diseases are related to (i) arteriolosclerosis and (ii) amyloid angiopathy.
Arteriolosclerosis is characterized by the loss of smooth muscle cells from the tunica media and deposits of fibro‐hyaline material that result in the narrowing of the vessel lumen and thickening of the wall. It is strongly associated with systemic vascular risk factors such as hypertension and diabetes and, consequently, affects not only the brain but also other organs and tissues (e.g. kidneys and retinas).14 Amyloid angiopathy is characterized by the accumulation of amyloid protein in the wall of leptomeningeal and cortical small‐to‐medium‐sized arteries, arterioles, and, to a lesser extent, capillaries and veins. This condition is frequently documented in clinicopathological studies enrolling older participants16 and is considered among the neuropathological hallmarks of AD.17 It represents a major cause of cerebral lobar haemorrhages (frequently showing a recurrent course) and microbleeds but has also been associated with ischemic changes such as white matter lesions and microinfarcts.14,18
The effects of small‐vessel disease on the brain parenchyma are heterogeneous and include both ischemic and haemorrhagic manifestations. Accordingly, it is responsible for diverse MRI changes encompassing white matter lesions, lacunes, microinfarcts, and microbleeds13 (Table 6.1).
Altered proteins
The aggregation of misfolded proteins is a characteristic feature of neurodegenerative disorders (e.g. AD, PD, frontotemporal dementias, Lewy body dementia, amyotrophic lateral sclerosis) and the normal ageing process.19 Various clinicopathological studies have shown that altered proteins like hyperphosphorylated‐tau, amyloid‐β, α‐synuclein, and TDP‐43 can also be found in the brain of cognitively normal and relatively healthy older individuals.19–21 Interestingly, these protein alterations are rarely isolated and can result in a wide array (i.e. more than 230) of combined or mixed neuropathologies in subjects presenting or not presenting the phenotypic manifestations of underlying neurodegenerative processes.22 These observations highlight an important question: Would elderly individuals with AD‐related/PD‐related pathologies ever have developed dementia/PD later in their lives? Alternatively, might these individuals have lived well beyond a normal lifespan without neurologic symptoms because of, not despite, AD/PD pathology?19 In other words, could we consider protein accumulation not pathogenic per se, but rather a compensatory or even protective mechanism for the brain? The answer to this question will allow the development of targeted therapeutic strategies to slow or even stop neurodegenerative processes.
Neurobiological hallmarks of brain ageing
Like other organ systems, the brain exhibits diverse alterations at the cellular, molecular, and system levels during ageing. These deficits contribute to a progressive loss of physiological integrity, impaired function, and increased vulnerability to neurodegenerative diseases. According to a recent categorization, 10 candidate hallmarks of brain ageing can be identified23 (Figure 6.1). These modifications do not occur in isolation but act synergistically, involving highly interdependent and interactive signalling pathways.
Mitochondrial dysfunction
Most cell types in the brain likely experience the accumulation of mitochondrial dysfunctions during ageing, as repeatedly observed in animal models.23 These alterations include, among others, the enlargement and fragmentation of organelles, oxidative damage to mitochondrial DNA, dysfunction of the electron transport chain, and impaired calcium buffering and permeability transition, and can result in a decline in cellular energy metabolism.23,24
Figure 6.1 The hallmarks of brain ageing.
Source: Modified from Mattson and Arumugam23.
Oxidative damage
Progressive impairment of the oxidative balance, consisting of increased production of reactive oxygen species (e.g. superoxide anion radical, nitric oxide) and reduced antioxidant defences, can occur in neurons. In turn, this can promote and sustain the accumulation of dysfunctional and aggregated proteins and mitochondria. Moreover, it can lead to a dysfunction of proteasome and lysosome and, ultimately, to global cellular damage.23,25
Loss of proteostasis
The ability to remove damaged and dysfunctional molecules by proteasomes and lysosomes is crucial for neurons, given their post‐mitotic status. Nevertheless, the autophagic and proteasomal degradation processes are impaired during ageing. This can result in the intraneuronal accumulation of autophagosomes/autophagic vesicles with undegraded cargos, organelles, and polyubiquitinated proteins.23,26
Dysregulation of calcium homeostasis
The ability of neurons to control Ca2+ dynamics is compromised during ageing. Aberrant levels of cytoplasmatic calcium can produce a dysregulation of protein phosphorylation, gene expression, and cytoskeletal function. Moreover, the loss of calcium homeostasis can lead to the activation of proteases and promote caspase‐dependent apoptosis, resulting in neuronal death (calcium‐mediated excitotoxicity).23,27
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