The interactive effect of intra-beat and inter-beat blood pressure variability on neurodegeneration in older adults.

Blood pressure variability (BPV) and arterial stiffness are age-related hemodynamic risk factors for neurodegenerative disease, but it remains unclear whether they exert independent or interactive effects on brain health. When combined with high inter-beat BPV, increased intra-beat BPV indicative of arterial stiffness could convey greater pressure wave fluctuations deeper into the cerebrovasculature, exacerbating neurodegeneration. This interactive effect was studied in older adults using multiple markers of neurodegeneration, including medial temporal lobe (MTL) volume, plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Older adults (N=105) without major neurological or systemic disease were recruited and underwent brain MRI and continuous BP monitoring to quantify inter-beat BPV through systolic average real variability (ARV) and intra-beat variability through arterial stiffness index (ASI). Plasma NfL and GFAP were assessed. The interactive effect of ARV and ASI on MTL atrophy, plasma NfL, and GFAP was studied using hierarchical linear regression. Voxel-based morphometry (VBM) was used to confirm region-of-interest analysis findings. The interaction between higher ARV and higher ASI was significantly associated with left-sided MTL atrophy in both the region-of-interest and false discovery rate-corrected VBM analysis. The interactive effect was also significantly associated with increased plasma NfL, but not GFAP. The interaction between higher ARV and higher ASI is independently associated with increased neurodegenerative markers, including MTL atrophy and plasma NfL, in independently living older adults. Findings could suggest the increased risk for neurodegeneration associated with higher inter-beat BPV may be compounded by increased intra-beat variability due to arterial stiffness.

Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles.

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of ß-amyloid (Aß) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.

Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old.

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

Alzheimer-like pathology in the parietal cortex and hippocampus of aged donkeys.

Neurodegenerative disorders are gaining ever more importance in ageing populations of animals and people. Altered insulin signaling and type II diabetes have been linked to the development of Alzheimer's disease (AD) in humans and AD-like neurodegeneration in other long-lived animals. Donkeys are unusual amongst domestic species for their exceptional longevity and are additionally predisposed to abnormalities of insulin metabolism similar to those found in humans. In this study, the parietal lobe and hippocampus of 13 aged (>30 years) and 2 younger control donkeys were evaluated immunohistologically for the presence, distribution, and frequency of neurofibrillary tangles (NFT) and amyloid plaques (AP); the characteristic lesions of AD. AP were in parietal cortices of 9 donkeys, with a predilection for deep sulci, and NFT-like structures were observed in 7 donkeys, primarily within cortical areas. No changes were observed in the control donkeys. This represents the first identification of both AP and NFT in equids and is a stimulus for future work assessing their metabolic status in parallel.

Cognitive Dysfunction in Cats: Update on Neuropathological and Behavioural Changes Plus Clinical Management.

Cognitive dysfunction syndrome (CDS) is an established condition in cats that shares many similarities with human Alzheimer's disease (AD), where cognitive decline ultimately results in dementia. Cats with CDS display behavioural abnormalities, including excessive Vocalisation, altered Interaction with owners (increased affection/attention), altered Sleep-wake cycles, House-soiling, Disorientation (spatial and/or temporal), alterations in Activity, Anxiety, and/or Learning/memory deficits (i.e., VISHDAAL). These cats develop neuropathologies, such as accumulation of ß-amyloid and hyperphosphorylated tau deposits. Because of its similarities to those in the brains of people with cognitive impairment and AD, the domestic cat could be a natural model for human dementia studies. It is important to diagnose CDS promptly in cats, ruling out other causes for these behavioural changes, to provide effective management. Interventions include environmental enrichment (e.g., easy access to key resources, calming pheromones), dietary supplementations (e.g., Senilife, Aktivait for cats, SAMe), specific diets (e.g., containing antioxidants, medium-chain triglycerides) and, potentially, medication (e.g., selegiline or propentofylline). This article reviews the literature about CDS in cats, its causes, neuropathology, clinical signs, diagnosis and potential management options. By doing so, it furthers our understanding of this condition and allows improved health, welfare and quality of life of affected cats.

Neuropathology of Aging in Cats and its Similarities to Human Alzheimer's Disease.

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer's disease (AD), including the extracellular accumulation of ß-amyloid (Aß) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aß and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aß, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aß were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aß senile plaques in people with AD have a dense core, extracellular Aß deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aß deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aß deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling.

Potential Causes of Increased Vocalisation in Elderly Cats with Cognitive Dysfunction Syndrome as Assessed by Their Owners.

The objectives of this study were to explore owner perception of the causes of increased vocalisation in cats diagnosed with cognitive dysfunction syndrome (CDS) and consider what impact this vocalisation may have on the cat's household. Owners of cats diagnosed with CDS that presented with increased vocalisation were invited to complete an online survey. The survey consisted of 28 questions including the cat's signalment, its medical history, and questions pertaining to the owner's perception of what motivated their cat´s increased vocalisation. This was determined by looking at the cat's behaviour when vocalising, where it was looking when it was vocalising, and if the vocalisation stopped when the owner interacted with it, e.g., petting or feeding it. The owners were also asked how stressful they found their cat's vocalisation. There were 37 responses. The majority of owners reported that the main cause of their cat's vocalisation appeared to be disorientation (40.5%) or attention seeking (40.5%). Seeking a resource such as food was reported in 16.2%, and pain was perceived to be the cause in only 2.7% of cats. However, the majority of owners (64.8%) believed there was >1 cause of their cat's increased vocalisation. Importantly, when owners were asked how stressful they found their cat's increased vocalisation, 40.5% scored ≥3 (where 1 = not stressful; 5 = significantly stressful). This study provides novel insight into owner perception of feline CDS, as well as potential causes for increased vocalisation; this will allow veterinarians to better advise owners on how to manage their cat with CDS.

Prevalence of Disease and Age-Related Behavioural Changes in Cats: Past and Present.

(1) Background: age-related changes in behaviour and health may be thought of as "normal" ageing; however, they can reflect under-diagnosed, potentially treatable, conditions. This paper describes the prevalence of age-related behavioural changes and disease in two UK cat populations at separate time-points. (2) Methods: owners of cats aged ≥11 years completed questionnaires in 1995 (cohort 1: n = 1236), and from 2010-2015 (cohort 2: n = 883). (3) Results: the most important behavioural changes in these cats were increased affection towards their owners (reported by 51.9% in 1995; 35.8% in 2010-2015), increased vocalisation (63.5%; 58.9%, respectively), particularly at night (32%; 43.6%), and house-soiling (29.3%; 55.8%). Most (79.4%; 81%) of the cats had visited a veterinary surgeon since becoming 11 years old. The main reasons, aside from vaccinations, were dental disease, renal disease and lower urinary tract disorders in 1995, and dental disease, renal disease and hyperthyroidism in 2010-2015. All major diagnoses were reported significantly more frequently in 2010-2015 than in 1995; behavioural changes were variably associated with these diseases. (4) Conclusion: elderly cats display age-related behavioural changes and develop diseases that may be under-diagnosed. Veterinarians need to ask owners about these behavioural changes, as they may signify manageable conditions rather than reflect "normal" ageing.

Feline Aging: Promoting Physiologic and Emotional Well-Being.

Caring for an increasingly aging population of pet cats presents challenges. The interplay between emotional and physical health is an important consideration; their ability to cope with stress is reduced. Optimizing the environment can improve quality of life at home and within the clinic, as does early diagnosis and treatment of medical or behavioral problems. This may be complicated by multiple, often interacting diseases, and the overlap of clinical signs, including behavioral change. Client education evenings and elderly cat clinics play a crucial role in making owners aware of normal aging changes. Differential diagnoses behind behavioral changes such are considered.

In the Eye of the Beholder: Owner Preferences for Variations in Cats' Appearances with Specific Focus on Skull Morphology.

Changes in the popularity of cat breeds are largely driven by human perceptions of, and selection for, phenotypic traits including skull morphology. The popularity of breeds with altered skull shapes appears to be increasing, and owner preferences are an important part of this dynamic. This study sought to establish how and why a range of phenotypic attributes, including skull shape, affect preferences shown by cat owners. Two questionnaires were distributed on-line to cat owners who were asked to rate preferences for pictures of cats on a 0-10 scale. Veterinarian consensus established the skull types of the cats pictured (i.e., level of brachycephaly (BC) or dolichocephaly (DC)). Preferences were then explored relative to cat skull type, coat and eye color, and coat length. Generalized estimating equations identified relationships between physical characteristics and respondent ratings. Further sub-analyses explored effects of respondents' occupation, location and previous cat ownership on rating scores. Overall, cats with extreme changes in skull morphology (both BC and DC) were significantly less preferred than mesocephalic cats. Green eyes, ginger coat color and medium length coat were most preferred. Current owners of a BC or DC pure bred cat showed significantly greater preference for cats with similar features and significantly lower preference for the opposite extreme. Respondents from Asia were significantly more likely to prefer both BC and DC cats as compared to respondents from other locations. Finally, those in an animal care profession, as compared to other professions, provided a significantly lower preference rating for BC cats but not for DC cats. This work, despite the acknowledged limitations, provides preliminary evidence that preferences for cat breeds, and their associated skull morphologies, are driven by both cultural and experiential parameters. This information may allow for better targeting of educational materials concerning cat breeds.