The cholesterol is a vital component of cell membranes and myelin sheaths, and a precursor for essential molecules such as steroid hormones. In humans, cholesterol is partially obtained through the diet, while the majority is synthesized in the body, primarily in the liver. However, the limited exchange between the central nervous system and peripheral circulation, due to the presence of the blood-brain barrier, necessitates cholesterol in the brain to be exclusively acquired from local de novo synthesis. This cholesterol is reutilized efficiently, rendering a much slower overall turnover of the compound in the brain as compared with the periphery. Furthermore, brain cholesterol is regulated independently from peripheral cholesterol. Numerous enzymes, proteins, and other factors are involved in cholesterol synthesis and metabolism in the brain. Understanding the unique mechanisms and pathways involved in the maintenance of cholesterol homeostasis in the brain is critical, considering perturbations to these processes are implicated in numerous neurodegenerative diseases. This review focuses on the developing understanding of cholesterol metabolism in the brain, discussing the sites and processes involved in its synthesis and regulation, as well as the mechanisms involved in its distribution throughout, and elimination from, the brain.

Small fiber neuropathy (SFN) is a relatively common, but largely understudied neurological syndrome which has affected the lives of many globally. The common symptoms of SFN include pain, dysesthesia, and autonomic dysfunction, which are caused by damage to small nerve fibers. Due to its heterogeneous nature, SFN causes a multitude of symptoms which makes the disease and its subtypes difficult to diagnose. Furthermore, as the pathophysiology of SFN remains largely enigmatic, no cause is found in around 50% of the cases and these are classified as idiopathic SFN (iSFN). The difficult task of diagnosing SFN, and the even more elusive feat of hunting for the underlying etiology, demands accurate, precise, preferably noninvasive, and affordable tools, or a combination of them. Accordingly, appropriate biomarkers for SFN are needed to stratify patients and develop cause-centered treatments in addition to symptomatic treatments. As peripheral axons grow and repair, identifying underlying causes of SFN and intervening early may spur axonal regeneration in young patients, which can greatly improve their symptoms and improve quality of life. This narrative review aims to objectively highlight functional, histological, and molecular biomarkers to aid clinicians in discerning the diagnostic tests they should use to diagnose, confirm and determine the etiology of SFN. The strengths and limitations of each potential biomarker will be discussed. Clearer diagnostic criteria, guidelines, and work-up for SFN are required for clinicians to better identify the disease in patients presenting with non-specific symptoms.

Depression is a known risk factor for dementia. Antidepressants are the most commonly used treatment for this condition, and are effective in at least half to two-thirds of cases. Extensive evidence from in vitro and animal models suggests that antidepressants have anti-inflammatory and neuroprotective properties. These effects have been shown to reduce the oxidative damage, amyloid aggregation, and expression of pro-inflammatory genes associated with animal models of neurodegenerative disorders. However, longitudinal research in humans has shown that antidepressants do not protect against dementia, and may even be associated with a risk of cognitive deterioration over time in older adults. The contrast between two sets of findings represents a paradox of significant clinical and public health significance, particularly when treating depression in late life. This review paper attempts to resolve this paradox by critically reviewing the medium- and long-term effects of antidepressants on peripheral immune-inflammatory responses, infection risk, gut microbiota, and neuroendocrine responses to stress, and how these effects may influence the risk of neurodegeneration. Briefly stated, it is possible that the peripheral actions of antidepressant medications may antagonize their beneficial effects against neuroinflammation. The implications of these findings are then explored with a particular focus on the development and testing of multimodal neuroprotective and anti-inflammatory treatments that could reduce the risk of Alzheimer’s and related dementias in patients suffering from depression.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above sixty years. It is caused by an interaction between genetic and environmental risk factors. Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) is pathologically characterizing the disease and responsible for the cardinal motor symptoms, most notably, bradykinesia, rest tremors, rigidity, and loss of postural reflexes. Non-motor signs such as olfactory deficits, cognitive impairment, sleep behavior disorders, and gastrointestinal disturbances are reflecting disturbances in the non-dopaminergic system. They precede dopaminergic neuronal degenerations by 5–10 years and are considered the main contributors to patients’ disability, particularly after the successful implementation of levodopa (L-dopa) treatment of motor symptoms. The present general review aimed to briefly update non-motor signs and their underlying pathophysiology in PD.

Phosphoinositides are membrane phospholipids involved in a variety of cellular processes like growth, development, metabolism, and transport. This review focuses on the maintenance of cellular homeostasis of phosphatidylinositol 4,5-bisphosphate (PIP₂), and phosphatidylinositol 3,4,5-trisphosphate (PIP₃). The critical balance of these PIPs is crucial for regulation of neuronal form and function. The activity of PIP₂ and PIP₃ can be regulated through kinases, phosphatases, phospholipases and cholesterol microdomains. PIP₂ and PIP₃ carry out their functions either indirectly through their effectors activating integral signaling pathways, or through direct regulation of membrane channels, transporters, and cytoskeletal proteins. Any perturbations to the balance between PIP₂ and PIP₃ signaling result in neurodevelopmental and neurodegenerative disorders. This review will discuss the upstream modulators and downstream effectors of the PIP₂ and PIP₃ signaling, in the context of neuronal health and disease.

The currently available pharmacological anti-dementia treatments provide only temporary and limited benefits. Not surprisingly, patients and professionals increasingly explore non-pharmacological interventions that may alleviate dementia symptoms. Among these interventions is hyperbaric oxygen therapy (HBOT). A brief review is presented on HBOT use in medicine, with its mode of action in dementia, specifically Alzheimer’s disease, as well as a case report of self-initiated HBOT in a 62-year-old man with a clinical diagnosis of probable Alzheimer’s disease. He had over 400 HBOT sessions [2–3 times weekly, with a duration of 30–50 min, in a multi-place hyperbaric chamber at 2 atmospheres absolute (ATA)] over 7 years and use of donepezil (10 mg daily) for the last 3 years when formally diagnosed by the National Health Service (NHS) Memory Service. The patient’s longitudinal neurocognitive and neuroradiological evidence over 7 years of follow-up remained stable (with no major cognitive decline and no behavioral changes) when compared to his initial presentation when diagnosed by the private health provider. His driving remains unimpaired, and he continues to be independent. This highlights the potential HBOT benefits including those on visuospatial ability and activities of daily living in people with Alzheimer’s disease. This case report argues for more extensive research into the clinical effects of HBOT in Alzheimer’s disease. Discussion of HBOT use is along with the latest advances in anti-amyloid immunotherapy for Alzheimer’s disease, as well as HBOT augmentation of current and novel dementia drug delivery via nanotechnology.