Non-motor symptoms of Parkinson's disease contribute substantially to a reduction in health-related quality of life for patients and carers. Whilst some non-motor symptoms are dopamine-responsive, current treatment options for many are limited and often unsatisfactory. We report on early observations of non-motor symptoms in seven Parkinson's disease patients treated with daily transcranial red and near infrared photobiomodulation, over periods ranging from six to thirty-four months. Six of seven patients used home-made devices, including bucket light hats with unpulsed 630 nm-850 nm LED strips, and/or a commercial helmet delivering 40Hz-pulsed sequential 670 nm and 810 nm light. One patient used a home-made 660nm intra-nasal device. Progress was assessed by the subjects themselves, their spouse and attending clinicians. A range of non-motor symptoms appeared to improve during photobiomodulation treatment, especially fatigue, sleep, apathy, mood, anxiety, concentration/attention, anhedonia and olfaction. There were also improvements in motor signs and in the "sense of self". Photobiomodulation was well-tolerated, with no adverse effects and high patient compliance. In summary, daily photobiomodulation helped elicited and maintain improvements in otherwise difficult to treat symptoms.
Alzheimer's Disease (AD) is becoming more widely recognized as a condition of brain energy metabolism, wherein lipid dysregulation plays a crucial, although unrecognized, role. In addition to functioning as structural elements of neuronal membranes, lipids such as phospholipids, sphingolipids, and cholesterol play a crucial role in regulating mitochondrial bioenergetics, synaptic activity, and membrane-associated signaling pathways. In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates. These alterations intensify oxidative stress, impair glucose and ketone utilization, and stimulate neuroinflammatory pathways that further diminish metabolic capacity. Progress in lipidomics has uncovered disease-specific lipid signatures, providing a fresh understanding of the relationship between lipid homeostasis and neuronal energy loss. Despite extensive focus on amyloid and tau, lipid-mediated bioenergetic failure remains underrepresented in integrative AD models; this chapter addresses this gap and consolidates existing information connecting lipid modifications to metabolic dysfunction in AD, emphasizing molecular pathways and prospective treatment strategies aimed at lipid metabolism to re-establish bioenergetic equilibrium.
Alzheimer's disease (AD) is a progressive, irreversible, and multifaceted neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairment, posing a major global health challenge. Its multifactorial pathology includes cholinergic dysfunction, amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Among these, impairment of the cholinergic system, characterized by reduced acetylcholine levels, plays a crucial role in cognitive deficits. The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which hydrolyze acetylcholine, are closely involved in disease progression and serve as important therapeutic and diagnostic targets in AD. This book chapter provides a comprehensive overview of therapeutic and diagnostic agents targeting AChE and BChE in AD, and discusses small-molecule inhibitors, multifunctional ligands, and emerging strategies to modulate cholinesterase activity and restore cholinergic neurotransmission, alleviating disease symptoms. In addition, the chapter highlights advances in diagnostic approaches using fluorescent probes, particularly near-infrared (NIR) probes, for selective detection and imaging of AChE and BChE, including their molecular design, photophysical properties, enzyme selectivity, and mechanisms of action, all of which are critically examined. Targeting AChE and BChE offers a dual advantage in AD by enabling both symptomatic treatment and early-stage diagnosis. This chapter aims to present a clear and comprehensive overview of recent advances in therapeutic and diagnostic approaches, offering meaningful insights for researchers in developing effective strategies for the treatment and monitoring of AD.
Metabolic dysregulation has emerged as a crucial pathogenic factor that contributes in progression of Alzheimer's disease (AD), and is often found to precede classical AD's pathologies, the amyloid-β accumulation and hyperphosphorylated tau proteinopathies. The key metabolic underpinnings associated with Alzheimer's disease (AD) includes cerebral glucose hypometabolism, insulin resistance, mitochondrial dysfunction, altered lipid metabolism, vascular and systemic metabolic impairments, disrupted amino acid and nitrogen metabolism driving secondary metabolic disturbances. The chapter outlines the current evidences on dysregulated metabolic processes, and highlights emerging metabolic biomarkers that are identified through advanced neuroimaging modalities, plasma/cerebrospinal fluid (CSF) profiles, lipidomic signatures and markers of mitochondrial impairment, underscoring their diagnostic and prognostic potential. Furthermore, the chapter discusses about the therapeutic prospects targeting metabolic pathways, addressing current challenges in development of therapeutic strategies, reinforcing the need for integrative and precision-based interventions for early diagnosis and disease modifying therapeutic strategies in AD.
Alzheimer's disease (AD) has traditionally been characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Emerging evidence reveals that metabolic dysfunction represents a key pathological feature central to disease progression. Mitochondrial dysfunction in AD leads to impaired electron transport chain activity and reduced level of adenosine triphosphate (ATP) synthesis, preceding neurodegeneration and structural abnormalities in cognitive centres of the brain. Early glucose hypometabolism and lactate deprivation or interference with their utilization represent a primary bioenergetic failure driving mitochondrial dysfunction and neuroinflammation prior to the clinical manifestation of AD. While the brain relies on lactate as a prominent energy substrate, astrocytic metabolic defects lead to impaired neuronal energy homeostasis, thereby promoting neurodegeneration. In turn, this metabolic uncoupling could also be associated with defects in regenerative mechanisms by impairing adult neurogenesis in the hippocampus due to energy deprivation, accounting for memory deficits. This chapter discusses the evidence for the energetic crisis in AD, focusing on the disruption of the astrocyte-neuron lactate shuttle (ANLS), hypometabolism of glucose, and mitochondrial vulnerability, as interconnected pathogenic mechanisms. We emphasise cerebral bioenergetic metabolic failure as a central driver of cognitive decline, arising from irreversible reactive gliosis and neuroblastosis mechanisms and highlight various therapeutic options, including restoration of ANLS to mitigate the pathogenesis and memory loss in AD.
Alzheimer's disease (AD) is increasingly recognized as a disorder marked not only by amyloid-β and tau pathology, but also by profound disturbances in brain energy metabolism that arise early in disease progression. Accumulating evidence indicates that impairments in glucose utilization, insulin signaling, and mitochondrial function precede neurodegeneration and contribute directly to synaptic failure and cognitive decline. This chapter presents a comprehensive overview of Alzheimer's disease through the lens of metabolic dysfunction, highlighting disrupted neuronal bioenergetics as a central and unifying feature of pathogenesis. We examine key metabolic pathways implicated in AD, including cerebral glucose hypometabolism, brain insulin resistance, impaired glycolysis, mitochondrial oxidative phosphorylation deficits, oxidative stress, and altered mitochondrial dynamics. The chapter further discusses therapeutic strategies aimed at restoring metabolic homeostasis, such as insulin sensitization, enhancement of glucose transport, activation of mitochondrial biogenesis, modulation of the electron transport chain, and the use of mitochondria-targeted antioxidants. In parallel, alternative energy approaches-including ketone metabolism, fatty acid oxidation, and pentose phosphate pathway activation-are explored as promising avenues to bypass glucose-dependent energy deficits and reinforce neuronal resilience. Emerging directions in metabolic therapeutics are also highlighted, including combination treatment strategies, NAD+-sirtuin and AMPK signaling, and the expanding role of the gut microbiome-brain metabolism axis. By integrating insights from experimental models, neuroimaging studies, and clinical trials, this chapter underscores the potential of metabolic interventions to enable early, disease-modifying strategies for Alzheimer's disease.
Alzheimer's disease is a progressive neurodegenerative condition characterized by cognitive deterioration, memory loss, and persistent neuroinflammation. Notwithstanding considerable scientific advancements, current therapy strategies predominantly address symptoms and are ineffective in arresting illness progression. Recent studies have demonstrated the crucial role of epigenetic changes, especially histone modifications, in the pathophysiology of Alzheimer's disease. Removal of the acetyl group from histones and non-histone proteins by histone deacetylases (HDACs) plays a pivotal role in the regulation of gene expression, synaptic plasticity, and neuronal survival. Such changes lead to dysregulated HDAC activity, which is further associated with significant clinical characteristics of Alzheimer's disease, including amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. In Alzheimer's disease and other neurodegenerative diseases, the histone acetylation equilibrium is markedly disrupted, resulting in a shift towards hypoacetylation, which further inhibits the production of neuroprotective genes. Pharmacological inhibition of HDACs can reinstate hyperacetylation, therefore facilitating neuroprotective effects. This chapter explores the therapeutic potential of HDAC inhibitors in relation to Alzheimer's disease. This chapter also focuses on various HDAC isoforms associated with disease progression and explores the detailed mechanism by which HDAC inhibitors affect the epigenetic regulation and neuronal function. Preclinical investigations focusing on the role of HDAC inhibitors in mitigating neuroinflammation and Alzheimer's diseases, with a special focus on HDAC inhibitors in clinical trials, present intriguing opportunities for therapeutic advancement. The chapter further explores various challenges such as off-target effects, restricted isoform specificity, and inadequate blood-brain barrier permeability. To address these constraints, various strategies such as isoform-selective inhibitors, targeted delivery methods, and combination treatments are also explored. Thus, the chapter provides in-depth information on the role of HDAC inhibitors, which hold significant potential as disease-modifying agents in the treatment of Alzheimer's disease.
Alzheimer's disease and Parkinson's disease are increasingly recognized as disorders marked not only by protein aggregation but by a sustained failure of brain energy metabolism. Years before overt cognitive or motor symptoms emerge, neurons begin to experience impaired glucose utilization, mitochondrial dysfunction, and declining ATP production. Because the brain is highly energy-dependent, even subtle metabolic disturbances can disrupt synaptic function, impair neuronal signaling, and trigger oxidative stress. As mitochondrial efficiency declines, reactive oxygen species accumulate, inflammatory pathways become chronically activated, and damaged cellular components are insufficiently cleared, creating a vicious cycle that accelerates neurodegeneration. Conventional metabolic therapies, including antioxidants and mitochondrial cofactors, have produced limited clinical success, largely due to poor penetration across the blood-brain barrier and lack of specificity for vulnerable neuronal populations and intracellular targets such as mitochondria. Nanotechnology introduces a more precise therapeutic strategy by enabling targeted delivery of metabolic modulators directly to the brain. Engineered nanocarriers can be designed to cross biological barriers, enhance drug stability, and release therapeutic agents in a controlled or stimuli-responsive manner within diseased regions. Advanced systems including polymeric nanoparticles, lipid-based carriers, intranasal nano formulations, biomimetic vesicles, and catalytic nanozymes offer the ability to simultaneously modulate oxidative stress, restore mitochondrial function, and regulate neuroinflammation. By integrating delivery precision with metabolic intervention, neuro-nanomedicine shifts the therapeutic focus from symptomatic management toward addressing the underlying bioenergetic crisis. Although challenges remain in safety validation, scalability, and clinical translation, targeted nanotherapeutic strategies hold significant promise for transforming the treatment landscape of these debilitating neurodegenerative disorders.
Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease process resulting in progressive cognitive deterioration and synaptic dysfunction. The primary research approach in AD has traditionally focused on amyloid- pathology however an increasingly evidence suggests that tau protein is a key mediator of neuronal damage via a direct action on mitochondrial bioenergetics. In this chapter we look at the nature of the tau-mitochondrial interface, and propose a paradigm of tau-induced energy failure in AD. Physiologically tau provides stability to the microtubules and is involved in transport mechanisms within cells. In AD, tau is excessively post-translationally modified hyperphosphorylated and truncated tau species form toxic oligomers that incorrectly translocate to mitochondria, interacting pathologically with critical proteins such as voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocase (ANT), impeding the mitochondrial ATP/ADP exchange and reducing oxidative phosphorylation efficiency. Tau also further damages mitochondria by excessive fission, inhibition of axonal transport and Inhibition of mitophagy by interrupting PINK1-Parkin signaling. In turn, the build-up of dysfunctional mitochondria leads to ROS production, mtDNA damage and calcium imbalance creating a vicious cycle toward oxidative stress and tau pathology. At the cellular level they cause an energy depletion of the synapse and at the systems level cause glucose hypometabolism and activation of neuroinflammation. The chapter additionally discusses novel therapeutic approaches that target both tau and mitochondrial abnormalities, namely antisense oligonucleotides (ASO), mitochondria targeted compounds and mitophagy modifiers, stressing that it would be more effective to utilize a cocktail of these inhibitors. As a whole, in the context of decreased bioenergetics, the tau-mitochondria axis is an important factor to consider in the successful treatment of AD.
Schizophrenia is a neuropsychiatric illness characterized by progressive deterioration of thought processes and marked behavioral abnormalities arising from an unknown pathogenesis underlying the false perceptions, primarily hallucinations and delusions. The clinical symptoms of schizophrenia also include apathy, communication disorders and suicidal thoughts. Although the etiopathogenesis of schizophrenia remains not fully elucidated, the development of schizophrenia has been linked to adverse pregnancy, obstetric complications, neurodevelopmental disorders, neurotransmission imbalance and aberrant neurogenic events. Astrocytes are the most predominant glial cell type in the central nervous system (CNS), where they provide metabolic support, regulate neuroimmune mechanisms, facilitate neurotransmitter reuptake, and sustain synaptic homeostasis. Abnormal neural transmission is considered central to the pathogenesis of schizophrenia. Recent studies have highlighted that malformations in glial cells, particularly dysfunctional or reactive astrocytes, play a crucial role in the pathophysiology. Astrocytic dysregulation in schizophrenia is likely to result in synaptic dysfunction due to altered levels of key gliotransmitters such as glutamate, gamma-aminobutyric acid (GABA) and D-serine leading to altered neurobehavioral outcomes. Thus, insight into the scientific concepts that interrelate the pathophysiology of schizophrenia with astroglia dysregulation at the level of gliotransmitter imbalance could provide innovative hints for developing therapeutic strategies for the treatment of schizophrenia. This chapter describes the key roles of astrocytes and emphasizes imbalances in gliotransmitters as main contributors to the pathophysiology of schizophrenia.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, posing a significant public health risk. Although they are separate diseases, they have similar neuropsychological characteristics. Despite making up only a small portion of total body mass, the brain requires a disproportionately large amount of energy to maintain neuronal activity, synapse function, and cellular homeostasis. Disruption of energy metabolism is thus a major contributor to neurodegeneration. Energy metabolism has a wide-ranging impact on brain function, including cognitive and psychological processes, and gets increasingly compromised in neurodegenerative disorders. This chapter aims to offer a thorough overview of the link between altered brain energy metabolism and neuropsychological impairment in AD and PD.
Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.
