Pathy's Principles and Practice of Geriatric Medicine. Группа авторов
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Impaired adaptive cellular stress responses
The main neuronal signalling pathways responding to and mitigating cellular (e.g. metabolic, ionic, oxidative) stresses may become impaired with ageing.23,28 For instance, the adaptive pathways mediated by neurotrophic factors (e.g. brain‐derived neurotrophic factor [BDNF], nerve growth factor [NGF]), calmodulin‐dependent transcriptions factors, and nitric oxide are perturbed or compromised, thus rendering neurons more vulnerable to damage and death.23
Inflammation
Inflammation is a common hallmark of brain ageing and diseases. Neuroinflammation is mediated by diverse cytokines, chemokines, reactive oxygen species, and secondary messengers produced by resident glial cells (i.e. microglia and astrocytes), endothelial cells, and peripheral immune cells. Despite exerting a potentially protective role, such inflammatory responses can have negative consequences such as oedema, tissue damage, and cell death.23,29
Aberrant neuronal network activity and altered synaptic plasticity
During ageing, communication and network activity within and between brain areas can be altered, with profound implications. For example, the excitatory imbalance resulting from impaired inhibitory signalling (e.g. GABA) can result in hyperexcitability and excitotoxicity. The dysregulation of other neurotransmitter systems (e.g. acetylcholine, dopamine, serotonin) has been linked with neurodegeneration and impaired brain function.23,30
As a consequence of impaired neuronal network activity, synaptic plasticity mechanisms are also affected during ageing. Synaptic plasticity refers to mechanisms responsible for activity‐dependent modification of the strength or efficacy of synaptic transmission at pre‐existing synapses,31 thus representing the neurobiological substrate of learning and memory,32 and can be experimentally explored in vivo by non‐invasive brain‐stimulation techniques.33 Advanced non‐invasive brain stimulation techniques have documented a progressive reduction of brain plasticity mechanisms with ageing34 – similar to that observed in AD‐like and PD‐like conditions – responsible for cognitive and motor impairment.35,36 Taken together, these observations contribute to the understanding of the clinical features observed during neurological examination of the elderly.
Impaired DNA repair
Several studies have documented that brain ageing is associated with an increase in the amount of damaged nuclear and mitochondrial DNA and a concomitant reduced expression and activity of some DNA repair proteins. In aged neurons, DNA is thereby more prone to accumulating oxidative damage with important implications in terms of gene expression, synaptic plasticity, and mitochondrial function.23,37
Impaired neurogenesis
Neurogenesis occurs throughout life in the ventricular‐subventricular zone of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus. During ageing, neural stem cells and their progenitors lose their proliferative potential and become quiescent. This is thought to contribute to age‐related cognitive impairment and reduced brain plasticity.23,38
Dysregulated energy metabolism
Like other organ systems, neurons may develop insulin resistance and decreased glucose transport. The consequent reduction in glucose utilization can be demonstrated by positron emission tomography imaging of radiolabelled glucose uptake and is more evident in the frontal, parietal, and temporal lobes.39 The brain metabolism of lipids can also be altered with ageing, as indicated by the accumulation of ceramides and lipid‐laden cells and declining levels of omega‐3 fatty acids.23
Changes in the neurological examination with ageing
Age‐related changes involving both the central and peripheral nervous system may result in clinical abnormalities that can be detected during a neurological examination (Table 6.2).40,41 Typically, such neurological signs and deficits do not occur in the context of overt diseases and can be considered normal manifestations of the ageing process.40 On one hand, they should not be overestimated, to avoid the risk of overdiagnosis and overmedicalization. On the other hand, these age‐related changes should not be overlooked, as they may contribute to functional loss and poor perceived well‐being. In this regard, even when a finding is considered within the normal limits for age, targeted interventions should be considered to optimize daily function (e.g. correction of vision and hearing loss). Moreover, it is noteworthy that some of these impairments may represent the phenotypic expressions of long prodromal phases preceding the onset of full‐blown pathological conditions. For example, olfactory dysfunction and constipation are regarded among the earliest nonmotor features of PD and can anticipate the onset of motor symptoms by years.42,43 Finally, it should be acknowledged that the detection of neurological abnormalities might be hampered by the concomitant decline of cognitive functioning, potentially limiting the clinical assessment’s reliability.
Table 6.2 Changes in the neurological examination with ageing.
Sources: Schott40; Seraji‐Bzorgzad, Paulson, and Heidebrink41.
Function | Most commonly observed changes |
---|---|
Sensation | Impaired vibration sense in distal lower extremities Reduced pain perception Reduced joint position sense |
Reflexes | Loss of ankle jerk reflexes Presence of ‘primitive’ reflexes (palmomental, snout, grasping, sustained glabellar) |
Vision | Decreased near vision (presbyopia) Reduced pupillary size and reactivity Increase of saccadic latency and decrease of saccade frequency, amplitude, and velocity Breakdown of smooth eye pursuit movements with saccadic intrusions Deceased upward gaze and convergence |
Hearing | Hearing loss (presbycusis), especially at higher frequencies |
Smell | Diminished smell sense |
Taste | Reduced taste |
Gait | Decline in walking speed Decreased stride length Reduced tandem ability |
Muscle | Mild increase in muscle tone Mild decrease in muscle bulk and strength |
Posture | Increasingly stooped posture |
Balance | Reduced ability to stand on one leg |
Vision