of epileptic seizures. The aforementioned diseases were compared for lifetime seizure risk. The predictive value of the first clinical symptom regarding lifetime risk for seizures was analyzed and associations between the occurrence of seizures and survival was investigated.
Result
We analyzed 454 neuropathologically diagnosed cases with sufficient clinical data available. 144 had AD, 103 LBD, 93 PSP, 53 FTLD, 36 MSA, and 25 CBD. Lifetime risk for epileptic seizures was 31.3% in AD, 20.0% in CBD, 12.6% in LBD, 11.3% in FTLD, 8.3% in MSA and 7.5% in PSP. Patients with AD had a statistically significantly higher lifetime risk for seizures compared to patients with FTLD (p=0.005), LBD (p=0.001), MSA (p=0.005) and PSP (p<0.001). An increased lifetime seizure risk was found in patients with cognitive first symptoms when compared to those with non‐cognitive first symptoms (21.1% vs. 11.0%). A decreases lifetime risk for seizures was observed in cases with motor first symptoms when compared to those with non‐motor first symptoms (10.3% vs. 20.5%). MSA patients with seizures survived longer when compared to those without (12.3 vs. 7.0 years; p = 0.017).
Conclusion
In this clinical neuropathological correlation study, nearly every third AD patient and approximately every fifth patient with a neurodegenerative disease experienced epileptic seizures in the disease course. Therefore, epileptic seizures are an important comorbidity in neurodegenerative conditions, in particular in AD. Assessment of the first clinical symptom may improve early estimation of the lifetime seizure risk in the studied neurodegenerative diseases.
Research utilizing human tissue and its removal at post-mortem has given rise to many controversies in the media and posed many dilemmas in the fields of law and ethics. The law often lacks clear ...instructions and unambiguous guidelines. The absence of a harmonized international legislation with regard to post-mortem medical procedures and donation of tissue and organs contributes to the complexity of the issue. Therefore, within the BrainNet Europe (BNE) consortium, a consortium of 19 European brain banks, we drafted an ethical Code of Conduct for brain banking that covers basic legal rules and bioethical principles involved in brain banking. Sources include laws, regulations and guidelines (Declarations, Conventions, Recommendations, Guidelines and Directives) issued by international key organizations, such as the Council of Europe, European Commission, World Medical Association and World Health Organization. The Code of Conduct addresses fundamental topics as the rights of the persons donating their tissue, the obligations of the brain bank with regard to respect and observance of such rights, informed consent, confidentiality, protection of personal data, collections of human biological material and their management, and transparency and accountability within the organization of a brain bank. The Code of Conduct for brain banking is being adopted by the BNE network prior to being enshrined in official legislation for brain banking in Europe and beyond.
Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support ...current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.
New biological models are incorporating the realistic processes underlying biological responses to climate change and other human-caused disturbances. However, these more realistic models require ...detailed information, which is lacking for most species on Earth. Current monitoring efforts mainly document changes in biodiversity, rather than collecting the mechanistic data needed to predict future changes. We describe and prioritize the biological information needed to inform more realistic projections of species' responses to climate change. We also highlight how trait-based approaches and adaptive modeling can leverage sparse data to make broader predictions. We outline a global effort to collect the data necessary to better understand, anticipate, and reduce the damaging effects of climate change on biodiversity.
Extravasation of macrophages and formation of lipid-laden foam cells are key events in the development and progression of atherosclerosis. The degradation of atherogenic lipoproteins subsequently ...leads to alterations in cellular lipid metabolism that influence inflammatory signaling. Especially sphingolipids and ceramides are known to be involved in these processes. We therefore analyzed monocyte derived macrophages during differentiation and after loading with enzymatically (eLDL) and oxidatively (oxLDL) modified low-density lipoproteins (LDL).
Primary human monocytes were isolated from healthy, normolipidemic blood donors using leukapheresis and counterflow elutriation. On the fourth day of MCSF-induced differentiation eLDL (40 μg/ml) or oxLDL (80 μg/ml) were added for 48h. Lipid species were analyzed by quantitative tandem mass spectrometry. Taqman qPCR was performed to investigate transcriptional changes in enzymes involved in sphingolipid metabolism. Furthermore, membrane lipids were studied using flow cytometry and confocal microscopy.
MCSF dependent phagocytic differentiation of blood monocytes had only minor effects on the sphingolipid composition. Levels of total sphingomyelin and total ceramide remained unchanged, while lactosylceramides, cholesterylesters and free cholesterol decreased. At the species level most ceramide species showed a reduction upon phagocytic differentiation. Loading with eLDL preferentially increased cellular cholesterol while loading with oxLDL increased cellular ceramide content. Activation of the salvage pathway with a higher mRNA expression of acid and neutral sphingomyelinase, neutral sphingomyelinase activation associated factor and glucosylceramidase as well as increased surface expression of SMPD1 were identified as potentially underlying mechanisms. Moreover, flow-cytometric analysis revealed a higher cell-surface-expression of ceramide, lactosylceramide (CDw17), globotriaosylceramide (CD77), dodecasaccharide-ceramide (CD65s) and GM1 ganglioside upon oxLDL loading. ApoE in contrast to apoA-I preferentially bound to the ceramide enriched surfaces of oxLDL loaded cells. Confocal microscopy showed a co-localization of acid sphingomyelinase with ceramide rich membrane microdomains.
eLDL leads to the formation of lipid droplets and preferentially induces cholesterol/sphingomyelin rich membrane microdomains while oxLDL promotes the development of cholesterol/ceramide rich microdomains via activation of the salvage pathway.
Dysregulation of monocyte-macrophage differentiation is a hallmark of vascular and metabolic diseases and associated with persistent low grade inflammation. Plasmalogens represent ether lipids that ...play a role in diabesity and previous data show diminished plasmalogen levels in obese subjects. We therefore analyzed transcriptomic and lipidomic changes during monocyte-macrophage differentiation in vitro using a bioinformatic approach.
Elutriated monocytes from 13 healthy donors were differentiated in vitro to macrophages using rhM-CSF under serum-free conditions. Samples were taken on days 0, 1, 4 and 5 and analyzed for their lipidomic and transcriptomic profiles.
Gene expression analysis showed strong regulation of lipidome-related transcripts. Enzymes involved in fatty acid desaturation and elongation were increasingly expressed, peroxisomal and ER stress related genes were induced. Total plasmalogen levels remained unchanged, while the PE plasmalogen species pattern became more similar to circulating granulocytes, showing decreases in PUFA and increases in MUFA. A partial least squares discriminant analysis (PLS/DA) revealed that PE plasmalogens discriminate the stage of monocyte-derived macrophage differentiation. Partial correlation analysis could predict novel potential key nodes including DOCK1, PDK4, GNPTAB and FAM126A that might be involved in regulating lipid and especially plasmalogen homeostasis during differentiation. An in silico transcription analysis of lipid related regulation revealed known motifs such as PPAR-gamma and KLF4 as well as novel candidates such as NFY, RNF96 and Zinc-finger proteins.
Monocyte to macrophage differentiation goes along with profound changes in the lipid-related transcriptome. This leads to an induction of fatty-acid desaturation and elongation. In their PE-plasmalogen profile macrophages become more similar to granulocytes than monocytes, indicating terminal phagocytic differentiation. Therefore PE plasmalogens may represent potential biomarkers for cell activation. For the underlying transcriptional network we were able to predict a range of novel central key nodes and underlying transcription factors using a bioinformatic approach.
Oxidized and enzymatically modified low-density lipoproteins (oxLDL and eLDL) play a key role in early stages of atherogenesis. Their uptake by recruited macrophages leads to endolysosomal ...phospholipidosis or foam cell formation, respectively, each of which is preceded by highly differential lipid restructuring processes. We applied (1)H-NMR spectroscopy (NMRS) to elucidate these structural rearrangements both in consequence of lipoprotein modifications and following phagocytosis. Being specifically sensitive to the mobile lipid subset, NMRS of oxLDL and eLDL revealed a partial and total immobilization of lipids, respectively. NMRS of intact macrophages showed a sixfold increase in mobile lipids in case of loading with eLDL but no significant changes for oxLDL or native LDL. This finding reflected the disparate lipid storage in lipid droplets and in multilamellar endolysosomal clusters when loaded with either eLDL or oxLDL, respectively. Moreover, a significant shift of the degree of saturation towards mainly polyunsaturated fatty acid chains was found for the mobile lipid pool in eLDL-loaded macrophages. Additional analyses of lipid extracts by NMRS and mass spectrometry (MS) reflected these changes in lipid content and in fatty acid composition only partially. In summary, in-cell NMRS represents a unique lipidomics tool to investigate structural changes within the mobile lipid pool following atherogenic triggers that can be not detected by the analysis of lipid extracts by MS or NMRS.
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