Plaques In Cerebral Cortex Research Articles

Systematic Review on Pathology and Drug Efficacy Clinical Trials (1973-2023) for Cognitive Impairment and Alzheimer’s Dementia

Rationale: The systematic review evaluates the results of last fifty years (1973-2023) of clinical trials on pathology and treatment for cognitive impairment including Alzheimer’s dementia (AD dementia). Objectives: Alzheimer’s dementia is a growing public health concern worldwide. The systematic review analyzes the disease confirming pathological findings presented by modern imaging techniques MRI/ PET. In addition, we analyze the success of fifty years of therapeutic advancements of the neurological disabilities and count on the safe drugs to treat clinical conditions of AD dementia. Findings: We followed the PRISMA guidelines to determine the inclusion and exclusion criteria for the selection of clinical records collected from the NCBI databases. We analyzed the drug efficacy results on the three aspects of the AD brain: (a) morphological deformation of the choroid plexus and hippocampus; (b) senile plaques with amyloid beta42 (Abeta42) including hyperintensities of neurons; and (c) inhibitory action of acetylcholinesterase enzyme. The pathological findings include detection of Abeta42 plaques in cerebral cortex and retention ability of trial drugs in cerebrospinal fluid versus blood plasma of AD patients in the context of disease progression and treatment efficacy. The clinical trial records demonstrated evidence of genetic susceptibility factor(s) clustered in European populations. The susceptibility is also found due to mutations in the presenilin-1 gene and expression of the ApoEε-allele among the population. The clinical records demonstrate moderate efficacy of cholinesterase inhibitors Donepezil and Rivastigmine in improving cognition. The antibodies aducanumab, donanemab, and lecanemab show low to moderate success in removing plaques and reducing plasma Abeta burden. Conclusion: The cholinesterase inhibitors demonstrate moderate success in improving cognition. However, the overall efficacy of antibody treatment was poor. The findings suggest a need for new generation drugs which can clear plaques and improve cognition for AD.

Evaluation of anti-Alzheimer activity of Echinacea purpurea extracts in aluminum chloride-induced neurotoxicity in rat model

Alzheimer's disease (AD) is one of the neurodegenerative illnesses that impair individual life & increase the demand for caregivers with no available curative medication right now. Therefore, there is a growing concern about employing herbal medicine to limit AD progression & improve patients' life quality, thus potentiating its add-on therapy. In addition, herbs are cost-effective & accessible with nearly no side effects. In the same vein, our study aimed to investigate the potency of Echinacea purpurea (EP) flower extracts to ameliorate the neurodegenerative effect of Aluminum chloride (AlCl3) in a rat model. Moreover, mechanistic studies, including impact on the cholinesterase activity, redox status, inflammatory mediators, behavior performance, glucose level & histopathology, were carried on. Our results showed that 250 mg/kg of Aqueous (AQ) & Alcoholic (AL) extracts of EP inhibited cholinesterase, restored oxidative balance, down-regulated IL-6 & TNF-α cytokines & improved behavior performance in vivo that was reflected in the brain picture by decreasing neuronal degeneration & amyloid plaques in cerebral cortex & hippocampus. The potency of both extracts was compared to reference drugs & AlCl3 positive control group. The AQ extract showed greater potency against COX-1, COX-2 & α-amylase in vitro, while the AL extract was more potent against cholinesterase in vitro, inflammatory cytokines, behavior & pathological improvement in vivo. Conclusively EP overcame AlCl3-induced neurobehavioral toxicity in the rat model via different pathways, which support its regular administration to postpone progressive neural damage in AD patients.

Protective function of electroacupuncture on young mouse model of Alzheimer's disease and proteomic study

To screen protein target in prevention and treatment with electroacupuncture (EA) for Alzheimer's disease (AD) and explore the potential mechanism of EA in prevention of AD. A total of 40 APP/PS1 transgenic young male mice, 1.5-month old, were randomized into an EA group and a model group, 20 mice in each one, and 20 C57BL/6J mice were chosen as the normal control group. After adaptive housing for 1 week, the mice in the EA group were stimulated with EA at "Baihui" (GV 20), "Fengfu" (GV 16) and "Shenshu" (BL 23), with intermittent wave, 10 Hz in frequency and 2 mA in electric intensity. EA was given once daily, 20 min each time. There was 1 day at interval after EA for 6 days each week. Totally, the intervention lasted for 16 weeks. On day 3 after the end of EA intervention, Morris water maze test was adopted to detect learning and memory abilities of mice in each group. After water maze test, the label-free method was used to measure the difference expressions in cerebral cortex and hippocampus. Using Western blot method, the expressions of guanylate binding protein beta 5 (GNB 5) and histone-H 3 in cerebral cortex and hippocampus were verified. Using immunohistochemical method, the expressions of amyloid beta protein (Aβ) in cerebral cortex and hippocampus were detected. Compared with the normal control group, the escape latency (on day 2, 3 and 4) was prolonged, the frequency of crossing platform and the duration of platform stay were decreased in the mice of the model group (P<0.05). Compared with the model group, the escape latency (on day 3 and 4) was shortened, the frequency of crossing platform and the duration of platform stay were increased in the mice of the EA group (P<0.05). By the comparison among the three groups, the high mobility group nucleosome-binding domain-containing protein 5, band 3 anion transport protein, histone-H 3, epoxide hydrolase 4 (fragment), neurolysin (mitochondria), phosphoglycerate mutase 2, GNB5 and Aβ were the differential proteins with the larger fold-change difference in expression. Compared with the normal control group, the expression of histone-H 3 in cerebral cortex and hippocampus was reduced (P<0.001) and the expressions of GNB 5 and Aβ were increased (P<0.001, P<0.01) in the mice of the model group. Compared with the model group, the expression of histone-H 3 in cerebral cortex and hippocampus was increased (P<0.001) and the expressions of GNB 5 and Aβwere reduced (P<0.001, P<0.05) in the mice of the EA group. The intervention with EA effectively prevents from the decline of learning and memory ability and the formation of Aβ senile plaques in cerebral cortex and hippocampus in young mouse models of AD after growing up. Besides, EA plays a regulatory function for protein expression differences induced by AD model.

Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration

The accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer's disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo.

Receptor-Mediated Abeta Amyloid Antibody Targeting to Alzheimer’s Disease Mouse Brain

The goal of this work is the reduction in the Abeta amyloid peptide burden in brain of Alzheimer's disease (AD) transgenic mice without the concomitant elevation in plasma Abeta amyloid peptide. An anti-Abeta amyloid antibody (AAA) was re-engineered as a fusion protein with a blood-brain barrier (BBB) molecular Trojan horse. The AAA was engineered as a single chain Fv (ScFv) antibody, and the ScFv was fused to the heavy chain of a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), and this fusion protein was designated cTfRMAb-ScFv. The cTfRMAb-ScFv protein penetrates mouse brain from blood via transport on the BBB TfR, and the brain uptake is 3.5% of injected dose/gram brain following an intravenous administration. Double transgenic APPswe,PSEN1dE9 mice were studied at 12 months of age. The mice were shown to have extensive Abeta amyloid plaques in cerebral cortex based on immunocytochemistry. The mice were treated every 3-4 days by intravenous injections of either saline or the cTfRMAb-ScFv fusion protein at an injection dose of 1 mg/kg for 12 consecutive weeks. The brain Aβ¹⁻⁴² concentration was reduced 40% in the fusion protein treated mice, without any elevation in plasma Aβ¹⁻⁴² concentration. No cerebral microhemorrhage was observed in the treated mice. These results show that brain-penetrating antibody pharmaceutics can be developed for brain disorders such as AD following the re-engineering of the antibody as a fusion protein that is transported across the BBB via receptor-mediated transport.

Neuropathology in Parkinson’s disease with mild cognitive impairment

In a recent paper, Adler et al. [1] reported the neuropathologic findings in eight cases of Parkinson disease with mild cognitive impairment (PD-MC) (6 males, 2 females, mean age 82.8 years, mean PD duration 11.4 years). Four patients each had amnestic MCI memory only, three non-amnestic MCI with frontal executive and one with frontal executive and visuospatial dysfunctions. Using the Unified Lewy Body Staging System (ULBSS [2]), three cases each were brainstem-predominant (stage IIa), and brainstem–limbic predominant (stage III), and two neocortical LB stage (stage IV), while two PD cases with non-amnestic and one with amnestic MCI showed additional multiple brain infarcts. These data suggested a heterogenous neuropathology of PD-MCI, as found in Parkinson disease dementia (PDD). Unfortunately, no assessment of diffuse (amyloid) plaques and cerebral amyloid angiopathy (CAA) was performed, the impact of which on cognitive dysfunction in Lewy body diseases (LBDs) has been shown [7, 8]. Among 233 autopsy-confirmed cases of LBDs in the years 1989–2007 (54.6% cognitively unimpaired, 42% PDD), we found eight cases (3.4%) with PD-MCI (4 females and males each, mean age 76.6 years, mean duration of PD 13.4 years; mini-mental examination scores/ MMSE, 6–4 months prior to death 26–29). Demographic and morphologic findings are summarized in Table 1. Using current definitions of MCI in PD [5], four patients had been diagnosed with amnestic MCI memory only, three with non-amnestic MCI with frontal dysexecution, and one MCI involving multiple domains. Neuropathology revealed two cases in brainstem-predominant stage (Braak et al. [3, 4], ULBSS 2a [2]), five cases in brainstem–limbic predominant stage (Braak et al. [4], ULBSS 3), and one in neocortical LB stage (Braak et al. [5], ULBSS 4). Neuritic Braak stages ranged from I to III (mean 1.3); a few neuritic plaques in cerebral cortex (neocortex and limbic areas) were observed in only two cases (amnestic–memory predominant MCI and MCI multidomains). The severity of amyloid plaques in cerebral cortex, using a five-grading system [6, 7] ranged from 0 to 3? (mean 1.1), involving three cases. No diffuse amyloid plaques were observed in the basal ganglia. Mild to moderate generalized CAA in the meninges was observed in two brains (amnestic and multiple domain MCI, one each). In the case of MCI involving multiple domains, there was a correlation between the intensity of amyloid and neuritic plaques and meningeal CAA, while the other case showed some relations between amyloid plaque load and CAA confirming the suggestion that both amyloid plaque load and CAA may contribute to cognitive impairment in Lewy body disease or PD [7]. Mild lacunar state in striatum or thalamus was detected in three cases (one each with amnestic, non-amnestic, and multiple domains MCI), both without correlation to Lewy body or Alzheimer pathology stages, confirming the absence of correlations between cerebrovascular lesions and the other pathologic or clinical findings in PD [6]. The presently available scarce data in PD-MCI suggest a heterogenous neuropathology simular to those found in MCI cases without PD [9, 11–14], except the scarcity of cerebrovascular pathology and white matter lesions (data not shown) in the present series. MCI stages and their neuropathologic correlations in dementia with Lewy bodies (MCI-DLB [10]), to the best of our knowledge, have not been defined so far. The findings of these two small clinicopathologic cohorts of PD-MCI implicate the necessity for further prospective studies in well documented PD cases with MCI. K. A. Jellinger (&) Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria e-mail: kurt.jellinger@univie.ac.at

Spatial learning and exploration of environmental stimuli in 24-month-old female APP23 transgenic mice with the Swedish mutation

Transgenic mice overexpressing the βAPP gene with the Swedish mutation under the control of the murine thy1 promoter show Alzheimer-like characteristics such as Aβ plaques in cerebral cortex and vessel walls. By comparison to age-matched non-transgenic controls, 2-year-old female APP23 transgenic mice crossed more segments in the open-field and had a higher number of fast ambulatory and stereotyped movements in a photocell activity chamber. In addition, APP23 mice entered more often and spent more time in the open arms of the elevated plus-maze. The acquisition of place learning in the Morris water maze was impaired in APP23 transgenic mice, but not in probe and visible platform subtasks. These results indicate that hyperactivity and impaired learning abilities characterize this mouse model of Alzheimer's disease and cerebral angiopathy.

Dementia-parkinsonism syndrome with numerous lewy bodies and senile plaques in cerebral cortex

Five cases of age range 62-72 years with progressive dementia and muscular rigidity are reported and discussed from the clinicopathologic point of view. The neuropathology of these cases was characterized by the widespread occurrence of Lewy bodies (LB) in the CNS as well as the presence of senile changes. The presence of numerous LB in the cerebral cortex and basal ganglia was especially characteristic, although their distribution pattern in the diencephalon and brain stem was identical to that found in paralysis agitans. On the other hand, the presence of senile changes in the cerebral cortex was almost identical to the neuropathology of senile dementia or Alzheimer's disease. Nosologically, the present cases may represent either a combination of atypical paralysis agitans with senile dementia and Alzheimer's disease, or a new disease.