Concomitant Mitral Regurgitation in Severe Aortic Stenosis　- Insights From the CURRENT AS Registry-2.

BACKGROUND: Data on concomitant mitral regurgitation (MR) in patients with severe aortic stenosis (AS) are scarce.Methods and Results: We investigated the risk of concomitant MR in patients with severe AS in the CURRENT AS Registry-2 according to initial treatment strategy (transcatheter aortic valve implantation [TAVI], surgical aortic valve replacement [SAVR], or conservative). Among 3,365 patients with severe AS, 384 (11.4%) had moderate/severe MR (TAVI: n=126/1,148; SAVR: n=68/591; conservative: n=190/1,626). The cumulative 3-year incidence for death or heart failure (HF) hospitalization was significantly higher in the moderate/severe than no/mild MR group in the entire population (54.6% vs. 34.3%, respectively; P<0.001) and for each treatment strategy (TAVI: 45.0% vs. 31.8% [P=0.006]; SAVR: 31.9% vs. 18.7% [P<0.001]; conservative: 67.8% vs. 41.6% [P<0.001]). The higher adjusted risk of moderate/severe MR relative to no/mild MR for death or HF hospitalization was not significant in the entire population (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.95-1.39; P=0.15); however, the risk was significant in the SAVR (HR 1.92; 95% CI 1.04-3.56; P=0.04) and conservative (HR 1.30; 95% CI 1.02-1.67; P=0.04) groups, but not in the TAVI group (HR 1.03; 95% CI 0.70-1.52; P=0.86), despite no significant interaction (Pinteraction=0.37). CONCLUSIONS: Moderate/severe MR was associated with a higher risk for death or HF hospitalization in the initial SAVR and conservative strategies, while the association was less pronounced in the initial TAVI strategy.

In-hospital outcomes after SAVR or TAVI in patients with severe aortic stenosis.

There were no data comparing the in-hospital outcomes after transcatheter aortic valve implantation (TAVI) with those after surgical aortic valve replacement (SAVR) in Japan. Among consecutive patients with severe AS between April 2018 and December 2020 in the CURRENT AS Registry-2, we identified 1714 patients who underwent aortic valve replacement (TAVI group: 1134 patients, and SAVR group: 580 patients). Patients in the TAVI group were much older (84.4 versus 73.6 years, P < 0.001) and more often had comorbidities than those in the SAVR group. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group (0.6% versus 2.2%). After excluding patients with dialysis, in-hospital death rate was very low and comparable in the TAVI and SAVR groups (0.6% versus 0.8%). The rates of major bleeding and new-onset atrial fibrillation during index hospitalization were higher after SAVR than after TAVI (72% versus 20%, and 26% versus 4.6%, respectively), while the rate of pacemaker implantation was higher after TAVI than after SAVR (8.1% versus 2.4%). Regarding the echocardiographic data at discharge, the prevalence of patient-prosthesis mismatch was lower in the TAVI group than in the SAVR group (moderate: 9.0% versus 26%, and severe: 2.6% versus 4.8%). In this real-world data in Japan, TAVI compared with SAVR was chosen in much older patients with more comorbidities with severe AS. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group.

A case of infundibular cyst with neutrophil cannibalism by squamous cells in a dog.

A 6-years and 6-months-old, neutered male mongrel dog had a skin mass between the left eye and nose. Fine needle aspiration biopsy of the mass revealed giant epithelial cells containing many neutrophils in the cytoplasm. The mass was excised and histopathologically diagnosed as an infundibular cyst with giant epithelial-like cells containing neutrophils in part of the lumen. The giant cells were immunopositive for cytokeratin and immunonegative for vimentin. Cell cannibalism is a cell engulfing phenomenon in which a cell incorporates either the same or a different type of cell and the incorporated cells are degenerate or necrotic. In this case, epithelial cells in the lumen of the cyst incorporated neutrophils, which corresponds to neutrophil cannibalism by squamous epithelial cells.

Abdominal Aortic Aneurysm Shrinkage up to 2 Years Following Endovascular Repair with PEmbolization for Preventing Type 2 Endoleak: A Retrospective Single Center Study.

BACKGROUND: The aim of the present study was to evaluate the efficacy of preemptive embolization of aneurysm side branches that cause type 2 endoleak (T2EL). METHODS: We performed a retrospective review of consecutive patients who underwent endovascular aneurysm repair (EVAR) in our facility between April 2009 and April 2019. All the patients underwent the preemptive embolization for preventing T2EL since April 2014. The patients were divided into the nonembolization group (between April 2009 and May 2014) or the embolization group (between April 2014 and April 2019). We used a support wire to improve a success rate of the preemptive embolization. The aneurysm sac shrinkage (≧5 mm), freedom from all-cause death and aneurysm-related death, T2EL-related reinterventions, aneurysm sac enlargement (≧5 mm), and complications related to the endovascular procedure were compared between the 2 groups. RESULTS: Two-hundred patients with abdominal aortic aneurysm were included. They were divided into the nonembolization group (N = 103) and the embolization group (N = 97). We successfully embolized 89% of all the patent aneurysm side branches in the embolization group. The characteristics of the 2 groups were similar except for hypertension, patent lumbar arteries, and the use of Zenith, Excluder, and Endurant. The preemptive embolization group showed better aneurysm sac shrinkage (73% vs. 42%; P < 0.0001), no aneurysm sac enlargement (0% vs. 5%; P < 0.05), and lower T2EL-related reintervention rate (hazard ratio, 0.11; 95% confidence interval, 0.0061-0.60; P < 0.01) up to 2 years after EVAR. There were no significant differences in freedom from all-cause death, aneurysm-related death, and complications between the 2 groups. CONCLUSIONS: The present study showed the high success rate of preemptive embolization of aneurysm side branches resulting in better anatomical changes in the aneurysm sac and lower T2EL-related intervention rate in the embolization group up to 2 years after EVAR.

Tryptophan-tyrosine dipeptide improves tau-related symptoms in tauopathy mice.

Neurodegenerative diseases involving pathological tau protein aggregation are collectively known as tauopathies and include Alzheimer's disease and Pick's disease. Recent studies show that the intake of tryptophan-tyrosine (Trp-Tyr)-related ß-lactopeptides, including ß-lactolin, attenuates cognitive decline in the elderly and prevents the amyloid pathology in mouse models of Alzheimer's disease. However, the effects of Trp-Tyr-related ß-lactopeptides on tau-related pathology have not been investigated. In the present study, we examined the effects of Trp-Tyr dipeptide intake on tauopathy in PS19 transgenic mice, a well-established tauopathy model. Intake of Trp-Tyr dipeptide improved the behavioral deficits observed in the open field test, prevented tau phosphorylation, and increased the dopamine turnover and synaptophysin expression in the frontal cortex. Levels of short-chain fatty acids in the cecum were lower in PS19 mice than those in wild-type mice and were increased by treatment with Trp-Tyr dipeptide. In addition, intake of Trp-Tyr dipeptide extended the lifespan of PS19 mice. These findings suggest that the intake of Trp-Tyr-related peptides improves tauopathy symptoms, resulting in improvements in behavioral deficits and longevity. Hence, the intake of Trp-Tyr-related peptides, including ß-lactolin, may be beneficial for preventing dementia.

Hamster polyomavirus-associated T-cell lymphomas in Syrian hamsters (Mesocricetus auratus).

Hamster polyomavirus (HaPyV) infection has been associated with lymphomas in Syrian hamsters. In the present study, 14 cases of lymphoma in pet Syrian hamsters were pathologically examined and the involvement of HaPyV was investigated. Among 14 cases, 11 were abdominal and 3 were cutaneous lymphomas. The average ages of hamsters with abdominal lymphoma and cutaneous lymphoma were 7 months (range: 4-12 months) and 14 months (range: 6-23 months), respectively. Histologically, abdominal lymphomas were characterized by the diffuse growth of tumor cells with intermediate or large nuclei, low mitotic rates, the presence of tingible body macrophages, and the T-cell immunophenotype. Furthermore, 4/11 abdominal lymphomas were immunopositive for T-cell intracellular antigen-1, suggesting cytotoxic T-cell lymphomas. Cutaneous lymphomas were diagnosed as nonepitheliotropic T-cell lymphoma. Polymerase chain reaction (PCR) detected HaPyV DNA in 12/14 samples, and a sequence analysis of PCR amplicons confirmed >99% nucleotide identity to the published HaPyV sequences. In situ hybridization (ISH) for HaPyV DNA resulted in diffuse nuclear signals within tumor cells in 10/14 cases. Consistent with previous findings, all HaPyV-associated lymphomas were observed in the abdominal cavity of young hamsters. Polymerase chain reaction and ISH were useful for identifying the involvement of HaPyV in lymphomas, and ISH results indicated the presence of episomal HaPyV in neoplastic lymphocytes. The present study suggests that HaPyV infection is highly involved in abdominal lymphomas in young pet Syrian hamsters in Japan and provides diagnostic information on HaPyV-associated lymphoma.

Genomic integration and expression of Felis catus papillomavirus type 2 oncogenes in feline Merkel cell carcinoma.

The involvement of Felis catus papillomavirus type 2 (FcaPV2) in feline Merkel cell carcinoma (MCC) has been previously hypothesized. In this study, the expression and localization of FcaPV2 oncogene mRNA, the integration of FcaPV2 genes, and p53 mutations in feline MCC were examined by RNAscope in situ hybridization (ISH), whole genome sequencing (WGS), and Sanger DNA sequencing, respectively. Furthermore, the morphological and molecular characteristics of FcaPV2-positive (FMX-MCC01) and FcaPV2-negative (AS-MCC01) MCC cell lines were compared in vitro and in vivo using immunofluorescence, ISH, xenotransplantation into mice, and immunohistochemistry. ISH for FcaPV2 E6/E7 detected viral RNA in 18/21 FcaPV2-positive MCC and not in 1/1 FcaPV2-negative MCC. WGS of 2 FcaPV2-positive cases revealed the integration of FcaPV2 genes in both cases. In cultured cells and xenograft tissues of FMX-MCC01, most cells were positive for E6/E7 by ISH and p16CDKN2A, a few cells were positive for the retinoblastoma protein (pRb), and all cells were negative for p53. In cultured cells and xenograft tissues of AS-MCC01, all cells were negative for p16CDKN2A, most cells were positive for pRb, and some cells were positive for p53. Missense mutations in p53 were identified in 8/10 FcaPV2-positive and 1/1 FcaPV2-negative MCC. These results suggest that the expression of integrated FcaPV2 oncogenes might be associated with reduced expression of the tumor suppressor proteins pRb and p53 and might contribute to the development of feline MCC. On the other hand, p53 mutations may be involved in both FcaPV2-positive and FcaPV2-negative MCC tumorigenesis.

Chronological transition of necropsy cases of animals in Tokyo, Japan.

There is no nationwide necropsy database of animals in Japan, and most of the records are available from the postwar period. To clarify the chronological transition of animal necropsy cases in Tokyo, Japan, the records accumulated in The University of Tokyo from 1902 were investigated. Of necropsy records on paper or electronic from 1902 to 2021 kept at the Laboratory of Veterinary Pathology, The University of Tokyo, totally 3,137 cases including 572 in 1903-1914 (the Meiji-Taisho period), 1,258 in 1956-1969 (the Showa period) and 1,307 in 2006-2020 (the Heisei-Reiwa period), respectively, were examined for species, breed, age and pathological diagnosis. Dogs (44.6%) and horses (34.8%) in the Meiji-Taisho period, dogs (62.9%) and cats (17.3%) in the Showa period, and dogs (46.0%), cats (26.1%) and exotic animals (20.5%) in the Heisei-Reiwa period were the most necropsied animal species. With the passage of time, the number of animal species increased, and the breeds of dogs and cats came to be more various. The median ages of death were 2 years, 3 years and 10 years old in dogs in the Meiji-Taisho, Showa and Heisei-Reiwa periods, respectively, and 2 years and 10 years old in cats in the Showa and Heisei-Reiwa periods, respectively. Viral, bacterial and parasitic infections were decreased, and inversely tumor cases increased due to the prolonged lifespan.

Developing Multidisciplinary Management of Heart Failure in the Super-Aging Society of Japan.

The Japanese population is rapidly aging because of its long life expectancy and low birth rate; additionally, the number of patients with heart failure (HF) is increasing to the extent that HF is now considered a pandemic. According to a recent HF registry study, Japanese patients with HF have both medical and care-related problems. Although hospitalization is used to provide medical services, and institutionalization is used to provide care for frail older adults, it can be difficult to distinguish between them. In this context, multidisciplinary management of HF has become increasingly important in preventing hospital readmissions and maintaining a patient's quality of life. Academia has promoted an increase in the number of certified HF nurses and educators. Researchers have issued numerous guidelines or statements on topics such as cardiac rehabilitation, nutrition, and palliative care, in addition to the diagnosis and treatment of acute and chronic HF. Moreover, the Japanese government has created incentives through various medical and long-term care systems adjustments to increase collaboration between these two fields. This review summarizes current epidemiological registries that focus not only on medical but also care-related problems and the 10 years of multidisciplinary management experience in Japanese medical and long-term care systems.

Exercise echocardiography for a differential diagnosis in a patient with radiation-induced heart disease: A case report.

Advances in radiation therapy (RT) have dramatically improved the survival rates of patients with cancer, but radiation-induced heart disease (RIHD) has become an emerging problem, which is complex and multifaceted.A 65-year-old man with a medical history of chemoradiotherapy for esophageal cancer, who had multiple admissions for acute heart failure (AHF), was readmitted to our hospital. Transthoracic echocardiography at rest revealed left ventricular diastolic dysfunction, moderate aortic stenosis with mild aortic regurgitation, and mild mitral regurgitation (MR). A diagnosis of RIHD was obtained, however, the main cause of the AHF was not clearly understood. Exercise echocardiography (ExE) revealed an exacerbation of the MR and exercise-induced pulmonary hypertension (EIPH), and the severe dynamic MR was considered to be the main cause of the AHF. A transcatheter edge-to-edge repair (TEER) with a MitraClip (Abbott Vascular, Menlo Park, CA, USA) was performed, and the post-procedural ExE showed the mitigation of the dynamic MR and EIPH. He had no further heart failure admissions for more than one year.Our case showed that ExE may be useful in the management of patients with RIHD, and a TEER with a MitraClip may be an effective treatment for RT-related dynamic MR. Learning objective: Radiation therapy (RT) has improved the survival rates of patients with cancer, but which involves radiation-induced heart disease (RIHD). RIHD is complex and multifaceted, and RT-related valvular disease may be underestimated with transthoracic echocardiography at rest alone. Then exercise echocardiography may be useful in the management. It is important to perform an individualized approach including medical therapy, surgery, and percutaneous intervention by a heart team.

Rationale, Design, and Baseline Characteristics of the CURRENT AS Registry-2.

BACKGROUND: There is scarce data evaluating the current practice pattern and clinical outcomes for patients with severe aortic stenosis (AS), including both those who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) and those who were managed conservatively in the TAVI era.Methods and Results: The Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis (CURRENT AS) Registry-2 is a prospective, physician-initiated, multicenter registry enrolling consecutive patients who were diagnosed with severe AS between April 2018 and December 2020 among 21 centers in Japan. The rationale for the prospective enrollment was to standardize the assessment of symptomatic status, echocardiographic evaluation, and other recommended diagnostic examinations such as computed tomography and measurement of B-type natriuretic peptide. Moreover, the schedule of clinical and echocardiographic follow up was prospectively defined and strongly recommended for patients who were managed conservatively. The entire study population consisted of 3,394 patients (mean age: 81.6 years and women: 60%). Etiology of AS was degenerative in 90% of patients. AS-related symptoms were present in 60% of patients; these were most often heart failure symptoms. The prevalence of high- and low-gradient AS was 58% and 42%, respectively, with classical and paradoxical low-flow low-gradient AS in 4.6% and 6.7%, respectively. CONCLUSIONS: The CURRENT AS Registry-2 might be large and meticulous enough to determine the appropriate timing of intervention for patients with severe AS in contemporary clinical practice.

mRNA sequencing analysis and growth inhibitory effects of palbociclib on cell lines from canine histiocytic proliferative disorders.

Canine histiocytic proliferative disorders include aggressive and fatal diseases, such as histiocytic sarcoma (HS) and histiocytosis (SyH). The molecular mechanisms underlying cell proliferation need to be elucidated for the development of effective treatments. In the present study, mRNA expression levels were comprehensively analysed in cell lines derived from localized HS, disseminated HS, SyH and Langerhans cell histiocytosis (LCH) in dogs. Based on the results obtained, the growth inhibitory effects of palbociclib, a CDK4/6 inhibitor, were verified with the cell lines in vitro and in xenograft mouse model. Hierarchical clustering and principal component analysis plots of mRNA expression profiles divided the cell lines into three groups: a localized HS group, disseminated HS/SyH group, and LCH. The results of an ingenuity pathway analysis suggested that the MAPK signalling pathway was activated in the localized HS and LCH cell lines, and the PI3K signalling pathway in the disseminated and localized HS cell lines. In all cell lines, the expression of the tumour suppressor genes TP53, CDKN2A and CDKN1A was down-regulated, whereas that of Rb was preserved. In vitro assessments revealed the growth inhibitory effects of palbociclib in all cell lines examined. In a xenograft mouse model using a cell line from disseminated HS, palbociclib exerted significant growth inhibitory effects. These results suggest the potential of palbociclib as a therapeutic drug candidate for the treatment of malignant histiocytic proliferative disorders of the dog.

Adult-Onset Focal Nesidioblastosis With Nodular Formation Mimicking Insulinoma.

Nesidioblastosis is defined as the neoformation of the islets of Langerhans from the pancreatic ductal epithelium and is recognized as the most common cause of hyperinsulinemic hypoglycemia in infants. We herein report an extremely rare case of adult-onset focal nesidioblastosis with the unusual feature of hyperplastic nodular formation. A 55-year-old woman was admitted to our hospital for a tumor detected in the body of the pancreas by magnetic resonance imaging screening. Laboratory examinations showed a high insulin level in the blood. Contrast-enhanced computed tomography and the selective arterial calcium injection test suggested the presence of multiple insulinomas in the body and tail of the pancreas, and, thus, the patient underwent distal pancreatectomy. A histopathological examination of the tumor in the body of the pancreas showed the nodular hyperplasia of islet-like cell clusters. In addition, many small intralobular ductules and islet cells appeared to be budding from the proliferating ductal epithelium, forming "ductuloinsular complexes". No other abnormal lesion was detected in the remainder of the pancreas. The histopathological diagnosis was focal nesidioblastosis. The patient has remained free of the recurrence of hypoglycemic episodes for more than 31 months. The present case of rare adult-onset focal nesidioblastosis with hyperplastic nodular formation was preoperatively identified as an apparent pancreatic tumor mimicking insulinoma. Nesidioblastosis and insulinoma need to be considered in cases of hyperinsulinemic hypoglycemia, even in adult patients.

Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload.

Heart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.

Involvement of Felis catus papillomavirus type 2 in the tumorigenesis of feline Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine tumor. We recently demonstrated that cats with MCC often have other proliferative cutaneous lesions, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Based on this finding, we hypothesize that Felis catus papillomavirus (FcaPV) is involved in the development of MCC in cats, similar to SCC and BCC. To investigate this hypothesis, the presence of FcaPV nucleic acid and immunoreactivity for tumor suppressor proteins were examined in 21 feline MCC cases. Polymerase chain reaction using FcaPV type-specific primers detected FcaPV2 DNA in 20/21 samples of MCC. The complete FcaPV2 sequence was characterized in one case. In situ hybridization for FcaPV2 E7 revealed punctate nuclear signals within tumor cells in 19/21 MCC. Increased immunoreactivity for p16CDKN2A protein and decreased immunoreactivity for retinoblastoma (pRb) and p53 proteins were observed in 20/21 MCC. These results suggest that feline MCC cases are infected with FcaPV2 and the subsequent inhibition of pRb and p53 induced by integrated viral oncogenes is associated with feline MCC tumorigenesis, similar to other PV-induced proliferative cutaneous lesions. On the other hand, the single case of FcaPV2-negative MCC showed strong p53 immunoreactivity, suggesting mutations in p53 caused by cancer inducers other than FcaPV2 infection in this case. The present study suggests FcaPV2 as a cause of feline MCC.

Establishment and characterisation of cell lines and xenograft mouse models of canine systemic histiocytosis and disseminated histiocytic sarcoma.

Canine histiocytic proliferative disorders include reactive diseases (histiocytosis) and neoplastic diseases (histiocytic sarcoma [HS]), however discrimination is challenging due to their overlapping pathological features. In the present study, novel cell lines and xenograft mouse models of systemic histiocytosis (SyH) and disseminated HS were established, and examined together with cell lines previously established from localized HS and Langerhans cell histiocytosis (LCH). The chromosomal numbers of the SyH and HS cell lines were abnormal, and their population doubling time and morphological features were comparable. Immunophenotypically, SyH and HS cells were CD204+/E-cadherin+ in vitro and in vivo, like their original tissues. Western blot analysis for E-cadherin revealed an immunopositive band of full-length E-cadherin (120 kDa) in cultured cells of localized HS and LCH but not in disseminated HS and SyH; expression level was weaker in localized HS than in LCH. An immunopositive band of fragmented E-cadherin (45 kDa) was detected in cell lines of disseminated HS and SyH. These results suggest that cultured SyH cells have features that are similar to disseminated HS, including chromosomal aberration, high proliferation activity, weak cell adhesion, and expression of fragmented E-cadherin. Fragmentation of the E-cadherin cell adhesion molecule may be associated with the loss of cell adhesion and increased abilities of invasion and migration of neoplastic cells. The established cell lines and xenograft mouse models will aid in understanding the pathogenesis and developing novel treatments of canine histiocytic proliferative disorders.

Histological and immunohistochemical features of cutaneous mast cell tumor in six captive four-toed hedgehogs (Atelerix albiventris).

This report described the histopathological and immunohistochemical features of cutaneous mast cell tumor (MCT) in six hedgehogs. The hedgehogs presented single cutaneous mass with ulcer and crusting. Histologically, the neoplastic lesions were characterized by the proliferation of well-differentiated mast cells (3 cases), and atypical mast cells (3 cases) with one atypical histiocytic morphology. Immunohistochemically, tumor cells were positive for KIT and mast cell tryptase, and were negative for Iba-1. In well-differentiated MCT, all patients were clinically improved and survived more than 365 days after surgical excision, whereas an atypical histiocytic MCT showed aggressive behavior with re-recurrence, and the animal died 115 days after surgery. These findings suggest that, compatible with other animals, well-differentiated MCT has a better prognosis in hedgehogs.

Neuronal Deposition of Amyloid-ß Oligomers and Hyperphosphorylated Tau Is Closely Connected with Cognitive Dysfunction in Aged Dogs.

BACKGROUND: Canine cognitive dysfunction (CCD) is a progressive syndrome recognized in mature to aged dogs with a variety of neuropathological changes similar to human Alzheimer's disease (AD), for which it is thought to be a good natural model. However, the presence of hyperphosphorylated tau protein (p-Tau) in dogs with CCD has only been demonstrated infrequently. OBJECTIVE: The aim of the present study was to investigate the presence of p-Tau and amyloid-ß oligomer (Aßo) in cerebral cortex and hippocampus of dogs with CCD, with focus on an epitope retrieval protocol to unmask p-Tau. METHODS: Immunohistochemical and immunofluorescence analysis of the cortical and hippocampal regions of five CCD-affected and two nondemented aged dogs using 4G8 anti-Aßp, anti-Aß1 - 42 nanobody (PrioAD13) and AT8 anti-p-Tau (Ser202, Thr205) antibody were used to demonstrate the presence of Aß plaques (Aßp) and Aß1 - 42 oligomers and p-Tau deposits, respectively. RESULTS: The extracellular Aß senile plaques were of the diffuse type which lack the dense core normally seen in human AD. While p-Tau deposits displayed a widespread pattern and closely resembled the typical human neuropathology, they did not co-localize with the Aßp. Of considerable interest, however, widespread intraneuronal deposition of Aß1 - 42 oligomers were exhibited in the frontal cortex and hippocampal region that co-localized with p-Tau. CONCLUSION: Taken together, these findings reveal further shared neuropathologic features of AD and CCD, supporting the case that aged dogs afflicted with CCD offer a relevant model for investigating human AD.