Canine Cognitive Dysfunction (CCD) scores correlate with amyloid beta 42 levels in dog brain tissue.
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ABSTRACT:
SUBMITTER: Urfer SR
PROVIDER: S-EPMC8599551 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-?(1-42) and ? protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-?(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-?(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-?(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-?(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with ? burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-?(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between ? protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-? metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.
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Project description:Physical disturbances are common in dogs with canine cognitive dysfunction (CCD). However, the relation between these physical disturbances and CCD has not been clarified. The aim of this study was to clarify the physical disturbances in CCD by questionnaire survey. The questionnaire consisted of items of general information, physical disturbances (gait and posture abnormalities, and deteriorating perception) and a CCD assessment scale named the CCD rating scale (CCDR). The survey was conducted toward owners of dogs aged 10 years or older in two ways: A web-based (Web survey) and a paper-based (Paper survey) survey. To determine which physical disturbances were associated with CCD, ordinal logistic regression analyzes were performed. Through the Web survey, 726 valid responses were obtained, and the test results revealed that vision impairment, smell disturbance, tremor, swaying or falling and head ptosis were significantly associated with CCD. These items, except for head ptosis, were also significantly associated with, or tended to be associated with, CCD in 103 valid responses to the Paper survey. The prevalence of CCD was increased in the elderly dog population, especially in dogs aged 16 years or older. In contrast, physical signs gradually increased from 10 years of age. These results suggest that physical disturbances may appear in the early stages of CCD. In conclusion, the present study revealed new clinical signs of CCD linked to physical disturbances and suggested that these signs could be useful for detecting early stage of CCD.
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Project description:Recent evidence has suggested a role for soluble oligomeric Abeta species in the pathology of Alzheimer's disease (AD). Fibrillar plaque deposits are present in non-demented individuals and levels of soluble Abeta correlate better with cognitive dysfunction in AD and transgenic mouse models. We have previously reported that there are at least two conformationally distinct types of Abeta oligomers: prefibrillar oligomers that are kinetic intermediates in fibril assembly reactions and are specifically recognized by A11 antibody and fibrillar oligomers that may represent fibril seeds or small pieces of fibrils and are recognized by a fibril specific antibody, OC. We have examined the levels of these two types of oligomers in the PBS soluble fraction of brain tissue from control cases, cases with senile degenerative changes (SDC) and AD patients. We found that the levels of soluble fibrillar oligomers detected by OC antibody are significantly elevated in multiple brain regions of AD patients. The elevated fibrillar oligomer levels were found not to be an artifact of tissue homogenization, nor a result of increased Abeta or APP levels. The concentration of fibrillar oligomers in adjacent brain regions of the same patient can vary widely and were not detected in post-mortem cerebrospinal fluid. In contrast, the level of prefibrillar oligomers are variable in both AD and age matched controls, indicating that they are not correlated with cognitive dysfunction and suggesting that they precede dementia in AD. Significant correlations were found between the levels of fibrillar oligomers and cognitive decline (MMSE scores) as well as the neuropathological hallmarks of AD. These results indicate that fibrillar oligomers may play a key role in the pathology of AD and may be a new target for diagnostic and therapeutic development.
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Project description:ObjectiveCognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease.MethodsA total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid β 1-42 (Aβ(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time.ResultsLower baseline CSF Aβ(1-42) was associated with more rapid cognitive decline. Subjects with CSF Aβ(1-42) levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline.ConclusionsReduced CSF Aβ(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.
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Project description:Globally, epilepsy is a common serious brain disorder. In addition to seizure activity, epilepsy is associated with cognitive impairments including static cognitive impairments present at onset, progressive seizure-induced impairments and co-morbid dementia. Epilepsy occurs naturally in domestic dogs but its impact on canine cognition has yet to be studied, despite canine cognitive dysfunction (CCD) recognised as a spontaneous model of dementia. Here we use data from a psychometrically validated tool, the canine cognitive dysfunction rating (CCDR) scale, to compare cognitive dysfunction in dogs diagnosed with idiopathic epilepsy (IE) with controls while accounting for age. An online cross-sectional study resulted in a sample of 4051 dogs, of which n = 286 had been diagnosed with IE. Four factors were significantly associated with a diagnosis of CCD (above the diagnostic cut-off of CCDR ?50): (i) epilepsy diagnosis: dogs with epilepsy were at higher risk; (ii) age: older dogs were at higher risk; (iii) weight: lighter dogs (kg) were at higher risk; (iv) training history: dogs with more exposure to training activities were at lower risk. Impairments in memory were most common in dogs with IE, but progression of impairments was not observed compared to controls. A significant interaction between epilepsy and age was identified, with IE dogs exhibiting a higher risk of CCD at a young age, while control dogs followed the expected pattern of low-risk throughout middle age, with risk increasing exponentially in geriatric years. Within the IE sub-population, dogs with a history of cluster seizures and high seizure frequency had higher CCDR scores. The age of onset, nature and progression of cognitive impairment in the current IE dogs appear divergent from those classically seen in CCD. Longitudinal monitoring of cognitive function from seizure onset is required to further characterise these impairments.
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Project description:Canine cognitive dysfunction (CCD) is common in aged dogs and has many similarities with Alzheimer's disease. Unfortunately, like Alzheimer's disease, CCD cannot be cured. In the present study, we treated dogs with CCD with our newly developed and characterized butyrylcholinesterase inhibitor (BChEi). Seventeen dogs were randomized into two groups (treated with BChEi and untreated) and followed for 6 months at regular check-ups. The dogs' cognitive status was determined by a Canine Dementia Scale (CADES) questionnaire and two cognitive tests. In dogs with moderate cognitive impairment, treatment caused significant improvement in the clinical rating of cognitive abilities and the performance-based tests of cognitive functioning when compared to the untreated group (p < 0.001). Dogs treated with BChEi showed markedly improved cognitive function with enhanced quality of life. No side effects were observed in the treated dogs with moderate cognitive impairment. According to the results of this preliminary study, there is an indication that novel BChEi may be a promising drug for the treatment of CCD in dogs and may be an interesting candidate for the treatment of Alzheimer's disease in humans. However, further clinical studies are needed to confirm this.
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Project description:BackgroundPrevious studies have used immunohistology to demonstrate Alzheimer's disease (AD) characteristic accumulation of amyloid-β (Aβ) in the retina of AD patients, a finding indicating retina examination as a potential diagnostic tool for AD pathology.ObjectiveTo further explore this idea by investigating whether levels of Aβ42 and Aβ40 in retina are associated with corresponding levels in hippocampus, neuropathological assessments, apolipoprotein E (APOE) genotype, and levels of islet amyloid polypeptide (IAPP).MethodsLevels of high molecular weight (HMW) Aβ42, Aβ40, and IAPP in ultra-centrifuged homogenates of retina and hippocampus from patients with AD, multiple sclerosis, AD with Lewy bodies, and non-demented controls were analyzed using Mesoscale Discovery electrochemiluminescence technology employing immunoassay and enzyme-linked immunosorbent assay.ResultsHigher levels of retinal and hippocampal Aβ42-HMW, Aβ40-HMW, and IAPP-HMW were found in individuals with high neuropathological scores of Aβ plaques and in individuals carrying the APOEɛ4 allele. The retinal levels of Aβ42-HMW and Aβ40-HMW correlated with corresponding levels in hippocampus as well as with neurofibrillary tangles (NFT) and Aβ scores. Retinal IAPP-HMW correlated with retinal levels of Aβ42-HMW and with NFT and Aβ scores.ConclusionThese results show that different isoforms of Aβ can be detected in the human retina and moreover support the growing number of studies indicating that AD-related pathological changes occurring in the brain could be reflected in the retina.
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Project description:Amyloid beta (Aβ) plays a major role in the pathogenesis of Alzheimer's disease and, more recently, has been shown to protect against liver fibrosis. Therefore, we studied Aβ-42 levels and the expression of genes involved in the generation, degradation, and transport of Aβ proteins in liver samples from patients at different stages of metabolic dysfunction-associated liver disease (MASLD) and under steatotic conditions in vitro/in vivo. Amyloid precursor protein (APP), key Aβ-metabolizing proteins, and Aβ-42 were analyzed using RT-PCR, Western blotting, Luminex analysis in steatotic in vitro and fatty liver mouse models, and TaqMan qRT-PCR analysis in hepatic samples from patients with MASLD. Hepatocytes loaded with palmitic acid induced APP, presenilin, and neprilysin (NEP) expression, which was reversed by oleic acid. Increased APP and NEP, decreased BACE1, and unchanged Aβ-42 protein levels were found in the steatotic mouse liver compared to the normal liver. Aβ-42 concentrations were low in MASLD samples of patients with moderate to severe fibrosis compared to the livers of patients with mild or no MASLD. Consistent with the reduced Aβ-42 levels, the mRNA expression of proteins involved in APP degradation (ADAM9/10/17, BACE2) and Aβ-42 cleavage (MMP2/7/9, ACE) was increased. In the steatotic liver, the expression of APP- and Aβ-metabolizing proteins is increased, most likely related to oxidative stress, but does not affect hepatic Aβ-42 levels. Consistent with our previous findings, low Aβ-42 levels in patients with liver fibrosis appear to be caused by the reduced production and enhanced non-amyloidogenic processing of APP.
| S-EPMC11354580 | biostudies-literature
Project description:Low CSF ?-amyloid 1-42 has been associated with cognitive decline in advanced Parkinson's disease; data from a single cohort suggest ?-amyloid 1-42 may be an early marker of cognitive impairment. Newly diagnosed Parkinson's participants (mean duration, 6.9 months) in the Parkinson's Progression Markers Initiative (n = 341) were assessed at baseline (untreated state) and followed for 2 years. CSF ?-amyloid 1-42, ?-synuclein, total tau, and tau phosphorylated at threonine 181 were collected at baseline. Participants were classified as having cognitive impairment (CI) if scores on two of six cognitive tests were 1.5 standard deviations below the standardized mean based on published norms in healthy controls. Multivariable regression analyses were used to determine the association between baseline CSF markers with cognitive impairment, defined by neuropsychological testing performance at 2-year follow-up. Fifty-five participants (16.1 %) had CI at baseline and were not included in further analyses. Thirty-seven of the 286 participants without CI at baseline (12.9 %) developed CI at 2 years. Participants with CI at 2 years had significantly lower mean baseline CSF ?-amyloid 1-42 levels than non-CI participants (343.8 vs. 380.4 pg/mL, p < 0.01); no significant difference was seen for ?-synuclein, T-tau, or P-tau 181. In a regression model of 286 participants without baseline CI adjusted for age, gender, disease duration, education, motor severity, and depression status, lower baseline ?-amyloid 1-42 levels were associated with higher odds of CI at 2 years. (OR(10pg/mL) = 1.04, 95 % CI 1.01-1.08, p < 0.05). CSF ?-amyloid 1-42 level at disease onset is an independent predictor of cognitive impairment in early Parkinson's disease.
| S-EPMC4738011 | biostudies-literature