INTRODUCTION:

Neurodegenerative Diseases (NDDs) are characterized by progressive dysfunction of synapses, Neurons, glial cells and their networks. A crucial Component of NDDs is the deposition of physicochemically altered variants of physiological Proteins in the nervous system. Importantly, not Only neurons but glial cells also accumulate these Pathological proteins.¹

The term is made up of the prefix “neuro” which refers to neurons, and “degeneration,” Which indicates to the loss of structure or function of tissues or organs. As a result, Neurodegenerative refers to any disease that predominantly affects neurons.² neurodegenerative diseases refer to a group of illnesses caused by the gradual deterioration of neurons and nervous system connections that are necessary for movement, coordination, Strength, sensibility, and cognition. Lots of individuals throughout the world suffer from Neurodegenerative illnesses.³ Bio-markers are the gold standard for diagnosing illness.

This is a necessary component of the therapeutic and diagnostic criteria. In neurodegenerative illnesses, such quantitative and conveniently available methods are desperately needed⁴.

Sources of Neuroinflamation in Neurodegenerative disorders:

1. Vascular dementia and neuroinflammation:

The cellular and molecular mechanisms of neuroinflammation are likely the same in aging and metabolic diseases such as hypertension, diabetes, depression, dementia or after cerebral insult Such as strokes⁵, and are considered as silent contributors of neuroinflammation (Fig. 1). In the elderly, inflammatory Mechanisms have been associated with the pathogenesis of Dementia and functional impairment. Systemic and local CNS inflammation significantly contributes to cerebral small Vessel disease (SVD)-vascular dementia^6,7, hypothesized as microvascular changes that result in a state of chronic Hypoperfusion, leading to continuous oligodendrocyte death and the consecutive degeneration of myelinated fibers that Increase low‑grade inflammation amplification of the risk of stroke.⁸ Another major risk factor for stroke and CNS Tissue destruction is atherosclerosis, the disease of arteries that Is characterized by vascular inflammation occasioned by the Infiltration of monocytes into the injured vascular wall and an Increase of interleukin (IL)‑6 associated with future intracranial large artery stenosis progression after a stroke episode⁹. As strong predictors of subclinical and clinical atherosclerosis and progression of hemorrhagic stroke, were identified in SVD^10-13. Furthermore, adipose tissue dysfunction identified in obesity and hypertension, contributes to chronic and Low‑grade inflammation, predisposing to type 2 diabetes Mellitus (DM) and cardiovascular disease^14-16 and could Determine a worse outcome in stroke patients¹⁷. Mortality In DM is primarily attributed to micro- and macro-vascular Complication as well as sensory neuropathic complications, Exacerbating the consequences of vascular disease.¹⁸

2. Depression and neuroinflammation:

Normal aging is associated with an increase in the expression level of systemic inflammatory factors¹⁹ such as pro‑inflammatory ccytokines^20-22. In the brain, this age-associated inflammation manifests Initially as the chronic activation of perivascular and parenchymal macrophage/microglia expressing pro‑inflammatory Cytokines together with an increased number of astrocytes.²³ Accordingly, the chronic activation of pro‑inflammatory signals In aging may contribute to an increase in vulnerability to neuropsychiatric disorders²⁴. In obese women, the inflammation State was associated with a higher concentration of pro‑inflammatory markers including IL-6, CRP and adipokines.²⁵ These Pro‑inflammatory markers correlated positively with symptoms of depression and anxiety.²⁶ Anxiety was alleviated with The reduction of inflammation following the surgical removal of fat tissue.²⁷ In agreement with those findings, metabolic Diseases such as obesity, hypertension, and being elderly are Prevalent risk factors of depression, cognitive dysfunction and Dementia²⁸ and there is an increase onset risk of aging-related Diseases affecting the cardiovascular, cerebrovascular, neuroendocrine, metabolic, and immune systems in patients suffering Major depression.^29-30 Although biological mechanisms of depression are poorly Understood, conventional antidepressant treatments procuring Beneficial effects were unsuccessful on one‑third of depressed Patients due to the inflammation that contributed to treatment RResistance.³¹ The putative mechanism linking inflammation And depression involved oxidative stress, elevated pro‑inflammatory cytokines IL‑6 and IL‑8³², endothelial nitric oxide Synthase uncoupling and hyperglutamatergia. Accordingly, Indirect evidence of neurovascular dysfunction have been Found in major depressive disorder (MDD)^33-34, a severe Psychiatric illness that is associated with increased levels of Inflammatory markers in periphery, depression and mortality From suicide.³⁵ Therefore, inflammatory markers identified in Neurodegenerative diseases including MDD cover chemokines, Adhesion molecules, cytokines and acute phase proteins.³⁶

3. Infections and neuroinflammation:

Dynamic immune and Inflammatory responses result from several offences in the CNS, of which infection is one³⁷. A virus can enter The CNS through two distinct hypothetical mechanisms, Including hematogenous dissemination by which the virus Gains access to the brain by BBB³⁸, and neuronal retrograde Dissemination.³⁹ However, it has been suggested that a Virus can replicate in macrophage and CCR5+T cells inside Of the CNS in relation to the development and progression of Dementia , as is the case for HIV proteins gp120⁴⁰ and Tat⁴¹ which are respectively able to induce the apoptosis of Neurons through the enhancement of CXCR4-PKC, and to Cause neuronal dysfunction through the disruption of mRNA Expression . Most importantly, as in the case of HIV infection, other viral insults are associated with highly secreted Cytokines, cholesterol increase, elevations of lipopolysaccharide (LPS) concentration, insulin resistance, testosterone Deficiency and APOE4⁴²

Fig. 1: Sources of neuroinflammation. Aging, metabolic diseases and viral infections are sources of inflammation that can affect vessels and neurons, leading to Neurodegenerative. SVD, small vessel disease.

Alzheimer’s Disease:

Alzheimer’s disease is the main cause of dementia and is quickly becoming one of the Most expensive, lethal, and burdening diseases of this century.⁴³ Since the Seminar published In 2016,⁴⁴ Important developments have taken place in the understanding of the underlying Pathology, the recognition of multiple causative and protective genes, the identification of New blood-based and imaging bio-markers, and the first cautious signals of positiveeffects of Disease-modifying treatments and lifestyle interventions.

Fig. 2: shows the different aspects of Alzheimer’s Disease

1. Clinical signs and symptoms:

Three cases, in panel illustrate the clinical spectrum of Alzheimer’s Disease. Case A highlights Alzheimer’s disease that is determined genetically, as per the Ongoing global initiatives of the Dominantly Inherited Alzheimer Network and Alzheimer Prevention Initiative and their associated clinical trials. Case B represents a language variant Of Alzheimer’s disease, usually occurring at a younger age (under 70 years), illustrating The difficulty in recognising Alzheimer’s disease in those for whom memory problems.

2. Methodological Consideration:

This review is limited to drugs approved by the Food and Drug Administration (FDA) specifically for Alzheimer’s disease, drugs approved for other conditions but used in patients with Alzheimer’s disease, and drugs under consideration for approval.^45-47 This sub scale is an 11-item assessment of memory, Orientation, attention, reasoning, language, and motor performance.⁴⁷ scores on this sub scale range from 0 (indicating no impairment) to 70 (severe impairment) (Table 1). Scores may decrease (i.e., improve) Over time in healthy elderly subjects as a result of a Learning effect. The average score on the cognitive sub scale of the Alzheimer’s Disease Assessment Scale Increases (i.e., worsens) by 4 to 5 percent in a six-month period (8 to 10 percent annually) in untreated patients with Alzheimer’s disease.⁴⁸ For a drug to Be considered effective, the scores of the persons receiving the drug should decrease significantly more Than the scores for persons receiving placebo. Differences in the score on the cognitive sub scale Of the Alzheimer’s Disease Assessment Scale may not Always be clinically obvious. Rating scales based on The clinician’s assessment, such as the Clinician Interview-Based Impression of Change scale13 and the Clinical Global Impression of Change scale,⁴⁹ have Also been recommended. These seven-point ordinal Scales allow physicians to rate changes from 1 (marked Improvement) to 7 (marked worsening) (Table 2). Over a period of six months, the increase in the scores On these scales is less than 1 percent of the total Range of the scale for healthy elderly people^50-51 and From 2 to 11 percent for people with Alzheimer’sDisease. Although these clinician-based ratings correlate well with scores on the cognitive sub scale of the Alzheimer’s Disease Assessment Scale, they are considered “independent, multidimensional assessments of cognitive, behavioral and functional change.”⁵²

Table 1: Criteria for the diagnosis of Alzheimer’s disease:

S. No.	Diagnosis	Criteria
1.	Probable Alzheimer’s disease	All of the following must be present: 1. Dementia established by examination and documented by objective testing impairment in memory at least one another cognitive function (language and perception) 2. No disturbance in consciousness 3. Onset between 40 and 90 years of age 4. Loss of motor skill
2.	Possible Alzheimer’s disease	Fulfillment of the above criteria with variation in the onset of symptoms: or a single, but gradually progressive, congnitive impairment with out an identifiable cause another brain disorder that is sufficient to produce dementia.
3.	Definite Alzheimer’s disease	Fulfillment of the above clinical criteria and histological evidence of Alzheimer’s disease based on examination of brain tissue obtained at biopsy or autopsy.

*Criteria were adapted from McKhann et al.⁵³

Parkinson’s disease:

Parkinson’s disease (PD) was first described by Dr. James Parkinson in 1817 as a “shaking palsy.” It is a chronic, progressive neurodegenerative disease characterized by both motor and non-motor features. The disease has a significant clinical impact on patients, families, and caregivers through its progressive degenerative effects on mobility and muscle control. The motor symptoms of PD are attributed to the loss of atrial dopaminergic neurons, although the presence of non-motor symptoms supports neuronal loss in nondopaminergic areas as well..^68-70 Research suggests that the pathophysiological changes associated with PD may start before the onset of motor features and may include a number of nonmotor presentations, such as sleep disorders, depression, and cognitive changes. Evidence for this preclinical phase has driven the enthusiasm for research that focuses on protective or preventive therapies.⁷¹ PD is one of the most common neurodegenerative disorders. The Parkinson’s Disease Foundation reports that approximately 1 million Americans currently have the disease.⁷² The incidence of PD in the U.S. is approximate (60,000 per year), with the mean age of onset close to 60 years. The prevalence of PD is reported to be approximately 1% in people 60 years of age and older and increases to 1% to 3% in the 80-plus age group. However, an important caveat associated with these numbers is that they do not reflect undiagnosed cases.^73-74

1. Pathophysiology:

PD is a disorder of the extra-pyramidal system, which includes motor structures of the basal ganglia, and is characterized by the loss of dopaminergic function and consequent diminished motor function, leading to clinical features of the disease.^71,75 Research in the late 1950s identified atrial dopamine depletion as the major cause of the motor symptoms of PD, although the presence of nonmotor features supports the involvement of other neurotransmitters of the glutamatergic, cholinergic, serotonergic, and adrenergic systems, in addition to the neuromodulators adenosine and enkephalins.^76-81 Further evidence suggests that PD may originate in the dorsal motor nucleus of the vagal and glossopharyngeal nerves and in the anterior olfactory nucleus, suggesting a disease pattern that begins in the brain stem and ascends to higher cortical levels.45 The histopathological features of PD include the loss of pigmented dopaminergic neurons and the presence of Lewy bodies (LBs).^82,83 Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which project to the striatum (the nigrostriatal pathway), results in the loss of dopaminergic function in individuals with PD. Typically, patients experience the motor features of PD only after 50% to 80% of dopaminergic neurons have been lost, suggesting the involvement of a compensatory mechanism in the early stages of the disease.⁸⁴ In addition, dopaminergic loss results not only in reduced activation of the thalamus but also in increased cholinergic activity due to the loss of dopamine’s normal inhibitory influence.^85-87 Research continues to support evidence that PD involves a diffuse global network dysfunction at multiple levels in the nervous system.⁸⁸

Fig. 3: shows the aspects and symptoms of the Parkinson’s disease.

2. Clinical syndrome:

The clinical criteria of the UK Parkinson’s Disease Society Brain Bank for probable PD require the presence of bradykinesia and one of the following features: rigidity, 4–6 Hz rest tremor, or postural instability; in addition, three supportive features Are⁸⁹ The International Parkinson’s and Movement Disorder Society(MDS) developed their own clinical diagnostic Criteria that include:

1. Presence of parkinsonism (bradykinesia Plus either rest tremor or rigidity)

2. Absence of absolute exclusionary criteria

3. Supportive criteria

4. No red flags.⁹⁰

In addition to a variety of clinical rating scales, particularly the Unified Parkinson’s Disease Rating Scale (UPDRS) used to assess Severity of the disease, reliable diagnostic, presymptomatic and Progression bio-markers are being developed to support the diagnosis and to track the course of the disease.^91,92 These areas in the brain stem have been proposed to degenerate Long before substantia nigra. Although this Braak hypothesis has Been challenged,⁹³ it is now well accepted that the involvement of non-dopaminergic pathways in the evolution of PD accounts For the increasingly recognised non-motor symptoms that Adversely impact the quality of life of patients with PD.^94-96 The Involvement of noradrenergic, glutamatergic, serotonergic and Adenosine pathways, among others, provides a biological basis For the various non-motor symptoms’ and suggests that modulation of these non-dopaminergic pathways can lead to alternative Therapeutic approaches.⁹⁷ The term ‘prodromal’ PD refers to a phase (up to 15–20 years Before onset of motor symptoms) during which clinical signs of Disease are not evident but underlying Neurodegenerative has Started and progressed⁹⁸ (figure 1). Clinical studies have shown That rapid eye movement sleep behaviour disorder (RBD), Depression, olfactory dysfunction, constipation and autonomic Dysfunction may be present during this period.^99,100,101.

Fig. 4: Course of PD from prodromal phase to clinical phase, including levodopa-related complications. PD, Parkinson’s disease; PIGD, posturalinstability-gaitdisorder RBD, rapid eye movement sleep behaviour disorder.

3. Treatment:

The management of Parkinson’s disease can be Subdivided into three categories: protective or preventive treatment, symptomatic treatment, and restorative or regenerative treatment. Protective Therapy None of the currently available treatments have Been proved to slow the progression of Parkinson’s Disease.¹⁰³ and Selegiline did not delay the development of dyskinesias or fluctuations in response to levodopa.¹⁰⁴ High Doses of the antioxidant vitamin E were ineffective in slowing the progression of the disease. Further Studies continue to suggest that selegiline is neuroprotective,¹⁰⁵ and recent studies indicate that it can Block apoptosis through a transcriptional effect of its Desmethyl derivative that is unrelated to MAO-B inhibition.¹⁰⁶ However, a study in the United Kingdom Found significantly higher mortality among patients Treated with selegiline plus levodopa than among Those treated with levodopa alone.¹⁰⁷ This study raises questions about the use of selegiline in Parkinson’s disease; however, other experience, including Follow-up of the large cohort in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonismstudy, has not shown higher mortality among patients treated with selegiline.^108-110

Stem cell therapy for Parkinson’s disease is a treatment approach that involve using stem cell, which are undifferentiated cell that can develop into various type of specialized cell, to replace damaged or lost cell in the brain associated the Parkinson’s disease.

SUMMARY AND CONCLUSION:

Degenerative nerve diseases affect many of your body’s activities, such as balance, movement, talking, breathing, and heart function. Many of these diseases are genetic. Sometimes the cause is a medical condition such as alcoholism, a tumor, or a stroke. Other causes may include toxins, chemicals, and viruses. Sometimes the cause is unknown.

Degenerative nerve diseases can be serious or life-threatening. It depends on the type. Most of them have no cure. Treatments may help improve symptoms, relieve pain, and increase mobility.

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Received on 10.06.2023 Modified on 07.02.2024

Asian J. Res. Pharm. Sci. 2024; 14(3):304-312.

DOI: 10.52711/2231-5659.2024.00049

S. No.	Tests	Range of source	Description	Purposes
1.	Alzheimer’s Disease Assessment Scale, Cognitive Subscale1⁵⁴	0 (no impairment) to 70 (severe impairment) Annual decline, 8–10% 6-mo decline, 4–5%	Standardizedassessment of cognitive domains: recall naming, language, orientation, construction, praxis, recognition	Used as a primary outcome measure to assesseffect on cognitive performance
2.	Clinical Global Impression of Change scale12⁵⁵	1(markedimprovement) to 7 (marked worsening) Annual decline, 19% 6-mo decline, 11%	Organizedbut unstructured method of cliniically assessing observable change by interview with patient, informants, and care givers	Used as a primary outcome measure to assessclinically relevant change
3.	Clinician Interview-Based Impression of Change Scale13⁵⁶	1 (marked improvement) to 7 (marked worsening) Annual decline, unavailable 6-mo decline, 1.4%†	Nonstructured scale for assessing clinical change. Clinician Interview-Based Impression of Change Plus includes information from informant and care giver	Used as a primary outcome measure to assess clinically relevant change
4.	Mini–Mental State Examination14⁵⁷	0 (severe impairment) to 30 (no impairment) Annual decline, 10% 6-mo decline, 5%	Standardized mental-status examination assessing orientation and briefly assessing memory and other cognitive skills	Used to identify a range of cognitive deficit for study enrollment and as a secondary outcome measure

Type of stem cell	Origin	Advantage	Disadvantage
Retinal progenitor cells	Derived from fetal or neonatal retinas, if isolated from the developing retina at a suitable stage, photoreceptor precursors may be obtained.	Can migrated into retinal norphological characteristics of various retinal cell types	Ethical and immune rejection issues.
Embryonic stem cells	Derived from inner cells mass of blastocyst stage embryos.	ESC can differentiate into photoreceptor progenitors, photoreceptors, or retinal pigments epithelium.	Ethical and immune rejection issues, associated with teratoma formation.
Induced pluripotent stem cells (IPS)	Pluripotent ESC-like cells reprogrammed in vitro from terminally differentiated somatic cells.	Use as disease model by integrating IPS derived from retinitis pigmentosa patient. IPS can differentiate into functional RPE and photoreceptor precursor cells.	It has the risk of viral integration and oncogene expression.