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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.
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Envejecimiento , Atrofia , Encéfalo , Tacrolimus , Animales , Perros , Femenino , Atrofia/patología , Masculino , Envejecimiento/patología , Encéfalo/patología , Encéfalo/efectos de los fármacos , Tacrolimus/farmacología , Conducta Animal/efectos de los fármacos , Imagen por Resonancia MagnéticaRESUMEN
TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.
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Enfermedad de Alzheimer , Proteínas de Unión al ADN , Proteinopatías TDP-43 , Humanos , Femenino , Anciano , Masculino , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteinopatías TDP-43/patología , Anciano de 80 o más Años , Bases de Datos Factuales , Degeneración Lobar Frontotemporal/patología , Degeneración Lobar Frontotemporal/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/metabolismo , Hipocampo/patología , Hipocampo/metabolismo , Persona de Mediana EdadRESUMEN
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.
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Envejecimiento , Disfunción Cognitiva , Esclerosis del Hipocampo , Hipocampo , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Envejecimiento/patología , Cognición , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Estudios de Cohortes , Esclerosis del Hipocampo/patología , Esclerosis del Hipocampo/fisiopatología , Hipocampo/patología , Hipocampo/fisiopatología , Modelos Logísticos , NeuropatologíaRESUMEN
BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Imagen por Resonancia Magnética , Humanos , Femenino , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/diagnóstico por imagen , Anciano , Masculino , Biomarcadores/sangre , Péptidos beta-Amiloides/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Fragmentos de Péptidos/sangre , Sistema Nervioso Autónomo/fisiopatología , Proteína Ácida Fibrilar de la Glía/sangre , Anciano de 80 o más Años , Proteínas de Neurofilamentos/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/etiologíaRESUMEN
Visit-to-visit blood pressure variability (BPV) predicts age-related hippocampal atrophy, neurodegeneration, and memory decline in older adults. Beat-to-beat BPV may represent a more reliable and efficient tool for prospective risk assessment, but it is unknown whether beat-to-beat BPV is similarly associated with hippocampal neurodegeneration, or with plasma markers of neuroaxonal/neuroglial injury. Independently living older adults without a history of dementia, stroke, or other major neurological disorders were recruited from the community (N = 104; age = 69.5 ± 6.7 (range 55-89); 63% female). Participants underwent continuous blood pressure monitoring, brain MRI, venipuncture, and cognitive testing over two visits. Hippocampal volumes, plasma neurofilament light, and glial fibrillary acidic protein levels were assessed. Beat-to-beat BPV was quantified as systolic blood pressure average real variability during 7-min of supine continuous blood pressure monitoring. The cross-sectional relationship between beat-to-beat BPV and hippocampal volumes, cognitive domain measures, and plasma biomarkers was assessed using multiple linear regression with adjustment for demographic covariates, vascular risk factors, and average systolic blood pressure. Elevated beat-to-beat BPV was associated with decreased left hippocampal volume (P = .008), increased plasma concentration of glial fibrillary acidic protein (P = .006), and decreased memory composite score (P = .02), independent of age, sex, average systolic blood pressure, total intracranial volume, and vascular risk factor burden. In summary, beat-to-beat BPV is independently associated with decreased left hippocampal volume, increased neuroglial injury, and worse memory ability. Findings are consistent with prior studies examining visit-to-visit BPV and suggest beat-to-beat BPV may be a useful marker of hemodynamic brain injury in older adults.
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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.
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Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.
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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.
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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Enfermedad de Alzheimer/patología , Animales , Diabetes Mellitus Tipo 2/metabolismo , Equidae , Hipocampo/patología , Humanos , Insulina/metabolismo , Ovillos Neurofibrilares/patología , Lóbulo Parietal/patología , Placa Amiloide/metabolismoRESUMEN
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.
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Enfermedad de Alzheimer , Enfermedades de los Gatos , Disfunción Cognitiva , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/veterinaria , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo , Enfermedades de los Gatos/diagnóstico , Enfermedades de los Gatos/terapia , Gatos , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/terapia , Calidad de VidaRESUMEN
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.
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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.
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Envejecimiento , Conducta Animal , Gatos/fisiología , Estrés Fisiológico , AnimalesRESUMEN
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.
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(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.
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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.