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PurposeThe purpose of this paper is to tackle the grand issue of climate change in a managerial perspective by proposing a new type of management.Design/methodology/approachClimate change has now been debated for many years, and in spite of different viewpoints, analyses and opinions, is a phenomenon that is accepted by all. There are thousands of studies on the nature of climate change and its consequences on the planet Earth and its inhabitants. However, there are few studies investigating the consequences of climate change on the founding tenets and practices of management. This paper aims to contribute to this facet of the issue. In the first part, it examines the main facts about climate change, their impact on businesses and proposes an adapted model of management for agriculture, industry, services and supply chains. In the second part, it advocates a shift in paradigm from the “maximization of profit” to the “maximization of well-being” as the foundation of a new managerial philosophy that can both address climate change and sustainability.FindingsCompanies and managers are in a much better position than politicians and consumers to find a solution to climate change problems for the very reason that they are not stupid in Cipolla's (2011) sense. Companies and managers do have the power to rewrite the rules of the game in order to get to a firm and management metamorphosis. Starting from a return to company ownership by and for the company itself (not just external shareholders), a switch in purpose from profit-seeking to people's well-being, fair remuneration of stakeholders, progress as a measure of success and long-term orientation are suggested as new tenets in management.Research limitations/implicationsAlthough this paper has several limitations (it may be too wide in scope, utopian, its ideas may sound unachievable and even sometimes naïve in their arguments), its starting point is very clear: the authors, as management scholars, must do something to try and stop the crash of economies and businesses in an ecological disaster. And its logic is very clear and straightforward as well: if people want things to change, then they have to change the foundations of management thinking, both in theory and in practice. The authors do not claim their solution is the only one or the best: avenues for future research aimed at providing better solutions are wide open from this point of view, and the authors genuinely encourage colleagues to continue in this direction and contribute to this work. What matters most, however, is to stop looking for precise answers to “wrong, well-defined, narrow problems” and to start looking for “approximate answers to important problems” (Brown et al., 2005) as the authors tried to do here.Practical implicationsDeveloping a new management operating model and foundations able to keep companies alive while not compromising mankind survival on planet Earth.Originality/valueThis paper addresses the Tourish (2020) challenge for purposeful research in management by providing some fresh ideas about the way companies and management principles and practices should change to prevent irreversible environmental damages.

BACKGROUND: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy. OBJECTIVE: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis. METHODS: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG). RESULTS: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95%. Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. CONCLUSION: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools. ispartof: JOURNAL OF ALZHEIMERS DISEASE vol:90 issue:4 pages:1739-1747 ispartof: location:Netherlands status: published

We aimed to evaluate the specificity of neurogranin (Ng) for Alzheimer's disease (AD) in a dementia cohort. Cerebrospinal fluid (CSF) Ng was measured (ELISA) in two independent cohorts: (1) clinical (n = 116; age 72±11 years): AD, non-AD (+high T-tau), and controls; and (2) autopsy-confirmed (n = 97; age 71±11 years): AD and non-AD, and 50 controls (age 60±6 years). In 16 autopsy-confirmed AD and 8 control subjects, Ng was measured in tissue (BA6+BA22). Ng was compared across diagnostic groups or neuropathological staging using multilinear regression models. Median[IQR] Ng concentrations were elevated in AD (414[315–499]pg/mL) and non-AD (464[319–699]pg/mL) compared to controls (260[193–306]pg/mL), but highest in AD-high-T-tau (874[716, 1148] pg/mL) and Creutzfeldt-Jakob disease (CJD; 828[703–1373]pg/mL) in cohort 1 (p < 0.01), but not in cohort 2: AD: 358[249–470]pg/mL; non-AD:245[137–416]pg/mL; controls: 259[193–370]pg/mL. Ng and tau biomarkers strongly correlated (r = 0.4–0.9, p < 0.05), except in CJD. CSF Ng concentrations were not associated with neuropathological AD hallmarks, nor with tissue Ng concentrations. CSF Ng is a general biomarker for synaptic degeneration, strongly correlating with CSF tau, but without added value for AD differential diagnosis.

Background: Despite decades of research on the optimization of the diagnosis of Alzheimer’s disease (AD), its biomarker-based diagnosis is being hampered by the lack of comparability of raw biomarker data. In order to overcome this limitation, the Erlangen Score (ES), among other approaches, was set up as a diagnostic-relevant interpretation algorithm. Objective: To validate the ES algorithm in a cohort of neuropathologically confirmed cases with AD (n = 106) and non-AD dementia (n = 57). Methods: Cerebrospinal fluid (CSF) biomarker concentrations of Aβ1-42, T-tau, and P-tau181 were measured with commercially available single analyte ELISA kits. Based on these biomarkers, ES was calculated as previously reported. Results: This algorithm proved to categorize AD in different degrees of likelihood, ranging from neurochemically “normal”, “improbably having AD”, “possibly having AD”, to “probably having AD”, with a diagnostic accuracy of 74% using the neuropathology as a reference. Conclusion: The ability of the ES to overcome the high variability of raw CSF biomarker data may provide a useful diagnostic tool for comparing neurochemical diagnoses between different labs or methods used.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS.

Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.

Additional file 1. Supplementary materials and methods. Detailed protocols and references. Supplementary results. Phasing compound heterozygous variants in the Belgian cohorts. Effect of VPS13C splice site variants on mRNA splicing. Supplementary tables. Table S1: Clinical and demographic characteristics of study cohorts. Table S2. Clinical data of patient carriers of rare homozygous or trans compound heterozygous VPS13C mutations. Table S3: Candidate genes and mutations identified in WGS data of family A. Table S4: VPS13C rare coding and splice site variants in DLB and PD patients and in controls. Table S5: Major genes associated with neurodegenerative brain diseases. Table S6: LBD patient carriers of cis compound heterozygous coding and splice site variants in VPS13C. Table S7: Control carriers of compound heterozygous coding and splice site variants in VPS13C. Table S8: Primer sequences. Table S9: In-silico predictions on VPS13C mRNA splicing of splice site variants in compound heterozygous carriers. Supplementary figures. Fig. S1: VPS13C rare coding and splice site variants in DLB (n=233) and PD patients (n=611), and in controls (844). Fig. S2: Late endosomal localization of VPS13C is lost in p.Trp395Cys and p.Ala444Pro mutations. Fig. S3: Lysosomal localization of VPS13C is lost in p.Trp395Cys and p.Ala444Pro mutations. Fig. S4: Missense mutations p.Trp395Cys and p.Ala444Pro disturb localization of VPS13C at the lysosomes. Fig. S5: Wild type and p.Trp395Cys or p.Ala444Pro mutant VPS13C does not accumulate at the endoplasmic reticulum. Fig. S6: Wild type and p.Trp395Cys or p.Ala444Pro mutant VPS13C does not accumulate at the cis- and medial-Golgi. Fig. S7: Wild type and p.Trp395Cys or p.Ala444Pro mutant VPS13C does not accumulate at the trans-Golgi. Fig S8: Western blot analysis of extracts from VPS13C knockout and wild type HeLa cells using the affinity-purified VPS13C antibody. Fig. S9: Haplotype sharing analysis. Fig. S10: Trans configuration of p.Met2711Ile/p.Ile2789Thr in patient P4 confirmed by allele specific PCR. Fig. S11: Family C. Fig. S12: Cis configuration of p.Met2764Ile/p.Val2765Leu in control C6. Fig. S13: Effect of c.4166-8C>A on VPS13C mRNA splicing.