(1) Age-related changes in the central and peripheral nervous sys(CNS and PNS) are responsible for many of the physioloand behavioural changes commonly associated with advancing age and senility.
(2) Many of the age-related degenerative CNS changes reported to occur in humans are believed by veterinary neurologists to occur in dogs and cats but they have been poorly documented.
(3) In decision making about treatment and prognosis it is important to relate observed neurological changes to the site of the underlesion. For example, it is important to differentiate upper motor neuron deficits from lower motor neuron deficits in patients with locomotor disease.
(4) The onset of seizures in old animals should promote a search for extracranial causes (e.g. hepatic disease) and for structural lesions in the CNS (e.g. brain tumours).
(5) Old patients requiring anticonvulsant therapy for seizures should be screened for liver disease and should be monitored for early detection of hepatotoxicity.
(6) Neuroendocrine disorders are probably much more common in old animals than is currently recognised clinically.
(7) The process of ageing may be a manifestation of a failure to regulate neuroendocrine function or ageing may be dependent upon neuroendocrine regulation running in parallel with other temporal factors the so-called genetic ‘programming’, ‘clock’ or pacemaker’ theory.
(8) Regular exercise is an important stimulator of neuroendocrine function and should be maintained throughout old age.
Age-related changes in the CNS or PNS may result in decreased or increased activity of neural tissue with corresponding signs of altered neurological or neuroendocrine function. A skilled clinician can determine the site of the changes from the neurological signs exhibited by an animal.
Reduced protein synthesis within cells is one of the main causes of age-related declines in tissue function and some authors believe that modification of neuroendocrine function offers the best prospect for delaying and reversing ageing changes ().
Modification of neuroendocrine function is probably one of the mechanisms by which calorie-restricted diets slow down ageing changes in body tissues, inhibit the development of disease and neoplasia, and significantly prolong the lifespan of rats and mice. Calorie-restricted diets decrease hormone secretion (in particular growth hormone and insulin-like growth factor 1) and also alter hormone receptor sensitivity, reduce whole-body metabolism (though basal metabolic rate per unit lean body mass remains the same) and lower gene expression.
As further support of this hypothesis the administration of hormones thymic peptides and some drugs can improve declining immune function thus improving resistance to infections, neoplasia and autoimmune disorders
In old dogs the administration of clonidine (an α 2-adrenergic agonist) increases the pulsatile secretion of growth hormone returning it to a young dog type of pattern. Furthermore administration of clonidine with growth hormone releasing hormone for 10 days significanily increases both the peak concentration and total amount of growth hormone released. A rapid radio-immunoassay for growth hormone in the dog has been described ().
Maladaptive responses of the neuroendocrine system to stressful stimuli (particularly in the hypothalamic-pituitary-adrenocortical system) are thought to accelerate the ageing process and reduce longevity. One study in rats suggests that longevity is inversely related to hyperactivity to stress and that this is genotype dependent. Basal cortisol levels have been reported to be increased in dogs and to be related to cognitive dysfunction associated with ageing.
During ageing, humans, rats and dogs have been shown to have hypercortisolaemia and diffuse Alzheimer’s-like brain lesions (extracellular A4-amyloid deposits and intracellular fibrillar structures (TAU-protein) called neurofibrillary tangles) and neuronal decay have been reported to occur in dog brains (). Recently a direct correlation has been demonstrated between behaviour changes as determined by cognitive tests and the severity of these pathological changes in beagles and these workers have suggested that cushingoid dogs might be a useful model for the study of Alzheimer’s disease in humans ().
Free radical damage may play a part in the age-related changes in catecholamine neurones in the hypothalamus and in the neurotransmission of catecholamines, acetylcholine and peptide co-transmitters. Changes in receptor-site numbers or sensitivity may decrease secretion from cells which are otherwise still capable of manufacturing hormones.
Age-related tissue changes
Central nervous system
In most organs ageing results in reduced cell division and replacement of active cells with connective tissue, however in the brain there is little connective tissue and postmitotic neuronal death results in a proliferation of active glial elements.
With advancing age the CNS may undergo morphological and chemical changes (see Table Morphological changes that may been seen in the CNS with advancing age and Table Chemical changes that may occur in the CNS with advancing age).
Table Morphological changes that may been seen in the CNS with advancing age.
- Reduced brain mass
- Reduced number of neurones
- Enlargement of the ventricles
- Increased lipofuscin deposition in neurones
- Leptomeningeal thickening
- Reduced number (denudation) of dendritic spines
- Astrocyte hypertrophy (gliosis)
- Argyrophilic (senile) plaque formation
- Corpora amylacea formation
- Perivascular haemorrhage is reported to be common in very old dogs
Table Chemical changes that may occur in the CNS with advancing age.
- Increased water content in the brain.
- Neurotransmitter enzyme concentrations may change with age.
- In the monoaminergic system there are increased levels of monoamine oxidase and decreased levels of noradrenaline, dopamine and serotonin (5-HT).
- Neurotransmitter receptors may change in number with age, for example D2 dopamine receptors reduce in number in rodents and humans, whereas the Dl dopamine receptors increase in number. Serotonin receptors S1 and S2 both decrease in numbers with age.
- In the cholinergic system the presynaptic marker acetylcholinesterase is reported to increase in concentration with age whereas choline acetyltransferase decreases. There is a decrease in the number of muscarinic receptors. Neuropeptide neurotransmitters show variable age-related changes in concentrations in different regions of the brain.
- Vascular disease such as arteriocapillary fibrosis or endothelial proliferation may reduce blood flow to the brain and so reduce oxygen transport and nutrient supply to the nerve cells, resulting in hypoxia and accumulation of intracellular waste products leading to functional decline with or without neuronal loss.
Peripheral nervous system
Segmental demyelination and wallerian-type degeneration have been described to occur with advancing age in humans, but the changes are usually mild. Slowing of peripheral and central nerve conduction has also been demonstrated in elderly people.
Peripheral neuropathies may develop secondary to metabolic diseases such as diabetes mellitus. In the cat diabetic neuropathy is associated with distal axonal degeneration and affected animals show hind limb paresis with distal muscle atrophy and hyporeflexia.
There are many functional changes that can occur with advancing age:
Central nervous system
Impaired neurotransmission results from the decreased production of neurotransmitters and reduced breakdown of those that are produced.
Reduced serotonin levels increase sleeping time and may cause neudisorders and depression. Depletion of noradrenaline in the brain is also associated with depression.
Hypoxia leads to short-term memory loss, but not a loss of long-term memory. Oxygen supplementation can reverse this memory loss.
Signs of senility are frequently recognised in older animals and are probably associated with ageing changes in the nervous system but the precise cause-effect relationships have been poorly documented (see Table Signs of senility frequently recognised in old cats and dogs).
Table Signs of senility frequently recognised in old cats and dogs.
- Reduced mental alertness
- Short-term memory loss
- Reduced learning ability
- Poor concentration – reduced attention span
- Poor motor co-ordination
- Delayed response to stimuli with slowed or decreased reflex responses
- Loss of house training
- Failure to recognise familiar surroundings/companions
- Personality and other behavioural changes
- Increased sleeping time
Regular exercise improves many bodily functions probably through its effects on the neuroendocrine system by increasing the secretion of growth hormone and reducing the secretion of adrenocorticotrophic hormone (ACTH) and glucocorticoids.
Peripheral nervous system
With advancing age reduced function may occur in both the sympathetic and parasympathetic parts of the peripheral nervous system. Changes may be presynaptic, synaptic or postsynaptic resulting in impaired transmission of impulses to and from the CNS. This may produce abnormal neurological and neuromuscular function leading to sluggish reflexes, reduced pain response, impaired proprioception and difficulty with locomotion. The animal may be less able to respond to sudden stresses placed on it because of impaired ability to maintain homeostasis through neuroendocrine control mechanisms.
Inexperienced clinicians may find it difficult to differentiate between proprioceptive deficits and muscular weakness in older animals.
Recently two drugs – propentofylline (VMtonin, Hoechst) and nicergoline (Fitergol, Rhone Meneux) – have been granted veterinary product licences based upon their ability to improve the signs associated with ageing in dogs such as lethargy and dullness. They both have numerous pharmaactions on the body but their main mechanism of action is thought to be an increase in blood supply to the brain resulting in improved neufunctions.
Is indicated for the treatment of lethargy and dullness in old dogs.
12.5-100 mg b.i.d. depending upon body weight.
Is an adrenoreceptor antagonist and is indicated in the treatment of age-related lethargy and dullness in dogs.
0.25-0.5 mg/kg daily.
Selections from the book: Mike Davies “Canine and Feline Geriatrics”, 1996.