National Institute of Health, Rome, Italy
3 Gardner Family Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA
Introduction
The ageing process is associated with structural and functional changes in the nervous system. Understanding the mechanisms and consequences of brain ageing has important implications for a number of reasons. First, the disorders of the ageing brain are one of the largest global healthcare issues. Age‐associated neurological diseases (e.g. stroke, Alzheimer’s disease [AD] and other dementias, Parkinson’s disease [PD]) represent a major cause of mortality and disability worldwide.1 Their public health impact will further increase in the future as a consequence of ongoing sociodemographic transitions. Moreover, most neurodegenerative conditions share some pathophysiological processes, neuropathological modifications, and phenotypic manifestations with the physiological ageing process.2 Therefore, understanding the neurobiological bases of brain ageing can drive fundamental advances in the development of effective therapies aimed at preventing or postponing neurodegenerative pathologies.3 Finally, brain functions and dysfunctions (even when they do not configure overt diseases) are crucial determinants for the main health‐related outcomes, such as mortality and functional dependence. They are also strongly associated with the frailty status of the individual: that is, with their risk of developing unfavourable health trajectories.4 Accordingly, identifying and promoting interventions and lifestyle modifications that might allow the maintenance or improvement of such competencies is essential for healthy ageing.
This chapter focuses on the main morphological changes and biological modifications occurring in the ageing brain. In addition, the central age‐related alterations at the neurological examination and in terms of cognitive functioning are addressed.
Structural age‐related brain changes
The human brain undergoes profound structural changes with ageing, characterized by marked variability in terms of (i) extension, (ii) trajectories, and (iii) impact on brain functions. The study of these modifications, previously based on neuropathological examinations, has greatly improved with the advent of modern neuroimaging techniques. The most common age‐related findings from brain magnetic resonance imaging (MRI) are summarized in Table 6.1.
Atrophy
The brain shrinks during normal ageing, with reductions in both grey and white matter.
A progressive decrease of grey matter volume is observed in older adults, with studies describing both linear effects across age and nonlinear trends.5 The cortical mantle becomes thinner, which is typically associated with the enlargement of ventricles and greater cerebrospinal fluid volumes. Some brain regions seem more susceptible to grey matter atrophy. Specifically, common patterns of atrophy involving the prefrontal cortex and, to a lesser extent, the medial temporal lobe and the parietal cortex have been described with ageing.5‐7 Conversely, the primary motor and sensory cortices are relatively spared and show less pronounced age effects.6,7 These modifications are consistent with a ‘last in, first out’ hypothesis of age‐related atrophy.8 That is, brain regions that are last to develop are the first to atrophy. This model has been supported by recent evidence that age‐related brain degeneration mirrors developmental maturation, with networks of higher‐order regions (i.e. lateral prefrontal cortex, frontal eye field, intraparietal sulcus, superior temporal sulcus, posterior cingulate cortex, and medial temporal lobe) that develop late during adolescence degenerating first in old age.9 Subcortical structures such as the cerebellum and caudate nucleus also show reduced volumes in older individuals5.
Table 6.1 Common structural age‐related changes detectable on anatomic brain MRI.
Source: Modified from Grajauskas et al.13
| MRI change | Description | Best MRI sequences to detect the change |
| Atrophy | Reduction of parenchymal tissue volume; enlargement of ventricles, sulci, and other CSF spaces. It can be diffuse to the entire brain or focally restricted to specific areas (e.g. frontal, medial temporal). | T1WI, T2WI, T2‐FLAIR (optimal) T2*GRE (possible) |
| Lacunes | Fluid‐filled cavities in subcortical areas, 3–15 mm in diameter. More prevalent in the basal ganglia, thalamus, pons, internal capsule, and cerebral white matter. | T2WI (optimal) T1WI, T2‐FLAIR (possible) |
| White matter lesions | Patches of abnormal signal intensity seen in the brain’s white matter. Referred to as hyperintensities due to their hypersignal in T2WI. They can consist of periventricular lesions, appearing as caps or patches surrounding ventricles, and/or deep white matter punctate or confluent lesions involving the white matter of cerebral lobes (mostly the frontal lobe). | T2‐FLAIR (optimal) T1WI, T2WI (possible) |
| Microinfarcts | Tiny areas of necrotic tissue. They are more likely to occur in watershed areas and the cerebral cortex. | T2‐FLAIR (optimal) T2WI (possible) |
| Microbleeds | Tiny areas of blood‐breakdown products within the brain, mostly involving the basal ganglia, thalamus, brainstem, cerebellum, and cerebral cortex. | T2*GRE (necessary) |
| Dilated perivascular spaces | Small (i.e. <3 mm) circular, oblong, or linear areas with a signal intensity similar to CSF. Typically symmetrically distributed. Common in the basal ganglia; also seen in the centrum semiovale along the path of penetrating pial arteries and in the midbrain. | T2WI (optimal) T1WI, T2‐FLAIR (possible) |
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