“Primary central white matter degeneration in old dogs.”

Ferrer et al.

Acta Neuropath 1993.

Degeneration of the central white matter is described in old dogs. The presence of ubiquitinimmunoreactive free granules and intracytoplasmic globules in glial cells and macrophages, together with galactocerebroside-immunoreactive precipitates and lipofuscin storage, point to the likelihood of a primary myelin degeneration with deposits of non-degraded ubiquitin-protein conjugates and complex galactolipids.

“Age-related Changes in the Brain of the Dog.”

Borras et al.

Vet Path 1999.

Changes affected meninges and choroid plexuses, meningeal and parenchymal vessels, neurons, and glial cells. Of special interest was the presence of polyglucosan bodies, cerebrovascular amyloid deposition, senile plaques, and ubiquitinated bodies. Some of the age-related changes found, particularly lipofuscin, polyglucosan bodies, and b-amyloid protein deposition, may play a role in the pathogenesis of the canine cognitive dysfunction syndrome.

“Changes of Magnetic Resonance Imaging on the Brain of Beagles with Aging.”

Kimotsuki et al.

J Vet Med Sci 2005.

Dilation of lateral ventricles, pervientricular white matter T2 hyperintensity (also commonly seen in people) Hypointensity in globus pallidus and substantia nigra correlated to accumulation of ferric ion on path (similar to what is seen in people in globus pallidus, red nucleus, caudate

“Measurement of interthalamic adhesion thickness as a criteria for brain atrophy in dogs with and without cognitive dysfunction (dementia)”

Hasegawa et al.

VRUS, Vol 46, No 6, 2005: 452-457

78 dogs of various breeds aged 6 months-18 years. Average ITA thickness was 6.79+/- 0.70mm in clinically normal dogs versus 3.82+/-0.79mm in clinically demented dogs.

Other typical signs of age-related brain atrophy include:

1. Enlargement of the ventricular system
2. Well-demarcated sulci (enlargement of the subarachnoidal space)
3. Diffuse and scattered T2 hyperintensity lesions in the periventricular white matter

1 and 2 come from parenchymal atrophy. T2 hyperintensity can come from myelin degeneration, gliosis, or enlarged Virchow-Robin spaces.

While smaller dogs had overall smaller ITA thicknesses, the only statistically significant correlation was between dogs with dementia and behaviorally normal dogs. A study looking at lysosomal storage disease documented progressive decrease in ITA size suggesting this can be a good measure of parenchymal loss. Another differential can include increased pressure from obstructive hydrocephalus as was noted in a separate case of a Golden with cerebellar meningioma and small ITA measurement presumed to be associated with intracranial pressure changes related to CSF flow obstruction.

“Therapeutic Options for Cognitive Decline in Senior Pets.”

Landsberg et al.

JAAHA 2006.

The diet is supplemented with vitamins E and C and other antioxidants, such as beta carotene, selenium, dl-α-lipoic acid, and a number of flavonoids and carotenoids from fruits and vegetables (e.g., spinach flakes, tomato pomace, grape pomace, carrot granules, citrus pulp). The addition of l-carnitine and dl-α-lipoicnacid is intended to enhance mitochondrial function.

Phosphatidylserine is a naturally occurring phospholipids that is a major building block of the cell membrane. Since neurons are highly dependent on their plasma membranes (e.g., for generation and transmission of impulses, synaptic communication, etc.), phosphatidylserine may facilitate membrane-dependent neuronal processes, such as signal transduction, release of secretory vesicles, and maintenance of the internal environment.

Ginkgo biloba inhibits monoamine oxidase (MAO) A and B, which increases dopamine levels.

Vitamin B6 (pyridoxine) is also reported to be a cofactor in the synthesis of neurotransmitters (e.g., serotonin, noradrenaline, dopamine), thereby supporting phosphatidylserine in normalizing neurotransmitter levels and synaptic transmission.

Selegiline is a selective and irreversible inhibitor of MAO B in the dog.61 Enhancement of dopamine and perhaps other catecholamines in the cortex and hippocampus is presumed to be a primary mode of action.

Nicergoline is an alpha-1 and alpha-2 adrenergic antagonist that is licensed in some countries for the treatment of age-related behavior disorders in dogs.68 It may increase cerebral blood flow, inhibit platelet aggregation, enhance neuronal transmission by increasing dopamine and noradrenaline turnover, and may have neuroprotective effects.68

Propentofylline is licensed for the treatment of dullness and lethargy in senior dogs in a number of European countries. It is purported to inhibit platelet aggregation and thrombus formation, may make red blood cells more pliable, and increases blood flow.

“Diffuse beta-amyloid plaques and hyperphosphorylated tau are unrelated processes in aged dogs with behavioral deficits.”

Pugliese et al.

Acta Neuropath 2006.

Behavioral impairment, as reported by the owners and tested in all dogs, correlated with increased A! burden in old dogs. Ab plaques were diffuse and they were not accompanied by modifications in synaptic protein expression. Plaques were not associated with increased active mitogen activated protein kinase (MAPK/ERKP) and p38 kinase (p38-P) expression, and tau hyperphosphorylation in neighboring cell processes. Yet tau hyperphosphorylation, as revealed with phospho-specific antibodies to tauThr181 and tauSer396, increased with age in individual neurons. Moreover, the subcellular pattern shifted from perinuclear localization to granular cytoplasmic and nuclear distribution with age. Our results in dog suggest that Ab diffuse plaque formation and tau hyperphosphorylation are independent events, both occurring during the process of aging. Although increased cognitive dysfunction is associated with increased tau hyperphosphorylation, further investigation is needed to understand whether tau hyperphosphorylation is causative of cognitive impairment or an independent process related to aging.

“Canine cognitive deficit correlates with diffuse plaque maturation and S100b (-) astrocytosis but not with insulin cerebrospinal fluid level.”

Pugilese et al.

Acta Neuropath 2006.

The aim of the present investigation was to study the link between the diffuse Ab plaque maturation and the astro- and microglial reactivity. The involvement of insulin and beta-subunit of S100 protein (S100b) overexpression in the process was also investigated. Ab plaques were measured and counted in prefrontal cortex of 16 pet dogs of different breeds, weight and sex, classified as control and with a light or severe cognitive deficit. A correlation between canine graded cognitive deficit, diffuse plaque maturation, and S100b (_) astrocytosis, but not with cerebrospinal fluid insulin level, was found that may reflect the very early events of Ab deposition in Alzheimer’s disease. Within the numerous risk factors for AD, insulin is considered important because of its fundamental role in controlling glucose metabolism, synaptic plasticity and competition with clearage of soluble Ab, leaving the peptide to clump into plaques. The correlation between CSF insulin level and aging, not found with the diffuse plaque stages, suggests that insulin participate in the aging process but not directly in the diffuse plaque formation and maturation.

“Complementary Distributions of Amyloid-b and Neprilysin in the Brains of Dogs and Cats.”

Takeuchi et al.

Vet Path 2008.

Neprilysin is an amyloid-b-degrading enzyme localized in the brain parenchyma. The involvement of neprilysin in the pathogenesis of Alzheimer’s disease has recently received much attention. We examined the localization of neprilysin and amyloid-b, as well as the activity of neprilysin, in the brains of dogs and cats of various ages to clarify the relationship between neprilysin activity and amyloid-b deposition. The distribution of neprilysin was almost identical in dogs and cats, being high in the striatum, globus pallidus, and substantia nigra, but very low in the cerebral cortex. The white matter and hippocampus were negative. Neprilysin activity in the brain regions in dogs and cats was ranked from high to low as follows: thalamus/striatum . cerebral cortex . hippocampus . white matter.

Amyloid-b deposition was first detected at 7 and 10 years of age in dogs and cats, respectively, and both the quantity and frequency of deposition increased with age. In both species, amyloid-b deposition appeared in the cerebral cortex and the hippocampus.  Ab deposition occurred in 2 patterns: diffuse accumulation (see Figs. 21–24) and diffuse-type senile plaques (see Figs. 25 and 26) in the cerebral parenchyma of both dogs and cats. No Ab deposition was observed in the white matter, caudate nucleus, putamen, globus pallidus, substantia nigra, or cerebellum of either species. Taken together, these facts suggest that, because NEP expression and activity in the cerebral cortex are lower than those in the striatum, Ab is not sufficiently degraded and consequently accumulates in the cortex. Ab deposition is not necessarily observed in the regions where NEP activity is low. In fact, Ab is degraded by not only NEP but also endothelin-converting enzyme, insulin-degrading enzyme (IDE), and angiotensin-converting enzyme.49 NEP cannot efficiently degrade some kinds of Ab variants.

“Cognitive dysfunction and the neurobiology of ageing in cats.”

Gunn-Moore et al.

JSAP 2008

A recent study suggests that 28 per cent of pet cats aged 11 to 14 years develop at least one geriatric onset behavioural problem, and this increases to over 50 per cent for cats of 15 years of age or older. The most commonly seen behavioural changes in CDS include spatial or temporal disorientation, altered interaction with the family, changes in sleep-wake cycles, housesoiling with inappropriate urination/defecation, changes in activity and/or inappropriate vocalization. Studies have revealed a number of changes in the brains of geriatric cats that showed signs of cognitive dysfunction, and potential causes include vascular insufficiency leading to hypoxia, increased free radical damage and the deposition of b-amyloid plaques and/or the modification of other proteins.

“An Observational Study with Long-Term Follow-Up of Canine Cognitive Dysfunction: Clinical Characteristics, Survival, and Risk Factors”

R. Fast, T. Schutt, N. Toft, A. Møller, and M. Berendt

J Vet Intern Med 2013; 27:822–829

Background: Canine cognitive dysfunction (CCD) is a neurodegenerative condition affecting geriatric dogs and sharing several characteristics with human Alzheimer’s disease (AD). CCD manifests as alterations of behavioral patterns and daily routines. Clinical signs are associated with neurodegenerative changes (eg, cortical atrophy and amyloid-beta deposits).

Objectives: To investigate clinical characteristics, survival, and risk factors with CCD. Vitamin E was investigated as a potential marker of CCD.

Methods: Ninety-four dogs>8 years of age were investigated with a validated CCD questionnaire and allocated to CCD, borderline CCD (b-CCD) and non-CCD groups. The dogs were included in 2008–2009 and followed up in an observational study until follow-up in 2012.

Results: Four key clinical signs dominated in dogs with CCD: sleeping during the day and restless at  night, decreased interaction, disorientation at home, and anxiety. A number of borderline CCD cases developed into CCD over time indicating that a prodromal stage of CCD may exist. CCD did not influence survival negatively. Small breeds did not show better survival than large breeds (P=.055) and there was no difference between sexes (P=.99).

Conclusions and Clinical Importance: A few key questions addressing sleep-wake cycle, interaction, and signs of confusion and anxiety can be used as a clinical marker of CCD. Special attention should be paid to anxiety in dogs with CCD because it may be especially stressful to both dog and owner. Dogs with CCD seem to have a good chance of living a full lifespan if supported by the veterinarian and the owner.

**Investigators propose early administration of questionnaire to all geriatric dogs, even if appears normal on exam.  Dogs in b-CCD may therefore benefit from treatment recommendations to slow progress of CCD.  Additionally, recognizing anxiety is important as educating the owner on behavior modification and use of anxiolytics can help with overall quality of life.  Finally, just because you are old and going senile doesn’t mean your overall survival will be poor.  These dogs are old already and the gradual progression is easier for owners to adjust to and accept over time.