CSF: cerebrospinal fluid; FLAIR: fluid‐attenuated inversion recovery; GRE: gradient‐echo; T1W1: T1‐weighted imaging; T2WI: T2‐weighted imaging.
Declines in white matter volume are reported to start later and to exhibit a faster rate of progression compared to grey matter changes. The ‘last in, first out’ model may also apply to white matter modifications. In fact, in most fascicles, the rate of development and decline are mirror‐symmetric.10 The majority of available neuroimaging studies reveal that frontal lobes are the first to manifest modifications in white matter integrity, whereas occipital lobes are the last to show age‐related declines.11 Such an anterior‐to‐posterior gradient is evident in the corpus callosum, with greater changes involving the orbitofrontal callosum compared to the motor and occipital callosum.10 In addition to structural changes, decline in the function and integrity of white matter has been shown using diffusion tensor imaging.12
With regard to pathophysiology, brain atrophy likely results from a combination of different processes including neuronal loss, reduction of dendrites and synapses, and loss of myelinated fibres.13
Small‐vessel disease
The term small‐vessel disease encompasses a wide range of pathological processes that affect the brain’s small vessels (i.e. small arteries, arterioles, capillaries and small veins).14 Small‐vessel disease has assumed special relevance since it has been recognized as a major cause of cognitive decline and other functional losses and disabilities in the older person (e.g. mood disorders, gait disturbances, sphincteric problems).15 The most common forms of cerebral small vessel 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
