Effects of aging on brain perfusion and serotonin-2A receptor binding in the normal canine brain measured with single photon emission tomography

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Abstract

Normal aging is associated with a decrease in number and size of neurons, loss of synapses and neuronal branching and with a reduced functioning neurotransmitter systems, such as the serotonergic system. These structural and functional alterations have important impact on the behavioural, cognitive and affective status of the individual. With the introduction of functional brain imaging in veterinary medicine, the canine brain can be examined in vivo, evaluating changes in perfusion, metabolism and neurotransmitter systems. Since cognitive decline is recognised in the aging dog, it was our aim to investigate whether age related changes concerning cerebral perfusion and binding index of the selective 5-HT2A receptor ligand 123I-5-I-R91150 could be found in the canine brain. A group of twelve normal, aging dogs, older than 96 months, was compared to a normal reference group (n=12), younger than 96 months. SPET images were obtained, using the radiopharmaceutical 99mTc-N,Nʺ-1,2-ethylene-diylbis-l-cysteine diethylester dihydrochloride (99mTc-ECD) for evaluation of the regional perfusion and the selective radioligand 123I-5-I-R91150 for visualization of the 5-HT2A receptor. Regional decrease of cerebral blood-flow was noted in the fronto- and temporocortical area and in the subcortical region. Age was negatively correlated with perfusion in the left and right fronto-cortical region. The binding index of the neuroreceptor radioligand was decreased in the fronto-cortical region, with a significant negative correlation with age in the right fronto-cortical area. No correlation was found between alteration of perfusion and binding index of the receptor ligand, suggesting that age related perfusion differences do not influence the binding of this radioligand. These results suggest that age related effects should be considered in functional canine brain imaging.

Introduction

Increasing interest has evolved on the pathophysiology of aging processes in the canine brain, not only to serve the dogs' own benefit but also to create a model for research on the human aging brain. Natural similarities with humans in symptomatology and neuropathologic findings (Head et al., 2000a) compared to rodents, and the ease to maintain and handle dogs compared to primates makes this model more favourable. Dogs are also more easy to obtain and are less expensive than primates Torp et al., 2000, Adams et al., 2000. The most obvious histological alterations in the aging canine brain are cell loss and accumulation of β-amyloid in brain tissue and cerebral vessels Morys et al., 1994, Cummings et al., 1996, Head et al., 1998, comparable to the alterations found in the aging human brain Andersson et al., 1992, Torp et al., 2000, Head et al., 2000a. Brain cell apoptosis has been observed in dogs, showing a relationship with the amount of amyloid deposition (Anderson et al., 2000) and correlating well with a dementia index, according to Uchino (Kiatipattanasakul et al., 1996). Similar apoptotic alterations of brain cells have been found to a larger extent in Alzheimer's disease patients, in comparison to their age matched controls (Lassmann et al., 1995).

Behavioural and cognitive observations in the aging dog, including the evaluation of the effect of environmental stimuli, pharmacological probes and nutritional interventions, pointed at a sociobiological substrate of canine age-related behaviour Siwak et al., 2000, Head et al., 2000a, Milgram et al., 2002. Cortical atrophy and an increase in cerebrospinal fluid containing ventricular spaces was demonstrated with post-mortem investigations and with morphologic imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT) Su et al., 1998, Gonzales-Soriano et al., 2001. Unfortunately, the structural changes in age-associated brain pathology occur later than functional disturbances and show a broad overlap with normal age related changes as is found in human brain Loessner et al., 1995, Mielke et al., 1998. Furthermore, structural changes do not correlate with observed neurological disease, as was demonstrated in a study on canine brain ventricular size in normal and pathologic conditions (Esteve-Ratsch et al., 2001).

The introduction of functional brain imaging in veterinary medicine recently led to the evaluation of the normal canine regional cerebral blood perfusion (rCBF) pattern with 99mTc-N,Nʺ-1,2-ethylene-diylbis-l-cysteine diethylester dihydrochloride (ECD) (Peremans et al., 2001a), enabling also the evaluation of brain metabolism, coupled with cerebral perfusion (already demonstrated in 1890 in dogs) (Roy and Sherrington, 1890), and to the evaluation of neurotransmitter receptor binding with specific radioligands (e.g., 123I-5I-R91150) (Peremans et al., 2001b), using SPET. Concerning brain perfusion or metabolism in aged subjects, controversy exists about the presence of a global decrease of human Waldemar et al., 1991, Markus et al., 1993, Petit-Taboue et al., 1998, Nobler et al., 1999 and canine (Su et al., 1998) brain perfusion and metabolism, but evidence for regional decrease is consistent in human literature. Most often, in human studies, reduction in frontal and temporal perfusion or metabolism is demonstrated in aged, but not cognitive disturbed, subjects Waldemar et al., 1991, Markus et al., 1993, Matsuda et al., 1993, Catafau et al., 1996, Goto et al., 1998, Petit-Taboue et al., 1998, Van Laere et al., 2001. Moreover, regional decreased metabolism has been demonstrated in aging non-anesthetised dogs (London et al., 1983). In general, research concerning in vivo SPET and PET receptor imaging with selective ligands could demonstrate age related reduced binding to serotonergic and dopaminergic receptors in the human brain Wong et al., 1984, Wong et al., 1997, Wang et al., 1995, Rosier et al., 1996, Meltzer et al., 1998a An age dependent decrease in dopaminergic, serotonergic and adrenergic receptor density was also found in rats and primates Gozlan et al., 1990, Robson et al., 1993, Nabeshima et al., 1994, Bigham and Lidow, 1995, Morris et al., 1999, Kakiuchi et al., 2000.

Increasing evidence emerges that the serotonergic system, involved in the regulation of mood and behaviour, plays a major role in the behavioural changes seen in age related disorders Meltzer et al., 1998b, Nobler et al., 1999.

In vivo SPET imaging of the serotonin-2a receptor, was already carried out in a reference population of healthy volunteers and in some clinical populations in human neuropsychiatric studies. These studies demonstrated an age-dependent reduction in serotonin-2a binding index. Up to now, animal studies were only limited to small, preclinical, rodent and primate studies. Recently, we demonstrated the feasibility of the technique in healthy canine subjects (Peremans et al., 2001b). In analogy with human studies in old aged subjects, one could expect a reduction in serotonin-2a binding index in old aged but cognitively intact dogs.

A possible relation between changes in brain perfusion and brain serotonin-2a binding index could exist through a mechanism by which the presence of serotonin decreases perfusion by altering vascular tone of the cerebral vasculature (Volkow et al., 2000). Changes in the permeability of the blood brain barrier (BBB) have been observed when brainstem serotonin raphe neurons are manipulated (Cohen et al., 1996), an interesting finding in view of the age related BBB alterations found recently on MRI in dogs (Su et al., 1998). After all, the serotonergic system plays a role in the innervation of blood vessels and in the modulation of brain perfusion (and metabolism) Cudennec et al., 1988, Cohen et al., 1996. Also, decreased perfusion on itself may alter the availability of neurotransmitter precursors and in the same line of thinking, altered metabolism may decrease neurotransmitter production.

The aim of this study was to investigate the effects of aging on regional cerebral blood flow and on the binding parameters of the 5-hydroxytryptamine-2A (5-HT2A) ligand. For clinical purposes, knowledge of normal variations and alterations in the distribution pattern of flow tracers in aging brain is necessary when investigating pathological states. In future, knowledge on the perfusion and serotonin-2A status can help in the diagnosis of age-related cognitive decline versus dementia in dogs and can serve as a model for pathophysiological and pharmaceutical intervention studies on age-related cognitive decline and dementia in human subjects.

Section snippets

Subjects

Twelve “aged” dogs, five males and seven females, all aged above 96 months, and a reference group (six males, six females), aged less than 96 months, were included. Table 1. All these dogs were privately owned and housed since young age. None of the dogs in both groups had a history of neurological disorders or behavioural abnormalities. No obvious cognitive decline was present in the “old age” group. None of the dogs were on medication or received a specific diet.

The Uchino dementia index

Results

Besides ventricular enlargement, no structural abnormalities were present on CT images obtained from all aged dogs.

Cerebral perfusion studies

In this study, decreased global cerebral perfusion was present, combined with a significant regional decrease in fronto-, temporocortical and subcortical region perfusion in the aged group compared with the reference group. Regression analysis revealed a significant decrease of perfusion in the frontal cortex with age.

Our finding of a global reduction of cortical perfusion is in line with most, but not all, findings in human medicine literature indicating a decrease in global age-related brain

Conclusion

A database is generated for the normal aging canine brain, including perfusion data and binding parameters for the selective 5-HT2A ligand. A significant decreased perfusion is noted in the fronto- and temporocortical regions and the subcortical area. Binding parameters for the 123I-5-I-R91150 selective ligand decrease in the frontal regions, but only the right frontal area is correlated with age. Although partial volume effects cannot be ruled out based on this investigation, studies on human

Acknowledgements

The authors would like to express their appreciation to Mr. M. Verdonck for his technical support.

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