Summary

Aging is a process which operates at many levels of physiological, genetic and molecular or­ganization and leads inevitably to death [18]. Brain macroscopic changes by MRI investigation during aging were observed in humans and dogs but chimpanzees did not display significant changes. This suggestion led to the statement that brain aging is different in various species. Although human brain changes, e.g. ß-amyloid storage, neurofibrillary tangle formation, li­pofuscin, are relatively well known, we are still looking for a suitable animal model to study the mechanisms of aging and neurodegenerative diseases. Therefore, this paper presents a comparative analysis of the changes described in the brains of senile dog, horse and gorilla. In addition we present the latest, non-invasive methods that can be applied in the diagnosis of old age in mammals. Our considerations have shown that the best animal model for further studies and observations on aging is the dog.

Key words:aging • brain • mammals • MRI

Abbreviations:

Aβ – β-amyloid; AD – Alzheimer disease; APP – amyloid protein precursor; CA – corpora amylacea; CAA – cerebral amyloid angiopathy; CNS – central nervous system; MRI – magnetic resonance imaging; MRS – magnetic resonance spectroscopy; MT – microtubule; NFT – neurofibrillary tan­gle; NMR – nuclear magnetic resonance; PAS – periodic acid Schiff; PGB – polyglucosan bodies; PHF – paired helical filaments; SN – substantia nigra; SP – senile plaques

Introduction

Various changes develop with age in the nervous system of man and animals. Lesions such senile plaques, cerebral ß-amyloid angiopathy, neurofibrillary tangles, corpora amylacea and mineralization appear with advancing age in the human brain but are not specific to the human brain. In the brains of aged dogs, horses and nonhuman primates similar changes have been reported frequently [30]. These species may therefore serve as animal models for investigating e.g. β-amyloidosis in Alzheimer’s disease [35]. However, comparable data on the effects of brain ag­ing in humans and chimpanzees differ from each other in several ways [28]. Therefore we hypothesized that in spite of mutual features in senile brain, there are spe­cies-dependent differences between animals and humans. According to us, the knowledge about the differences between species is important to find alternative animal models of human aging to study disability-free longevity, not just the addition of years. For this purpose we moni­tored morphological neurological changes in brains of dogs (living in the same environment as people), horses (which acquire many of the same diseases that plague humans) and primates (close relatives of humans) to cor­roborate the usefulness of natural animal models for the study of normal aging and neurodegenerative diseases.

Theories of aging

Biological, epidemiological, and demographic data have generated a number of theories that attempt to identify a cause or process to explain aging and its inevitable con­sequence, death. However, in recent years, the search for a single cause of aging, such as a single gene or the decline of a key body system, has been replaced by the view of ag­ing as an extremely complex, multifactor process. Several processes may interact simultaneously and may operate at many levels of functional organization [32]. Attempts to classify theories of aging have led to two major categories: programmed aging and wear and tear aging. Programmed aging is aging due to something inside an organism’s con­trol mechanisms that forces elderliness and deterioration -similar to the way genes programme other life stages such as cell differentiation during embryological devel­opment or sexual maturation at adolescence. By contrast aging due to wear and tear is not the result of any specific controlling programme, but is the result of the sum effect of many kinds of environmental assaults, damage due to radiation, chemical toxins, metal ions, free radicals, hydro­lysis, glycation, disulfide-bond cross-linking, etc. For many organs – particularly the brain, heart, lung and kidney – specific disease states associated with aging are of more significance than generalized deterioration. There is wide variation in the health status of specific organs among the elderly [1]. In the aging brain many signs of deterioration have been observed. We grouped them, and described the morphological changes below.

Macroscopic changes

Few macroscopic changes were observed in old dogs com­pared with young controls. Narrowing of gyri and wid­ening of sulci were evident in some of the oldest dogs together with an increase in ventricular volume. These changes are well known in humans but rarely reported in animals. Both cerebral atrophy and ventricular enlarge­ment have been related to the loss of cortical neuronal populations in elderly people. Whether this is also true in animals is unknown, but selective loss of neurons has been described by several authors for a variety of spe­cies. Although a quantitative analysis of neuronal loss was not performed, satellitosis and neuronophagia were found in dogs; neuronophagia was a clear indication of neuronal loss [3].

Amyloid (corpora amylacea)

β-amyloid (Aβ) deposition in brain is a progressive age-related process beginning with diffuse deposits of im­munologically cross-reacting proteins in the deep cor­tical layers followed by the development of deposits in other parts of the cortex [26,29,30]. Aβ structure is visible in light microscopy after staining with Congo red, cresyl violet, PAS reaction and by fluorescence and immunofluorescence microscopy [Fig. 1]. The various forms of Aβ are classified biochemically according to the protein precursors. To date, 25 different amyloid protein precursors (APP) have been identified [9]. The extracellular Aβ in brain is generated by enzymatic processing of APP. Overexpression of APP as seen in Down syndrome and induced mutations in transgenic mice may lead to early onset of Alzheimer’s disease (AD). Aβ is deposited in the cerebral vessel walls and in the brain cortex as senile plaques (SPs) accumulat­ing on and between the membranes of degenerating neural structures and an abundance of microglia and astrocytes [5,25,26]. Aβ- positive staining was found in the brains of 8.5-year-old dogs and in older dogs revealing vascular staining and plaques. Corpora am­ylacea (CA) have been observed in an albino gorilla (Gorilla gorilla gorilla) throughout the brain but with topographic predilection for the periventricular white matter, hippocampus, medial temporal cortex, medulla oblongata, and, more abundantly, the pars reticulate of the substantia nigra (SN). CA from the SN and hip­pocampus were smaller than those found in the rest of the gorilla’s brain. Most of the CA found in the gorilla had accumulations of ubiquitin and microtubule-as­sociated proteins similar to CA accumulated in human aging. However, CA located principally in the hippo­campus and SN in the gorilla were almost all negative to both these proteins and mostly had accumulations of phosphorylated neurofilaments and α-synuclein [16].

Figure 1. Brain; 14-month rat, β-amyloid deposition in pyramidal layer of cortex, Congo-red stain (author’s own research)

Tau and neurofibrillary tangles

Tau is a microtubule [MT]-associated protein stabilizing microtubules as tracks for axonal transport [19]. Neu­ronal microtubules play a central role in axonal growth and development by providing a structural framework for new axons by serving as substrates for membrane vesicle transport in the axon and stabilize microtubules against depolymerization. In brain, the expression and activity of tau are known to change during development. The immature brain tau proteins are a closely spaced doublet at 48 kDa, while adult brain tau is considerably more heterogeneous, with at least three prominent dou­blets. Tau appears to be only a single gene from which diversity is generated by both alternative splicing and posttranslational modifications, such as phosphorylation [23,24]. In degenerating neurites hyperphosphorylated cytoskeleton protein, tau and also ubiquitin have been encountered. Both are major components of paired he­lical filaments (PHF) in AD brains and lead to dementia. Polymerization of tau into PHF and binding of ubiquitin initiate neurofibrillary tangle (NFT) formation. Ubiquitin is a small heat shock protein involved in the degenera­tion of altered cytoplasmic proteins (target proteins for nonlysosomal ATP-dependent proteolysis). There is in­creasing concern about the role of ubiquitin in relation to NFTs [26]. Ubiquitin-positive immunoreactions were detected as granules and globules of various sizes in white matter of all old dogs but never in young control dogs. The density of ubiquitinated bodies increased with age. Immunoreactive bodies appeared among axonal fibres and were seen only occasionally in glial cells or neurons. A primary myelin disorder inducing increased levels of abnormal proteins or a decreased proteolytic rate has been proposed to explain the presence of these ubiqui­tinated bodies [3]. In dogs tau was detected in neurons of the hippocampus and cortex of the parietal lobe. The positivity was located in the cytoplasm as granules and in the axon processes as threads. The positive neurons resembled those in human brains during the early stage of tauopathy [26].

Lipofuscin

Lipopigments are cytoplasmic pigments that have an af­finity for neutral lipid stains. They are classified as those that occur normally in tissues (lipofuscin) and those gen­erated experimentally or associated with pathological conditions (ceroid) [8]. Lipofuscin, or age pigment, is an autofluorescent material which accumulates progres­sively with age within secondary lysosomes in long-lived postmitotic cells of man and animals. For all we know lipofuscin is a conglomerate of lipids, metals (iron, alu­minium, copper), organic molecules and biomolecules [4,20]. Typically, lipofuscin stains well with oil red O, Su­dan black, acid fast, and PAS stains [Fig. 2]. A variety of studies indicate that lipofuscin formation and accumu­lation within the lumen of secondary lysosomes is fun­damentally linked to the hydrolytic activity within lyso­somes. Intracellular digestion of substances taken into the cell by endocytosis occurs primarily in lysosomes, as does the degradation of molecules and organelles of the cytoplasm constantly targeted and removed by au­tophagy. Also, lipofuscin-overloaded lysosomes might be unable to further handle peroxidized material formed during oxidative stress, which would increase the intra­cellular concentration of lipid peroxidation, such as malo­ndialdehyde, impairing critical cellular functions. [2,12]. Intraneuronal lipofuscin deposits were observed also in horses and the quantity of the pigment and the number of areas affected increased with age. In young horses, in­traneuronal lipofuscin was largely confined to the mes­encephalic trigeminal nucleus, the red nucleus, and the vestibular nucleus. In other equine studies, the olivary nucleus and the pyramidal cells of the cortex were the re­gions affected in young horses. However, it was suggested that the anatomical distribution of lipofuscin is related to the activity of the nuclei. Age-related glial and neuropil lipofuscin deposition in horses were confined to the ros­tral part of the brain. Lipofuscin deposition is caused by intracellular accumulation of cell debris after autophagic lysosomal degeneration. Finding this pigment in neuro­pil may be the result of occasional exocytosis. Another theory is that glial cells containing lipofuscin pigment become pyknotic and die, and afterward only extracel­lular deposit can be observed [13]. Lipofuscin storage was present in aged dogs, with a wide distribution in cerebral cortex, basal nuclei, thalamus, hippocampal pyramidal neurons, cerebellar dentate nuclei, and some midbrain nuclei. Although lipofuscin in young control dogs ap­peared as small perinuclear and granular deposits, old dogs had more diffuse granular deposits affecting the pericardia and proximal dendritic tree [3].

Figure 2. Brain; 14-month rat, lipofuscin in Purkinje cells of cerebellum, PAS stain (author’s own research)

Vascular changes

Vascular age-related changes in CNS include: thicken­ing, fibrosis, hyalinosis of small arteries, calcification of the tunica externa of blood vessels and choroid plexus, microhaemorrhages and Aβ in small blood vessels of the cerebral cortex (cerebral amyloid angiopathy). The most prominent change observed in old dogs was fibrosis of the vessel walls. Adventitial thickening showed a focal distribution in most cases, affecting both meningeal and parenchymal (especially thalamic) vessel walls and being more frequent in small-diameter veins than arteries. This change seemed to have a variable age distribution but was more marked in 14- and 15-year-old dogs. Other vascular abnormalities were hyalinosis and microhaemorrhages. Hyalinosis affected the tunica media of some arterioles, but there were no other associated vascular or perivas­cular lesions. Vascular changes were also observed in go­rilla brain and were characterized by thickening, fibrosis and hyalinosis of small arteries. Diffuse microspongiosis, which was more accentuated in perivascular spaces, was observed throughout the nervous parenchyma [16]. The hyalinized vessel walls in brain of horses could not be established. However, age-related vascular changes have been described in humans consisting of thickening of ves­sel walls, fibrosis and hyalinization [13].

Mineralization in the wall of CNS blood vessels occurs most commonly in aged humans (atherosclerosis), but is also found in animals. In the CNS of aged horses it was observed to affect parenchymal blood vessels, especially in the dentate nuclei and globus pallidus, internal capsule and caudate nucleus, and not to pertain to generalized vascular diseases. In elderly people, a mild degree of cal­cification inside and around blood vessels is a common incidental finding in the cerebral grey or white matter, without associated symptoms [15]. The morphology and histochemistry of cerebral mineralization in monkeys closely resembled those of human cases commonly found in the globus pallidus. In monkeys no neurological symp­toms or signs were recognized, as observed in humans. Because cerebral mineralization induces no clinical signs, it might be physiological rather than pathological, as with mineralization of the pineal gland or choroid plexus cur­rently observed in monkeys. In human Fahr’s disease with severe mineralization, lesions of the basal ganglia were observed on radiographs or with computed tomography, showing pathological changes similar to those in mild pallidal vascular mineralization [34].

Cerebrovascular amyloidosis was detected in old dogs, affecting leptomeningeal and parenchymal medium and small calibre arterioles and capillaries. Amyloid pro­tein was also deposited in the external tunica media of vessel walls [35]. Congophilic material was detected in some small blood vessels of the cerebral cortex in go­rilla brain [16].

Spheroids

Axonal dystrophy and spheroids are hallmarks of CNS axon pathology [17]. Spheroids were shaped as round or oblong eosinophilic structures of variable size, between 15 µm and 30 µm in diameter, strongly stained with Biel­schowsky stain. Immunohistochemical studies showed ubiquitin, α-β-crystallin, tau, and 200 KDa neurofilament accumulation within the spheroids. Perls’ method clearly revealed iron deposition in the neuropil and within some spheroids. Increased neuromelanin pigment was also ob­served in this area. The accumulation of neurofilaments indicates that at least part of the accumulated material inside the spheroids comes from the degraded neuronal cytoskeleton. Tau accumulation in spheroids would in­dicate an attempt to repair the axonal damage. The α-β- crystallin overexpression in spheroids would protect ax­ons from the aggregation of intermediate filaments and proteins triggered by iron-mediated oxidative stress. The ubiquitin immunostaining of spheroids would indicate activation of the proteolytic nonlysosomal system for the degradation of abnormal filamentous cytoskeletal proteins. Dystrophic axons are usually smaller swellings often associated with continuity of the axon. One or both of these aberrant axon morphologies are found in a wide range of neurodegenerative disorders, including stroke, myelin disorders, tauopathies, amyotrophic lateral scle­rosis, traumatic brain injury, AD, Creutzfeldt-Jakob dis­ease, HIV dementia, hereditary spastic paraplegia and Niemann-Pick disease. They also occur during normal ageing and secondarily in some serious illnesses. More­over, in nonhuman primates, pallido-nigral spheroids associated with iron deposition have been observed in clinically normal gorillas as a normal aging phenome­non [16]. In some instances in horses, the spheroids were associated with coalescing vacuoles in the surrounding grey and white matter, and some spheroids were also vacuolated. Spheroids were common in the brainstem particularly in the nucleus funiculus lat. [13]. In aged dogs spheroids were seen in cerebral grey matter and, more frequently, in cerebral white matter (cortical ra­diations, corona radiate and capsula interna). Spheroids were negative for neurofilament immunostaining, and only occasional ubiquitin-positive immunoreactions were seen. This differential staining may indicate a different pathogenic mechanism, the former being a consequence of altered axonal retrograde transport and the latter be­ing the result of a defect of normal cellular catabolism [3].

Other changes

Neuronal, neuropil and white matter vacuolation has been reported in the nervous system of a few domestic species [11,13]. In the horse, the main involved areas of neuronal vacuoles were the mesencephalic trigeminal nucleus, the Purkinje cells and the neurons in the raphe at the level of the obex. Neuropil vacuolation contributes significantly to clinically detectable reduced neuronal function and was linked with autolysis, which may predis­pose brain tissue to artefactual vacuolation. The oculomo­tor nucleus was the main site affected by neuropil vacu­olation in horses. White matter vacuolation in the horses occurred mainly in the internal capsule of the basal gan­glia. Vacuolation of white matter has been associated with congenital and acquired degenerative diseases, but the most commonly attributed reasons include hepatic encephalopathy and uraemia, where the vacuolation is distributed at the junction of grey and white matter [13].

Glial changes affected mostly astrocytes. Astrogliosis was seen in old dogs, but astrocytosis (increased number of astrocytes) was observed only in a few dogs. These glial changes were diffuse, bilateral, and more prominent in white than in grey matter, mainly in the corticomedullary junction, corpus callosum, capsula interna, hippocampus, and other cerebellar white matter. Isomorphic gliosis was seen in cerebellar Bergman’s glia in old dogs [3]. Gliosis was also seen in horses in the cerebrum and in an aged al­bino gorilla throughout the nervous parenchyma [13,16].

Polyglucosan bodies (PGB) were detected in many areas, mainly as free neuropil inclusions affecting all aged dogs but not young controls. The term PGB refers to several different inclusion bodies composed mainly of glucose polymers. Lafora bodies and CA are the two main PGB reported in aged dogs. Ultrastructural canine brain stud­ies have determined the intraneuronal location of Lafora bodies, in both cytoplasm and axons, whereas CA are as­trocytic inclusions. Positive ubiquitin immunoreactions have also been described. Lafora bodies may have no overt neurological consequences in aged dogs, but their con­tribution to cognitive dysfunction syndrome needs more detailed study, especially considering that a disorder simi­lar to Lafora body disease in humans has been described in young dogs, with antecedents of epilepsy, depression, or somnolence [3].

Diagnostic method

Traditional investigations of brain aging were based on histological or immunohistological staining. Today inter­esting applications which have revolutionised medical di­agnosis are MRI and MRS, available for the ante-mortem investigation of various histological types of aging brain. MRI depends on the magnetic properties of some nuclei, most notably the protons in the hydrogen atoms of wa­ter, and was developed from its parent technique NMR spectroscopy, which is widely used in chemical analysis. Soft tissue contrast originates mainly in differences in the relaxation properties of the nuclei in different tis­sues, rather than in the smaller (about 15%) differences in water content [21,22,27]. MRI white matter hyperinten­sity has been reported in brains of aged dogs as well as in humans. The appearance of white matter hyperintensity is a common manifestation of vascular dementia and is connected with cerebral amyloid angiopathy [6]. We ap­ply this cost-effective MRI technique for investigation of macroscopic age changes in brain which were observed in humans and dogs.

MRS looks back to the analytical role of NMR, but adds spatial localisation, enabling biochemical analysis to be done in vivo [21]. The concentrations of most brain me­tabolites within the neurochemical profile are modified during development, reflecting the structural and func­tional evolution inherent to the differentiation of cerebral networks. Therefore, the non-invasively detected neu­rochemical profile may be taken as a marker for specific metabolic states which are associated with degeneration or acute injury. Although brain metabolism has wide dif­ferences among species, namely when comparing rodents to humans, once the role of measured neurochemicals is understood, high resolution NMR qualifies as the method of choice for in vivo investigation of preclinical animal models of human neurological and other pathologies dur­ing development or aging [7]. 1H-MRS can be used to assess neuronal loss (with the neuronal marker N-acety­laspartate) and thus the progress of neurodegenerative diseases and their response to therapy can be examined [14,21]. Neurochemical profile detection by 1H-MRS was also carried out in antioxidant defence, Huntington’s dis­ease, Parkinson’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease [7].

Conclusions

In the present study we note that several frequently oc­curring morphological changes were found in aged bra­ins of dogs, horses and gorillas. Otherwise all changes described in the study are similar to those seen in elderly people suffering from neurodegenerative disease. Already at the beginning of this paper, when analysing macrosco­pic changes, we drew attention to the similarities of senile brain between man and dog. Further discussed changes such as Aβ and lipofuscin deposition as well as vascular lesions also reflect similarities. Moreover, there are many well-documented physiological similarities between dogs and humans [31]; therefore tapping into the potential of this animal model will add to the existing strengths of co­nventional model systems. Additionally, it is worth noting that the quality of dogs’ lives has improved by enhancing veterinary care and hygiene, and using a proper diet, so the lifespan has increased similarly to human life. Horses and humans have a very similar aging process; both spe­cies have a tendency to gain weight as they age, which can result in an imbalance of hormones [33]. But in the case of Aβ deposition in the CNS no changes have been observed by scientific research, so it can be eliminated as an ideal model to study the neurodegeneration process. Monkeys and great apes apparently do not suffer from age-related neuropsychiatric illnesses which occur only in humans, such as AD. The vast majority of morphologi­cal studies of brains of aged nonhuman primates indicate that very few changes take place during aging. Impor­tantly, all current studies agree that no decrease in total neuron numbers in the cerebral cortex and in subcortical structures occurs in nonhuman primates [10]. In addition, primates such as gorillas, despite some morphological similarities in development of morphological changes in the brain and close affinity with humans, live in a com­pletely different environment compared to humans and domesticated dogs. Therefore, this also excludes them from the group of animals that may be a perfect model for human senile diseases.

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The authors have no potential conflicts of interest to declare.

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