Parkinson’s disease involves widespread neurodegeneration that extends far beyond the basal ganglia, giving rise to a diverse range of non-motor symptoms that frequently emerge before motor onset. These include autonomic dysfunction, cognitive decline, neuropsychiatric disturbances, sleep-related disorders, and sensory deficits. Here, we synthesize current evidence on the anatomical, neurochemical, and network-level mechanisms that drive these symptoms, and we examine how they shape disease progression and clinical heterogeneity. We highlight the limitations of dopamine-centric models and advocate for a framework that treats non-motor symptoms as the disorder’s primary, mechanistically distinct features. We also discuss how emerging technologies—such as multi-omic profiling, artificial intelligence, and network neuroscience—enable earlier identification, stratification of non-motor phenotypes, and the development of precision-based therapeutic strategies. Recognizing non-motor symptoms as central to Parkinson’s disease redefines how the disorder should be diagnosed, studied, and treated.

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, profoundly impacts health and quality of life. While cognitive impairments—such as memory loss, attention deficits, and disorientation—predominate in AD, motor symptoms, though common, remain underexplored. These motor symptoms, including gait disturbances, reduced cardiorespiratory fitness, muscle weakness, sarcopenia, and impaired balance, are often associated with advanced stages of AD and contribute to increased mortality. Emerging evidence, however, suggests that motor symptoms may be present in earlier stages and can serve as predictive markers for AD in older adults. Despite a limited understanding of the underlying mechanisms driving these motor symptoms, several key pathways have been identified, offering avenues for further investigation. This review provides an in-depth analysis of motor symptoms in AD, discussing its progression, potential mechanisms, and therapeutic strategies. Addressing motor symptoms alongside cognitive decline may enhance patient functionality, improve quality of life, and support more comprehensive disease management strategies.

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also modulate neuronal excitability and contribute to CNS homeostasis, promoting neuronal survival by clearance of neurotransmitters, transporting metabolites, and secreting trophic factors. Astrocytes are highly heterogeneous and respond to CNS injuries and diseases through a process known as reactive astrogliosis, which can contribute to both inflammation and its resolution. Recent evidence has revealed remarkable alterations in astrocyte transcriptomes in response to several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic and A2 or neuroprotective astrocytes. However, due to the vast heterogeneity of these cells, it is limited to classify them into only two phenotypes. This review explores the various physiological and pathophysiological roles, potential markers, and pathways that might be activated in different astrocytic phenotypes. Furthermore, we discuss the astrocyte heterogeneity in the main neurodegenerative diseases and identify potential therapeutic strategies. Understanding the underlying mechanisms in the differentiation and imbalance of the astrocytic population will allow the identification of specific biomarkers and timely therapeutic approaches in various neurodegenerative diseases.

Parkinson’s disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD.

Parkinson’s disease encompasses a spectrum of motor and non-motor manifestations, with the latter often preceding motor symptoms and influencing disease trajectory. Sensory dysfunction, sleep-related disorders, autonomic impairment, neuropsychiatric symptoms, and cognitive decline reflect widespread neurodegeneration involving the brainstem, limbic system, and peripheral nervous system. Hyposmia and visual dysfunction are emerging as early biomarkers, while chronic pain and paraesthesias indicate central and peripheral nociceptive dysregulation. Sleep-related disorders, particularly REM sleep behaviour disorder and insomnia, frequently arise in the prodromal phase, highlighting disruptions in circadian regulation and neuroanatomical integrity. Neuropsychiatric symptoms—including depression, anxiety, apathy, and hallucinations—result from complex dysregulation of dopaminergic, serotonergic, and noradrenergic pathways, compounding disease burden and impairing quality of life. Autonomic dysfunction, affecting cardiovascular, gastrointestinal, thermoregulatory, and genitourinary systems, underscores the systemic nature of the disease. Despite growing recognition of these non-motor features, treatment strategies remain limited, constrained by a dopamine-centric therapeutic framework that does not fully address broader neurobiological dysfunction. The lack of reliable biomarkers hampers early diagnosis and precision medicine approaches, while the conventional dichotomy between motor and non-motor symptoms has hindered the development of integrative treatment paradigms. While previous reviews have examined individual non-motor manifestations in detail, this article provides a comprehensive synthesis, offering a clinically relevant perspective for medical students, primary care physicians, and non-specialists. Recognizing non-motor symptoms as core disease manifestations rather than secondary sequelae is essential to refine diagnostic criteria and develop targeted therapies. Parkinson’s disease is a complex, multisystem neurodegenerative disorder that necessitates a paradigm shift in research priorities and clinical management. A broader, integrative perspective is required to redefine how the disease is understood, taught, and treated, ensuring that motor and non-motor symptoms are addressed to improve patient outcomes.

This systematic review investigates the timeline of Alzheimer's disease (AD)-like changes in the intracerebroventricular streptozotocin (ICV-STZ) rat model, a key tool for studying sporadic, non-genetic forms of AD. Following PRISMA guidelines, we analyzed 402 studies to characterize the progression of key pathological features, including cognitive deficits, insulin resistance, neurodegeneration, neuroinflammation, oxidative stress, tau pathology, amyloid aggregation, blood-brain barrier (BBB) dysfunction, and alterations in the gut-brain axis. Most studies used young male Wistar rats, revealing a sex and age bias. Results show cognitive impairment beginning within the first 24 h after ICV-STZ administration and persisting beyond 121 days, accompanied by early molecular changes, including disrupted insulin signaling, apoptosis (on day 1), and oxidative stress (on day 7). These events triggered a cascade of neuroinflammation, synaptic loss, tau hyperphosphorylation, amyloid plaque formation/accumulation, and neuronal death that closely resemble human AD. This work provides the first unified time-course of these alterations, confirming the model's ability to mimic the complexity of AD, while also identifying important gaps, such as its limited use of female and aged rats, underexplored areas like the BBB and gut-brain axis, and specific brain regions that require further investigation. The sporadic AD rat model induced by ICV-STZ serves as a powerful and versatile platform for dissecting the multifactorial nature of AD, identifying early biomarkers, and accelerating the development of targeted and disease-modifying therapies.