Ageing is a physiological process that affects living beings and manifests itself with modifications of the cell, tissue and organ functions and of behavioural responses. Ageing occurs by disorganising all the behaviours, facilitating the appearance of cognitive and emotional alterations and exacerbating already existing behavioural disorders. Although there are differences depending upon the species and the individual, it seems that alterations to the cell membranes, neuronal metabolism, receptors and neurotransmitter turnover underlie this disorganisation process. The central nervous system is in fact particularly sensitive to ageing as neurons struggle to regenerate and nerve cell deficiencies are rarely repaired.
In some species, senescence does not exist and, in those in which it is present and is a natural process, it may be a manmade creation due to the so-called environmental protection. A classic example is provided by the studies on mice, which, placed into optimal environmental conditions, live for two or more years while the majority of mice in the wild do not survive for longer than ten months. In these experiments, the “protected” mice spend the latter periods of life in a state of increasing “fragility”, which may be called senescence. In the dog and cat, environmental protection has reached extremely high levels, and it is therefore possible to hypothesise that in these species ageing is not a completely natural phenomenon.
It is worth noting that the passage from (“successful”) physiological ageing to (“unsuccessful”) pathological ageing is often slow and insidious: borderline areas exist which clinicians and researchers struggle to measure and define. There are three main dimensions that should be examined as part of cerebral senescence: the neurobiological, cognitive and behavioural dimensions.
CEREBRAL AGEING
The mechanisms underlying cerebral ageing are not yet well understood. For example, in human beings, cerebral blood flow is at greater levels around the first year of age while thereafter this parameter declines. Is it fair to say that ageing begins at this age? Certainly not, because cognitive performance, despite the decrease in cerebral blood flow, continues to evolve. In the elderly, in addition, there is a decrease in the volume and weight of the brain, accompanied by an increase in ventricular volume and in the spaces containing cerebrospinal fluid. In humans, the regions most affected by this phenomenon are the frontal lobes (14% of the volume of the cortex), the hippocampus (loss of approximately 35% of the volume) and the white matter (loss of approximately 26% of the volume). All these changes should be considered physiological and normal as they are commonly found in the majority of the population.
Studies conducted in human medicine regarding senile dementia and particularly Alzheimer’s disease have shown the presence of cortical atrophy associated with ventricular dilatation and neuronal loss in certain brain areas. Clusters of proteins are also present in higher amounts in the brain of “healthy” individuals with advancing age, as well as senile plaques (deposits of), neurofibrillary tangles(abnormal filaments of tau protein), granulovacuolar degeneration (seemingly empty vacuoles) and Hirano bodies (eosinophilic structures). The deposition of amyloid plaques, formed by the accumulation of amyloid substance outside the neurons, and neurofibrillary degeneration, due to the collection of fibrillar material inside the nerve cells, cause neuronal death which leads to cognitive function deficits.Some authors have detected the presence of these alterations even in healthy individuals and, thus, the presence of amyloid plaques and neurofibrillary degeneration is not sufficient to explain the aetiology of the disease. In the dog, M.A. Colle has identified the presence of cortical atrophy and plaques, constituted by a substance similar to amyloid, while no neurofibrillary degeneration has been found.
The central nervous system is particularly sensitive to ageing, since neurons have a reduced regeneration capacity and deficiencies in the nerve cells are rarely repaired. The cell membrane of neurons normally shows more rigid and more fluid areas which correspond to areas, known as microdomains, of different receptor mobility. Ageing is accompanied by the decrease in fluidity of the whole membrane due to the increase of cholesterol in phospholipids, the modification of the relationship between sphingomyelin and phosphatidylcholine and the presence of free radicals that originate as a result of neuronal death. This involves the alteration of the mobility of the membrane receptors and the appearance of hyper- or hyposensitivity in some microdomains that may be responsible for the implementation of inappropriate emotional responses resulting from the inability of the body to adapt to environmental changes.One type of cellular modification described in association with age is the pigmentosum type: lipofuscin and neuromelanin neuronal accumulations, pigments containing peroxidized proteins, enzymes and lipids. These may be the consequence of reduced elimination of substances resulting from cell damage. Alterations of glial cells, particularly of astrocytes, have been also documented.
The neurotransmission systems also undergo a process of disorganisation due both to the decreased synthesis of the neurotransmitter and to the numerical variation of the receptors.Inelderly animals, according to P. Pageat, the cholinergic system plays a key role in the mnemonic deficit since the number of muscarinic cholinergic receptors decreases, particularly in the cortex, and the synthesis and release of acetylcholine are reduced. Two types of cholinergic receptors are present: muscarinic and nicotinic receptors. Muscarinic receptorshavethe function of opening or closing the channelsfor potassium, calcium or chlorinewith the resultantdepolarisationorhyperpolarisationof the membrane.In the brain,nicotinicreceptorshavea lowerdensity thanmuscarinic receptors. Thecentralcholinergic systemplays an important roleinage-relatedcognitive changes. Studies performed withPEThave shown nocorrelation betweencholinergicsystem deficit and age. There may be ageneral reduction incerebral muscarinicand nicotinicreceptorsassociated with age,but the issueis still controversial.In humans, the alteration of mnemonic processes plays a key role in Alzheimer's disease and Alzheimer-type senile dementia in which progressive changes in memory appear, which initially only affect recently occurringepisodes while, later on, they go as far as causing temporal disorientation with change of language, repetition of movements for no apparent reason and inability to recognise people and objects.
Some studies, performed on living animals using Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) have shown that the serotonergic postsynaptic serotonergic function is reduced and that the 5- HT 1-a and 5-HT 2-a receptors tend to decrease in number and sensitivity with age. The most marked reduction in density of the two receptors has been identified, in healthy animals, in the frontal cortex. That system is, among other things, strongly involved in the processes of memory and learning. A deeper understanding of some mechanisms that link the function of these receptors to cognitive performance could improve the understanding of the relationship between age, memory and learning. The availability of dopaminergic tracers has allowed to study in vivo, using PET and SPECT, the activity and function of dopaminergic systems and their age-related degenerative changes in animals:there is a decline in levels of brain dopamine levels associated with age. Dopamine can easily undergo oxidation by producing cytotoxic residues. As this phenomenon increases with age, in older animals it could have a role in the degeneration of the dopaminergic neurons. The enzymatic activity of MAO-Bs seems to increase with age, contributing to the reduction in dopaminergic transmission. MAO-A activity does not seem to change with age. According to some authors, there is a gradual reduction in receptors almost linearly correlated to advancing age. In humans, the alteration of dopamine has been implicated in many behaviours, such as those of motivation, the reward phenomena, cognitive and language functions, working memory, Parkinson’s disease and schizophrenia, autism and attention deficit with hyperactivity disorder. Studies carried out on humans show an alteration in the D1 and D2 receptors which involves the presence of akinesia, muscle stiffening and tremors of the extremities and the head which characterise Parkinson’s disease. In older dogs, the number of dopaminergic and serotonergic receptors, especially 5HT1 and 5HT2, decreases and studies performed by P. Pageat have shown that these alterations are at the basis of cognitive, motor and mood changes. The production of catecholamines, particularly dopamine and serotonin, changes especially in the cortex, in the substantianigra, in the basal ganglia and in the limbic system.
Ageing is accompanied by the qualitative and quantitative reduction of alpha and beta adrenergic receptors especially in the cortex and hippocampus which involves an alteration to the mnemonic processes. In humans, a modest physiological reduction in the number of noradrenergic neurons has been documented in the locus coeruleus in old age. The concentration of noradrenalin in the cerebrospinal fluid is increased both in normal older individuals and in individuals with pathological cerebral ageing. Studies carried out on animals have shown the existence of partial damage to the noradrenergic neurons of the locus associated with increased activity of the same. This hyperactivity should be interpreted as compensatory, since neuronal loss is associated with an increase intyrosinehydroxylase, which leads to increased synthesis of noradrenalin in the remaining neurons unaffected by age-related degeneration. Some Authors, following experiments conducted on rats and dogs, have highlighted the selective survival of alpha 2 receptors.
GABA is an inhibitory neurotransmitter, which acts on three GABAergic receptor subtypes. Their activation increases the input of chlorine or calcium into the transmembrane channel and this event causes hyperpolarisation of the membrane itself with consequent neuronal inhibition. A high level of GABA in older animals, acting on presynaptic GABA A receptors, can cause chronic depolarisation and subsequent reduction in the neurotransmitter release with consequent dystrophy of the neuronal system. This theory is supported by the fact that, in human medicine, some drugs able to mitigate this phenomenon can delay ageing. The process of increased GABA synthesis in older patients, with the consequent impairment of specialised neuronal phenotypes differentiation, could be caused by the age-related reduction in mitochondrial production of ATP. This phenomenon, in turn, would cause the disinhibition of the enzyme activity of glutamic acid decarboxylase with a consequent increase in GABA synthesis. The more active this phenomenon, the more cerebral ageing is accelerated.
The use of glucose, as regards cellular metabolism, is reduced especially in the sensorial organs, in the limbic system and in the extrapyramidal system as the enzymes involved in glucidic metabolism change.
In older animals, endocrine changes may occur, particularly affecting thyroid hormone metabolism. The circulating rate of thyroxine (T4) and triiodothyronine (T3) is similar to that found in young animals but the biosynthesis and turnover of thyroxine are decreased. According to P. Pageat this reduction can vary from 25 to 50% and the secretion of the thyroid stimulating hormone (TSH) as a response to the stimulating factor secreted by the hypothalamus (TRH) is reduced. In this regard, P. Pageat conducted an experiment on a small number of dogs affected by Involutional Depression and being treated with clomipramine, by administering to them a triple or quadruple dose of thyroid hormone. He noted that the time taken to achieve sleep stabilisation was shorter. During ageing, due to an increased activity of monoamine - oxidase B, the negative feedback implemented by dopamine on the production of cholesterol in the hypothalamus-pituitary axis ceases, and in older animals there is the frequent occurrence of a spontaneous Cushing’s syndrome.
In recent decades, the average life expectancy of pets has increased with an increase of up to 25% in the dog and cat. A statistical survey conducted in North America showed that 11% of registered cats were over nine years old (Fig. 1). Behavioural diseases linked to ageing represent an increasingly significant percentage within specialist consultations.
BEHAVIOURAL DISEASES IN OLDER DOGS AND CATS
The data currently in our possession, as regards dogs and cats, does not allow us to establish a direct causal link between ageing and the appearance of behavioural diseases. It is possible, in fact, to identify “successful” ageing and “unsuccessful” ageing. In the former case, only the cognitive functions of the dog change; this results in a correct behavioural response which is however achieved more slowly with regard to environmental changes (involvement of the Basal Ganglia). In the latter case, severe emotional, cognitive and mood changes appear which signal the presence of a behavioural disorder. When the emotional responses can no longer be controlled by the animal and the cognitive processes are disorganised, a pathological process defined as involution appears.
In response to any stimulation of strong intensity (for example a loud noise), the dog and cat have an “inappropriate” behaviour characterised by agitation followed by a reduction of both exploratory behaviour and all activities of the animal. From the cognitive perspective, a regression occurs which involves the reappearance of infantile behaviours such as oral exploration and inappropriate elimination (Confusional Syndrome). When this primary pathological process is combined with a dysfunction of the inhibitory mechanisms (pathological inhibition), which involves the alteration of the sensory homeostasis and loss of self-control, the clinical picture of involutional depression appears in the dog.
The onset of the involution process is encouraged by the presence of exogenous and endogenous factors:
Exogenous Factors
Untreated states of anxiety (intermittent or permanent anxiety): among the most frequent pathologies it is possible to include a stage 2 sensory deprivation syndrome, separation anxiety, hypersensitivity-hyperactivity syndrome, communication disorders and sociopathies.
Interruption of physical activity: this is observed in working dogs (hunting dogs, search and rescue dogs and so on) when they cease their activity upon reaching old age. Symptoms may appear particularly when the activity ceases suddenly. In pet dogs, ceasing daily activities, such as accompanying their owners to the workplace due to painful arthrosis, may be an element that encourages the onset of the pathologies in question.
Change of emotional relationships: the change in the quality of the relationship between the owner and the older dog which, due to ageing, is less vivacious or emits bad odours due to the presence of organic diseases, may be an element that encourages the onset of the pathologies in question. A socio-emotional disturbance may also be an element that encourages the onset of these pathologies: the death of the owner or of a co-habiting animal, the birth of a child or the introduction of a puppy. Often the owner, to “rejuvenate” the old dog, brings in a puppy which quickly becomes the object of more attention by the family. The isolation of the old dog may lead to the manifestation of symptoms of “unsuccessful” ageing.
Treatments: some pharmacological treatments based, for example, upon corticosteroids, progestins, and anti-productive/sedative neuroleptics can encourage the onset of the pathologies in question.
Endogenous factors
- Cerebral ageing: cerebral ageing is the main endogenous factor underlying the pathologies in question.
- Tissue alterations:
- Thinning of the gyri and dilatation of the lateral ventricles;
- Neuronal loss;
- Deposit of amyloid-beta protein, amyloid plaques.
- Neurotransmitter changes: various neurotransmitters are affected in the pathologies in question:
- Dopaminergic system;
- Serotonergic system;
- Cholinergic system.
- Endocrine alterations: the depressive state in the older dog is also related to the alteration in thyroid hormone metabolism. In particular, there is an increase in the turnover of thyroxine (T4) and a reduction in its half-life, while the dosage of free T4 is unchanged. An alteration in the hypothalamus-pituitary axis is also observed.
- Cerebral neoplasms: the presence of cerebral neoplasms (of the cortex or diencephalon) may be responsible for the onset of involution symptoms. Behavioural symptoms usually appear before neurological symptoms.
- Inflammatory and infectious diseases: (hepatic and/or renal deficiency, chronic algogenic diseases, viral forms in cats).
Symptoms that characterise behavioural diseases in older dogs consist in cognitive changes, appetite and sleep disturbances. This trilogy is also present in neurological diseases (particularly related to tumours of the 1st or 2nd diencephalon), in endocrine diseases (such as, for example, hypothyroidism and Cushing’s Syndrome) and in diseases of infectious origin linked to the presence of viral forms. When there is an organic disease, behavioural symptoms appear suddenly (in the space of a few days) and the animal produces “incoherent and illogical” behavioural responses compared to the ethogram of the species. In addition, the medical history does not allow the identification of the evolution of the behavioural disorder and, following the behavioural examination, it is only possible to issue a functional diagnosis.
It should be noted that the endocrine system and central nervous system are profoundly linked at a functional level. The prolonged alteration of one inevitably leads to dysfunction of the other: for example, a state of anxiety of intermittent or permanent nature in place for many years and left untreated may lead to a change in thyroid function. Frequently, organic diseases, caused by the advanced age of dogs and cats, overlap with diseases linked to ageing, further complicating the symptomatology picture. In this case, it is necessary to perform a full haematological and thyroid or adrenal function examination before administering pharmacological treatment, as the psychotropic agent is able to alter hormonal secretions
According to Landsberg, the main symptoms exhibited by a cat affected by “unsuccessful” ageing are:
- Spatial disorganisation;
- Temporal disorganisation;
- Cognitive disorganisation;
- Altered social interaction.
Unlike the Anglo-Saxon approach, which groups all disorders of older dogs within the chapter of a Cognitive Dysfunction Syndrome, the model proposed by P. Pageat identifies a greater number of nosographic entities which differ from each other depending on the most affected component:
- Emotional disorders: involutional depression;
- Cognitive disorders: confusional syndrome in older dogs;
- Mood disorders: dysthymia of the elderly dog;
- Social conduct disorders: hyper-aggression in the elderly dog.
Suggested readings
- Arpaillange C. et Mège C., (2000), “Texte de conferences”, Scuola di Specializzazione in Patologia del Comportamento del cane e del gatto, Tolosa;
- Bourdin M., (2000), “Troubles comportementaux chez les carnivores âgés”, Scuola di Specializzazione in Patologia del Comportamento del cane e del gatto, Tolosa;
- Colangeli R., Giussani S., Medicina Comportamentale del cane e del gatto, Poletto editore, Gaggiano 2004;
- Colle M. A., (1998), “Troubles du comportement et dépôt de peptide A dans le cerveau du chien âgé: corrélations chimiopathologiques”, Thèse Doct. Méd. Vét.
- GECAF, (2001), Cours de base de GECAF ;
- Landsberg G., (2003), Invecchiamento cerebrale del cane e del gatto: disturbi cognitivi e comportamentali correlati. 46 ° Congresso Nazionale SCIVAC, Milano 8 – 11 maggio 2003 ;
- Pageat P., (1998), “ Pathologie du comportement du chien “, 2 éditions, Edition du Point Vétérinaire, Maison Alfort Cedex ;
- Pageat P., (2002), “Le patologie del comportamento del cane anziano”, 44° Congresso Nazionale SCIVAC, Milano maggio 2002;
- ZOOPSY, (2001), “ Le comportement du chien et du chat dans la pratique quotidienne “, Module prévention et éducation, Ecole Nationale Vétérinaire de Lyon ;
- ZOOPSY, (2001), “L’anxiété “, 3-5 octobre, Poitiers.