22 August 2012

Aging, neurodegeneration and Parkinson's disease

Article by John V. Hindle Aging, neurodegeneration and Parkinson's disease
published in the journal Age and Aging 2010; 39:156-161.
Translated by Evgenia Ryabtseva

ResumeOld age is the main risk factor for the development and progression of Parkinson's disease.

Aging affects many cellular processes, increasing the predisposition to neurodegeneration. The accumulation of age-associated somatic injuries, combined with a decrease in the effectiveness of compensatory mechanisms, may increase the likelihood of developing Parkinson's disease. The formation of Levi's bodies may indicate the launch of protective mechanisms that prevent age-related disorders of functioning and degeneration of the nervous system. Elderly people often have moderate manifestations of parkinsonism, the cause of which may be an age-related decrease in the activity of dopaminergic neurons, dementia with Lewy bodies, degenerative pathologies (early stages of Alzheimer's and Parkinson's diseases) or vascular disorders. Aging can affect the clinical picture of Parkinson's disease, changing the side effects of drugs and increasing the risk of developing dementia. The progression of Parkinson's disease, including the appearance of dementia and hallucinations, is more related to the actual age of the patient, rather than the age at which the symptoms of the disease appear. Parkinson's disease may be a reflection of the failure of compensatory cellular mechanisms in vulnerable regions of the brain, and the degree of their vulnerability increases with age. Parkinson's disease is one of the most obvious examples of an age-related disease.

IntroductionAll people age, and brain tissue inevitably ages, but neurodegenerative diseases, such as Parkinson's disease, do not develop at all.

Experts express different opinions about the causes of the development of this disease. Some believe that the pathological processes involved are the result of increased aging processes, which causes a general predisposition to this disease after reaching a certain age. Others are of the opinion that the aging process itself causes a predisposition to diseases such as Parkinson's disease. Still others believe that this pathology has nothing to do with aging at all. Apparently, the pathogenesis and clinical manifestations of Parkinson's disease are the result of complex interactions between aging processes and other predisposition factors, making this disease one of the most obvious examples of age-related pathology.

Epidemiology of Parkinson's diseaseThe probability of developing Parkinson's disease increases with age, and the incidence rate is generally comparable for all European countries.

Most likely, variations of this indicator on a global scale are a reflection of average life expectancy and the timeliness of detection. In the UK, the detection rate of primary Parkinson's disease (tremor paralysis) is 10.8 cases per 100,000 people per year, parkinsonism (the manifestation of the same symptoms caused by infectious, traumatic brain injury, infectious or drug effects, as well as vascular or tumor diseases) is 16.6 [1]. The results of most studies indicate that in most cases the symptoms of the disease appear after 70 years.

Aging and neurodegenerationAging is considered to be a stochastic process, the predicted and random effects of which lead to the accumulation of irreversible cellular damage, the weakening of cellular damage repair mechanisms and compensatory mechanisms [2].

Variations in the aging process are only 25% due to genes, whereas the main role belongs to lifestyle and environmental influences [2]. Despite the fact that brain cells are particularly susceptible to the accumulation of aging effects, their death is not programmed for a certain age. Damage at the cellular and molecular levels interacts with genes and environmental factors, which determines which cells age naturally and which undergo neurodegeneration. To date, it is unclear how such selective susceptibility is formed, which underlies the types of neurodegeneration that differ from each other in different diseases.

Aging is associated with mitochondrial dysfunction, increased production of free radicals and oxidative stress, which leads to genome instability and the occurrence of DNA mutations. The resulting shortening of telomeres in dividing cells correlates with low survival [3]. Aging is characterized by a decrease in the activity of proteasomes that ensure the degradation of damaged or ubiquitinated (marked for destruction) proteins, which leads to their abnormal deposition in brain tissue [4]. With age, the protein alpha-synuclein also accumulates in brain tissues. However, its aggregates are much larger in postmortem brain tissue samples of patients with Parkinson's disease than in tissue samples of people of the same age who did not have this disease. The revealed coexistence of pathological aggregates of beta-amyloid and alpha-synuclein indicates that the same mechanisms are involved in the pathogenesis of Alzheimer's and Parkinson's diseases [5]. Sirtuin proteins belong to the family of histone deacetylases involved in cell cycle management and cell survival. Inhibition of these proteins reduces the toxicity of alpha-synuclein in animal models, which indicates the existence of a relationship between aging and neurodegeneration [6]. Aging is associated with a decrease in the effectiveness of chaperone proteins, an imbalance of autophagic protein processing, changes in the course of inflammatory processes, complement activation, microglia functioning and impaired responses to neurotrophic factors, which impairs the ability of the brain to recover from damage [7]. As we age, progressive accumulation of iron occurs in brain tissue, including in the substantia nigra, which increases the susceptibility of cells to toxins [8]. Optimal functioning of the signaling mechanism mediated by insulin ensures longevity, and each tissue has its own critical level. Reduced activity disrupts metabolism and leads to the development of diabetes, while an increase in the level of insulin in the brain during aging is a factor predisposing to neurodegeneration [9].

Parkinson's disease is also characterized by the accumulation of deletions in the mitochondrial DNA of neurons of the substantia nigra, which leads to impaired functioning of these cells [10].

Other age-related changes include a decrease in the levels of tyrosine hydroxylase and dopamine in the striatum, a decrease in the number of pigmented neurons in the substantia nigra and the density of dopamine receptors. Despite the age-related death of pigmented neurons, there is evidence of compensatory hypertrophy of preserved cells [11]. All these age-related changes are related to the etiology and pathogenesis of Parkinson's disease.

Etiology of Parkinson's diseaseAging is the main independent risk factor for the development of Parkinson's disease.

External risk factors include exposure to pesticides, living in rural areas, the use of untreated water from natural sources, exposure to heavy metals and solvents, as well as welding and mining operations. Possible protective factors are tobacco smoking, caffeine consumption and the use of anti-inflammatory drugs [12]. 10-15% of patients with Parkinson's disease have a positive family history. At least 13 different groups of genes have been described, mainly associated with rare and early-onset forms of the disease, the clinical manifestations of which differ from the symptoms of sporadic cases [13].

Pathogenesis of Parkinson's diseaseThe pathogenesis of Parkinson's disease is a cascade of events leading to cell death (Fig. 1).

Fig.1. Etiology and pathogenesis of Parkinson's diseaseThis cascade includes oxidative stress, mitochondrial dysfunction, excitotoxicity (a pathological process leading to damage and death of nerve cells under the influence of glutamate and a number of other neurotransmitters), folding disorders (folding into a three-dimensional structure) of protein molecules and their aggregation due to dysfunction of the ubiquitin-proteasomal system, disorders of the lysosomal and mediated by chaperone proteins autophagy, as well as the formation of cytoplasmic inclusions – Levi's bodies, consisting of neurofilament proteins and ubiquitinated alpha-synuclein.

Inflammatory and humoral immune reactions contribute to the processes associated with cell death by apoptosis. Many of these mechanisms are similar to age-related changes. A variety of environmental agents can inhibit the functioning of proteasomes. In the rat model, this is enough to reproduce the key symptoms of Parkinson's disease [14]. The main parameters that should be considered when studying the relationship between aging and pathological processes characteristic of Parkinson's disease include the presence and distribution of Levi's bodies, specific profiles of cell death and protein accumulation.

Taurus LeviBraak divided the course of Parkinson's disease into stages depending on the pathological changes occurring in the ascending direction from the brain stem to the cortex, based on the presence of Levi's bodies [15].

At stage 1, according to this classification, changes are detected only in the dorsal motor nucleus and olfactory bulb, which is manifested by a dulling of the sense of smell – the main preclinical sign of Parkinson's disease, which can manifest several years before the onset of motor symptoms [16]. At the second stage, Levi's corpuscles are formed in the cells of the bridge and medulla oblongata, clinical motor symptoms appear at stages 3 and 4, and at stages 5 and 6 changes affect the neocortex, which leads to cognitive impairment and dementia. Early involvement of the brain stem in Parkinson's disease may correlate with the early appearance of autonomous symptoms, which is characteristic of older age and may outpace the appearance of motor manifestations [17].

The accumulation of alpha-synuclein in synapses leads to the loss of synaptic proteins and a decrease in the number of synaptic contacts [18]. The reverse transport of alpha-synuclein into the axon with the formation of a Levi's body can perform a protective function. Postmortem examination of brain tissue samples showed that diffuse Levi corpuscles in the cells of the cerebral cortex are found in 50% of people who have never suffered from dementia or Parkinson's disease during their lives. At the same time, the revealed profiles of the formation of Levi's bodies only partially confirmed the stage of the disease formulated by Braak [19]. Alpha-synucleopathy associated with the formation of Levi's bodies was detected in about 50% of brain tissue samples of patients with Alzheimer's disease and in 30% of samples of the control group, while in more than 10% of them significant Levi's body disease was not accompanied by symptoms of Parkinsonism [20]. Such a randomly detected disease of Levi's bodies is more typical for people of very advanced age and is associated with a decrease in the number of cells to a level that is intermediate between the indicators detected in Parkinson's disease and normal aging. It is quite possible that the appearance of Levi's bodies is a marker of the functioning of mechanisms that protect the nervous system from age-related disorders and degeneration.

Cell deathIn Parkinson's disease, not only dopaminergic cells of the substantia nigra die, but also cells of many other non-dopaminergic regions of the brain.

At the earliest stages of the disease, at which Levi's corpuscles appear only in the brain stem, death (up to 75%) of the cells of the substantia nigra already occurs, mainly in its ventral part [21]. With normal aging, it suffers mainly (in the ratio of 3:1) the dorsal part of the substantia nigra [11], while after 40 years, only 5% of cells die every next 10 years. The causes of selective cell death in Parkinson's disease are unclear; perhaps they lie in excitotoxicity and violation of calcium homeostasis in cells with altered levels of calcium-binding proteins [22].

Deposition of proteinsParkinson's disease is associated with abnormal deposition of proteins, especially alpha-synuclein, but the zones in which aggregates appear do not always correspond to the regions in which cell death is observed.

Alpha-synuclein toxicity may be associated with impaired storage and release of dopamine through a significant increase in apolipoprotein E levels and accumulation of insoluble amyloid [23]. The predisposition to cell death in Parkinson's disease may be correlated with an increase in pigment density and the formation of alpha-synuclein deposits under oxidative conditions, triggering a cascade that results in cell death. The accumulation of proteins, such as alpha-synuclein, leads to the formation of precursors of protein strands – protofibrils capable of stimulating cell death.

Clinical symptoms of Parkinson's disease and agingSigns of mild parkinsonism (muscle stiffness, bradykinesia, tremor, gait and balance disorders), characterized by relatively rare and mild manifestations, absence of tremor at rest, symmetry of manifestations and lack of response to dopaminergic therapy, are often detected when examining elderly people who do not suffer from neurological diseases, and are considered associated with aging [24].

Despite the existence of a relationship between impaired sense of smell and mild symptoms of Parkinsonism, indicating possible early involvement of the brain stem, the pathogenesis of these symptoms is unclear. Apparently, they have a multifactorial etiology, possibly including an age-related decrease in dopaminergic activity, Lewy body disease, degenerative pathologies (early stages of Parkinson's disease and Alzheimer's disease), or vascular pathology of the basal ganglia or deep layers of the white matter of the brain [24].

In Parkinson's disease, aging can lead to gait disorders and the ability to control body position as a result of the combined action of dopaminergic and dopaminergic mechanisms. Older patients with Parkinson's disease, due to the increasing acetylcholine deficiency as they age, are more prone to side effects of anti-cholenergic drugs, such as confusion and hallucinations. The severity of levodopa-induced dyskinesia may decrease with age, possibly due to the fact that relatively young patients are characterized by a higher rate of dopamine metabolism in relation to its production. One of the difficulties in studying the results of using a variety of drugs for the treatment of Parkinson's disease in people of particularly advanced age is the exclusion of the latter from clinical studies, which can lead to underestimation or overestimation of the effectiveness of therapy [26].

At the time of diagnosis of Parkinson's disease, patients may also have non-motor symptoms, the severity of which increases significantly with the progression of the disease, which leads to constipation, incontinence, falls, orthostatic hypotension, sweating disorders, dysphagia, salivation and mental disorders, including dementia and hallucinations. Long-term studies have shown that disability in Parkinson's disease is mostly due to the appearance of non-motor symptoms that do not respond to treatment with levodopa [27].

Factors indicating an increased risk of developing dementia are the onset of the disease at a late age, a long period of the presence of symptoms, the presence of a family history of Parkinson's disease, hallucinations and impaired memory or speech function. Pathologically, the cause of dementia may be the development of Alzheimer's disease and vascular pathology.

With age, the number of combined diseases increases in patients with Parkinson's disease, including other age-related pathologies such as neurodegenerative diseases, diseases of the cardiovascular and respiratory systems, diabetes, the consequences of frequent falls and incontinence, which increases mortality. The psychological effects of aging, including retirement, social isolation, poor living conditions, poor nutrition and poverty can also have an additional impact on the condition of patients with older Parkinson's disease.

Compensatory mechanisms and progressionCompensatory mechanisms ensure the maintenance of almost normal motor function for many years from the onset of the disease to the diagnosis.

These mechanisms include accelerated dopamine metabolism in the striatum and increased receptor sensitivity, increased levels of enkephalins in the striopallidar system and maintenance of activation of the motor cortex [29]. It is possible that the age-related loss of compensatory mechanisms demonstrated in primates, which ensure the efferent connection of the substantia nigra with the striatum, reduces the possibility of recovery of the body from damage accumulating with age.

As we age, as a result of exposure to polygenic factors and the accumulation of other damage, the probability of failure of these mechanisms increases, which leads to an acceleration of the progression of Parkinson's disease. A recent study of postmortem tissue samples of patients with Parkinson's disease who responded to levodopa therapy revealed three pathological models. The youngest group was characterized by the presence of Levi bodies corresponding to the Braak classification. The second group had early symptoms of severe dementia and pathology corresponding to dementia in Levi's taurus disease. In the representatives of the latter group, the disease was characterized by a later appearance of symptoms and a complex course with a shorter survival period against the background of more pronounced formation of Levi's corpuscles and other pathological manifestations, including plaques. This study does not confirm the existence of a single cause of all pathologies accompanied by the formation of Levi's bodies, but indicates the importance of more severe forms of the disease with a late onset [30].

Most experts describe the pattern of complications, such as dementia and hallucinations, as a linear progression from the age at which the first symptoms appeared. However, recent work has shown that the rate of accumulation of complications depends more on the actual age of the patient, while it increases significantly after 70 years [31]. However, recent work has shown that the rate of accumulation of complications depends more on the actual age of the patient, while it increases significantly after 70 years [31]. The development of Parkinson's disease in the initial stage may have a linear character, and with age it accelerates to a quadratic progression (Fig.2).

Fig. 2. A model of the relationship between aging and the progression of Parkinson's disease.The higher the rate of dopamine metabolism, the higher the probability of developing dyskinesia.

  1. Weakening of compensatory mechanisms.
  2. Aggravation of cell dysfunction and accumulation of other pathologies.
  3. Accumulation of complications (acceleration of progression).

ConclusionThe mechanisms of aging and neurodegeneration are very complex and interrelated.

Aging is the single most significant factor determining the clinical picture, course and progression of Parkinson's disease. Normal aging may be accompanied by mild symptoms of Parkinsonism, whereas Parkinson's disease has a characteristic clinical picture. Parkinson's disease reflects the failure of normal compensatory cellular mechanisms in vulnerable regions of the brain, the susceptibility of which is due to genetic factors, environmental influences and, most importantly, old age. The accumulation of age-related somatic injuries in combination with the insufficiency of compensatory mechanisms leads to the risk of developing and accelerating the progression of Parkinson's disease as we age.

The list of references to the article Aging, neurodegeneration and Parkinson's disease is given in a separate file.

The article printed herein has been translated from the original by Evgenia Riabtseva. S. Karger AG Basel cannot be held responsible for any errors or inaccuracies that may have occurred during translation.
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This article is a translation from the original made by Evgenia Ryabtseva. S. Karger AG Basel cannot be held responsible for any errors and inaccuracies that may have appeared as a result of the translation.
This article is protected by copyright law. Please note that reprinting and any further distribution of the translation is unacceptable without obtaining written consent from S. Karger, AG, Basel.

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