Describe the ageing changes in the central nervous system including the brain, and the degenerative diseases of the brain

Cellular changes. With age some neurons are lost and others shrink, and neurons attempt to compensate by dendritic proliferation. Support structures such as neuroglia increase. Unlike other systems, new neurons cannot grow to replace lost neurons, but the sheer number of CNS neurons means losses are not recognised until a threshold is crossed. Lipofuscin accumulates in nerve cells.

Structural and volume changes. Imaging shows selective, not generalised, atrophy. Global brain atrophy increases from 0.2% per year at ages 30–50 to 0.3–0.5% per year at ages 70–80. Grey matter loss is greater in frontal and parietal than in temporal and occipital cortices, while temporal lobe and hippocampal volumes decline continuously with accelerating loss after age 70.

Regional neuronal loss. There is relative preservation of cortical and hippocampal neuronal populations, but subcortical structures — the basal forebrain, locus ceruleus and substantia nigra — do show neuronal loss. Plasticity persists through dendritic sprouting, though this compensatory ability declines with age.

Mechanisms of brain ageing. Mitochondrial dysfunction with oxidative damage to mitochondrial DNA; oxidative damage from increased reactive oxygen species and reduced antioxidant defence; loss of proteostasis with impaired autophagic and proteasomal degradation; dysregulation of calcium homeostasis causing calcium-mediated excitotoxicity; impaired adaptive stress responses (reduced BDNF and NGF signalling); neuroinflammation from microglia and astrocytes; impaired DNA repair; impaired neurogenesis in the subventricular zone and hippocampal dentate gyrus; and dysregulated energy metabolism with neuronal insulin resistance.

Neurotransmitter and network changes. Impaired inhibitory GABA signalling causes excitatory imbalance, hyperexcitability and excitotoxicity, and dysregulation of acetylcholine, dopamine and serotonin is linked with neurodegeneration and impaired brain function. There is a progressive reduction of synaptic plasticity with ageing, similar to that seen in Alzheimer-like and Parkinson-like conditions, underlying cognitive and motor impairment.

Neuropathology of the normal ageing brain. Both neurofibrillary pathology (tangles and neuropil threads) and senile neuritic plaques — the hallmarks of the Alzheimer brain — are found in cognitively normal older individuals. Neurofibrillary pathology follows a stereotyped hierarchical pattern, appearing first in the transentorhinal cortex (Braak staging), and spread to hippocampal and association cortex parallels the appearance of cognitive decline. Senile plaques have a broader, more variable distribution, and a significant burden may coexist with normal cognition. Similarly, α-synuclein-immunopositive Lewy bodies and Lewy neurites are found in ageing but asymptomatic brains.

Vascular changes. Vascular change becomes more frequent in the ageing brain, manifested as leukoaraiosis — small-vessel ischaemic change in white matter — and silent infarcts, possibly related to elevated blood pressure and cholesterol in midlife. Age-related vascular changes also reduce cerebral perfusion and impair endothelial function.

Cognitive ageing. Typical cognitive ageing involves losses in processing speed, cognitive flexibility, and the efficiency of working memory and sustained attention, so it takes longer or more trials to learn new information. Vocabulary, access to remotely learned information including semantic networks, and retention of well-encoded new information are spared — therefore impairment in these latter domains is a sensitive indicator of pathology rather than physiology. Memory decline in healthy ageing is largely secondary to reduced processing speed.

Clinical signs of the ageing nervous system (Tables 6.2 and 44.1). Sensory — impaired distal vibration sense (about one-third of healthy people over 60), reduced pain perception and joint position sense. Reflexes — loss of ankle jerks in almost one-third of healthy people by age 80 while knee, biceps and triceps jerks are maintained, and emergence of primitive reflexes (palmomental, snout, sustained glabellar, grasp). Cranial nerves — diminished olfaction after 60, presbyopia, senile miosis, reduced upward conjugate gaze and convergence, increased saccadic latency, presbycusis. Motor — loss of muscle bulk and strength, mild increase in tone with paratonia (gegenhalten), mild parkinsonism, ageing-related tremor. Gait, posture and balance — reduced walking speed and stride length, reduced tandem ability, stooped posture, reduced ability to stand on one leg with increased postural sway.

Degenerative diseases of the brain (Essentials Table 6-7). Degenerative CNS diseases — Alzheimer's disease, dementia associated with Lewy bodies, Parkinson's disease, Pick disease (frontotemporal degeneration), Huntington's disease and progressive supranuclear palsy. Vascular dementias — multi-infarct dementia, Binswanger disease, arteritis, and anoxic damage. Traumatic — craniocerebral injury including dementia pugilistica. Infective — HIV-associated dementia, opportunistic infections, Creutzfeldt–Jakob disease, progressive multifocal leukoencephalopathy, post-encephalitic dementia. Alzheimer's disease affects 6–8% of those over 65 with prevalence doubling every five years, reaching nearly 30% over 85. The crucial clinical principle is that neurodegenerative conditions share pathophysiological processes, neuropathological modifications and phenotypic manifestations with the physiological ageing process, so the key skill is to juxtapose the signs of ageing against those of incipient neurological disease. Ageing versus disease — the discriminating features Domain Normal ageing Suggests disease Memory Slower learning; retrieval helped by cueing; Impaired recognition and loss of well-encoded preserved semantic and well-encoded memory information; no benefit from cueing Gait Reduced speed and stride length; stooped Freezing, festination, early falls, wide-based posture ataxia, step-wise decline Tone Mild increase; paratonia True lead-pipe rigidity with bradykinesia Reflexes Absent ankle jerks; primitive reflexes Loss of knee, biceps or triceps jerks; extensor plantars Eye movements Reduced upgaze and convergence Reduced downgaze — suggests progressive supranuclear palsy Function Instrumental and basic ADLs preserved Loss of independence in ADLs Latest Updates — 2 Points

Neurodegenerative disease is now defined biologically, not clinically. The 2024 revised Alzheimer's Association criteria (Jack et al., Alzheimer's & Dementia 2024) define Alzheimer's disease by core biomarkers of amyloid and tau — including blood-based p-tau217 — rather than by syndrome, and anti-amyloid monoclonal antibodies (lecanemab, donanemab) are now approved for early symptomatic disease. In parallel, the NSD-ISS and SynNeurGe frameworks (Lancet Neurology 2024) redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease using α-synuclein seed amplification assay. The practical consequence is that the boundary between "brain ageing" and "early degenerative disease" is increasingly drawn by biomarkers rather than symptoms.

Much of late-life cognitive decline is preventable. The 2024 Lancet Commission on dementia prevention, intervention and care identified 14 modifiable risk factors accounting for about 45% of dementia cases worldwide, adding untreated vision loss and high LDL cholesterol to the previous twelve (low education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity, diabetes, excess alcohol, traumatic brain injury, air pollution, social isolation). This reframes the ageing brain as a modifiable rather than purely degenerative target, and is highly relevant to India, where hypertension, diabetes, low education, hearing loss, cataract-related visual impairment and air pollution are all highly prevalent.