New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism

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Abstract

Brain-derived neurotrophic factor is an extensively studied neurotrophin implicated in the pathology of multiple neurodegenerative and psychiatric disorders including, but not limited to, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, traumatic brain injury, major de-pressive disorder, and schizophrenia. Here we provide a brief summary of current knowledge on the role of BDNF and the common human single nucleotide polymorphism, rs6265, in driving the pathogenesis and rehabilitation in these disorders, as well as the status of BDNF-targeted therapies. A common trend has emerged correlating low BDNF levels, either detected within the central nervous system or peripherally, to disease states, suggesting that BDNF replacement therapies may hold clinical promise. In addition, we introduce evidence for a distinct role of the BDNF pro-peptide as a biologically active ligand and the need for continuing studies on its neurological function outside of that as a molecular chaperone. Finally, we highlight the latest research describing the role of rs6265 expression in mechanisms of neurodegeneration as well as paradoxical advances in the understanding of this genetic variant in neuroregeneration. All of this is discussed in the context of personalized medicine, acknowledging there is no “one size fits all” therapy for neurodegenerative or psychiatric disorders and that continued study of the multiple BDNF isoforms and genetic variants represents an avenue for discovery ripe with therapeutic potential.

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The neuropathological diagnosis of Alzheimer’s disease

Michael DeTure, Dennis W. Dickson (2019)

Alzheimer’s disease is a progressive neurodegenerative disease most often associated with memory deficits and cognitive decline, although less common clinical presentations are increasingly recognized. The cardinal pathological features of the disease have been known for more than one hundred years, and today the presence of these amyloid plaques and neurofibrillary tangles are still required for a pathological diagnosis. Alzheimer’s disease is the most common cause of dementia globally. There remain no effective treatment options for the great majority of patients, and the primary causes of the disease are unknown except in a small number of familial cases driven by genetic mutations. Confounding efforts to develop effective diagnostic tools and disease-modifying therapies is the realization that Alzheimer’s disease is a mixed proteinopathy (amyloid and tau) frequently associated with other age-related processes such as cerebrovascular disease and Lewy body disease. Defining the relationships between and interdependence of various co-pathologies remains an active area of investigation. This review outlines etiologically-linked pathologic features of Alzheimer’s disease, as well as those that are inevitable findings of uncertain significance, such as granulovacuolar degeneration and Hirano bodies. Other disease processes that are frequent, but not inevitable, are also discussed, including pathologic processes that can clinically mimic Alzheimer’s disease. These include cerebrovascular disease, Lewy body disease, TDP-43 proteinopathies and argyrophilic grain disease. The purpose of this review is to provide an overview of Alzheimer’s disease pathology, its defining pathologic substrates and the related pathologies that can affect diagnosis and treatment. Electronic supplementary material The online version of this article (10.1186/s13024-019-0333-5) contains supplementary material, which is available to authorized users.

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Parkinson's disease

Bastiaan Bloem, Michael Okun, Christine Klein (2021)

Parkinson's disease is a recognisable clinical syndrome with a range of causes and clinical presentations. Parkinson's disease represents a fast-growing neurodegenerative condition; the rising prevalence worldwide resembles the many characteristics typically observed during a pandemic, except for an infectious cause. In most populations, 3-5% of Parkinson's disease is explained by genetic causes linked to known Parkinson's disease genes, thus representing monogenic Parkinson's disease, whereas 90 genetic risk variants collectively explain 16-36% of the heritable risk of non-monogenic Parkinson's disease. Additional causal associations include having a relative with Parkinson's disease or tremor, constipation, and being a non-smoker, each at least doubling the risk of Parkinson's disease. The diagnosis is clinically based; ancillary testing is reserved for people with an atypical presentation. Current criteria define Parkinson's disease as the presence of bradykinesia combined with either rest tremor, rigidity, or both. However, the clinical presentation is multifaceted and includes many non-motor symptoms. Prognostic counselling is guided by awareness of disease subtypes. Clinically manifest Parkinson's disease is preceded by a potentially long prodromal period. Presently, establishment of prodromal symptoms has no clinical implications other than symptom suppression, although recognition of prodromal parkinsonism will probably have consequences when disease-modifying treatments become available. Treatment goals vary from person to person, emphasising the need for personalised management. There is no reason to postpone symptomatic treatment in people developing disability due to Parkinson's disease. Levodopa is the most common medication used as first-line therapy. Optimal management should start at diagnosis and requires a multidisciplinary team approach, including a growing repertoire of non-pharmacological interventions. At present, no therapy can slow down or arrest the progression of Parkinson's disease, but informed by new insights in genetic causes and mechanisms of neuronal death, several promising strategies are being tested for disease-modifying potential. With the perspective of people with Parkinson's disease as a so-called red thread throughout this Seminar, we will show how personalised management of Parkinson's disease can be optimised.