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DEGENERATIVE AND COGNITIVE DISEASES: Edited by Mathieu Ceccaldi

Editorial: Facing up to the complexity of neuro degenerative disorders in order to deal with them more effectively

Ceccaldi, Mathieu

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Current Opinion in Neurology: April 2019 - Volume 32 - Issue 2 - p 253-254
doi: 10.1097/WCO.0000000000000670
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The current classification of neuro degenerative disorders (NDD) promotes a ‘pure’ or ‘predominant’ central nervous system (CNS) proteinopathy-based approach. In particular, a research framework was recently proposed to predict diagnosis of Alzheimer Disease according the ‘A/T/N’ classification system: A refers to the value of a β-amyloid biomarker, T refers to a Tau biomarker and N to biomarkers of neurodegeneration [1]. This biological definition is related to the current context of clinical trials, targeting a ‘single’ protein (such as Aβ, or more recently Tau), and will probably serve to clarify the practical and logistical application of this approach. Nevertheless, this classification – in its present form – is ‘biomarker technology-driven’ and, to date, does not include other possible pathological lesions that can be found in brains from patients with Alzheimer Disease, such as microinfarcts, or other possible concomitant proteinopathies such as TDP 43 or α-synuclein. Moreover, it does not also consider potentially important proteinopathy companion processes which are represented, for example, by immunological signatures and by the characteristics of the neuronal networks which may be damaged by the various NDD. In other words, in order to be more effective in due course in therapeutic terms, this presentation of Alzheimer Disease masks much of its physiopathological complexity.

In this issue of Current Opinion in Neurology, we have included papers which illustrate and document several important recent findings and concepts which should enrich and modulate the conceptual framework of clinical research in the field of NDD.

DIFFERENTIAL NETWORKS’ SUSCEPTIBILITY TO PROTEINOPATHIES?

Primary progressive aphasia (PPA) refers to a variety of clinical syndromes with a predominant alteration of language and speech, which are caused by neuronal damage selectively affecting various specific brain networks. As detailed by Tee and Gorno-Temini (pp. 255–265), each clinical variant – semantic (svPPA), nonfluent/agrammatic (nfvPPA), and logopenic (lvPPA) – is strongly associated with distinct patterns of grey matter atrophy and white matter damage. Moreover, clinico-anatomical phenotyping of PPA is a good predictor of in-vivo CNS proteinopathies, including β-amyloid, Tau, and TDP-43. By consequence, studying ‘focal’ degenerative cortical syndromes such as PPA could provide a great deal of knowledge on the dynamics of the different deposition patterns of toxic proteins, and, to some extent, on the ‘brain mapping’ of neuronal susceptibility to proteinopathies.

VARIOUS PROTEINOPATHIES ACTING AS BRAIN OR EVEN EXTRA BRAIN ‘PROPAGON’?

A review by Duyckaerts et al. (pp. 266–271) on the recent evidence on prion-like mechanisms in Alzheimer Disease and Parkinson Disease emphasizes the various potential dimensions of transmission and propagation of toxic CNS proteins: at the tissue level, at systemic level or from individual to individual (‘infectious propagon’). The currently available data suggest that Tau and α-synuclein pathologies behave like a propagon at the tissue level, with a progression of the disorders through neuronal connexions. Some recent evidences of human to human iatrogenic transmission of β-amyloid disorder suggest that Aβ may also act as an ‘infectious propagon’. Quite apart from its interest with regard to knowledge of the course of the NDD, these reports should lead to the exclusion of donors with Alzheimer Disease in graft procedures.

ROLE OF MICROGLIA AND PERIPHERAL MYELOÏD CELLS IN PROTEINOPATHY-BASED NEURODEGENERATION

Previous studies on the genes implicated in frontotemporal dementia (FTD) suggest that inflammatory mechanisms are likely to significantly contribute to the disease pathogenesis. Sirkis et al. (pp. 272–278) present data from recent human studies, which emphasize the role of microglia – the ‘brain resident macrophages’ – in the process of neurodegeneration in patients with fronto-temporal lobar degeneration (FTLD). They also suggest that peripheral myeloid cells show significant alteration in FTLD. Furthermore, data from novel mouse models highlight the role of Trem 2 deficiency and that of APOE – via a potential modulation of microglial function – in Tauopathy. Moreover, some experimental data suggest that enhancing the microglial response may be a potential key in treatment of FTLD with TDP-43 pathology.

COMORBIDITY IN NEURO DEGENERATIVE DISORDERS IS NOT A RARE CONDITION !

Concomitant multiple proteinopathies in the brain (comorbidity) is not an infrequent condition. Kovacs (pp. 279–291) reports growing evidence of combinations of neurodegenerative proteinopathies in brains from patients with Alzheimer Disease and other NDD. Recent experimental studies suggest that the co-deposition of multiple pathological proteins in NDD may be because of direct and synergistic interactions or cross-seeding of proteins. However, this hypothesis cannot yet be accepted in man, and other explanations are possible: aging as a risk factor of comorbidity, common pathways shared by different proteins and possible influence of variations of genes. In any case, comorbidity may influence the cognitive profile and the progression of NDD, and it would appear essential to attempt to deal with it preferably within the present context of clinical trials in NDD targeting single proteins, and in the future in more appropriate perspective of combined therapeutic strategies.

PERSPECTIVES FOR NON-INVASIVE BRAIN STIMULATION IN ALZHEIMER DISEASE

Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES) are the two most widely studied noninvasive brain stimulation (NIBS) techniques. The review by Buss et al. (pp. 292–304) focused on studies published in the last 2 years concerning the treatment of cognition in patients with Alzheimer Disease and in patients with mild cognitive impairment (MCI). To date, encouraging results have been obtained after repetitive TMS, with improvement of overall cognition and memory measures from 20 studies in patients with a clinical diagnosis of Alzheimer Disease or a related disorder. This approach might prove to be a supplementary tool in the context of a disorder with complex physiopathology. Nevertheless, the assessment of nonpharmacological tools such as this one should be supported by more extensive studies to define the optimum stimulation parameters, involving larger numbers of participants and also using a biomarker-based approach for selecting potential candidates.

Finally, this issue highlights the extent to which research in these areas remains active, rich in discoveries, and full of promise. Innovation and inventiveness must always be the cornerstones of NDD research, and their excellent definition given by Gabor G. Kovacs in the introduction of his paper must be borne in mind: ‘neurodegenerative diseases can be defined as a long-standing dynamic process of dysfunctional networks and interaction of neurons and glia and abnormal protein processing on a diverse genetic and epigenetic background, leading inevitably to loss of neurons’.

Acknowledgements

Special Thanks to the authors contributing to this issue.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCE

1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimer's Dementia 2018; 14:535–562.
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