Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood-brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aß) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE-Aß interaction inhibitors produced positive results in transgenic AD mouse models.

Cerebrovascular disease in suspected non-Alzheimer's pathophysiology and cognitive decline over time.

BACKGROUND: The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid-beta (A), designated as Suspected non-Alzheimer's pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A-N- and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients. METHODS: A total of 216 individuals from a prospective memory clinic cohort (mean [SD] age, 72.7 [7.3] years, 100 women [56.5%]) were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5 years. Carbon 11-labeled Pittsburgh Compound B ([11 C]-PiB) or [18 F]-flutafuranol-positron emission spectrometry imaging was performed to ascertain amyloid-beta status. Magnetic resonance imaging was performed to assess neurodegeneration as measured by medial temporal atrophy ≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count ≥1, Fazekas score ≥2, lacune count ≥2 or cerebral microbleed count ≥2. RESULTS: Of the 216 individuals, 50 (23.1%) A-N+ were (SNAP), 93 (43.1%) A-N-, 36 (16.7%) A+N- and 37 (17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A-N-. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A-N- over 5 years (p = 0.042). CONCLUSIONS: These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP individuals should be carefully assessed and treated for CeVD.

Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology.

BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. METHODS: Individuals were classified based on CSF amyloid beta (Aß)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.

Comparison of the decreases in regional cerebral blood flow in the posterior cingulate cortex, precuneus, and parietal lobe between suspected non-Alzheimer's disease pathophysiology and Alzheimer's disease.

BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) shows Alzheimer's disease (AD)-like neurodegeneration; however, amyloid ß, which is a biological marker in AD, remains within normal levels. Since the effectiveness of anti-dementia drugs for AD on SNAP is unknown, it is important to distinguish between patients with SNAP and AD. We aimed to compare decreases in regional cerebral blood flow (rCBF) of the posterior cingulate cortex (PCC), precuneus, and parietal lobe critical to AD between SNAP and AD groups using the easy Z-score imaging system in single-photon emission computed tomography (eZIS-SPECT). METHODS: We retrospectively analysed eZIS-SPECT data of 13 SNAP and 24 AD patients. The three indicators (severity, extent, and ratio) that distinguished AD patients from healthy controls in previous studies were automatically calculated and were compared between the SNAP and AD groups. Receiver operating characteristic curve analysis and the area under the curve (AUC) were used to evaluate the diagnostic performance of the three indicators of eZIS in discriminating between the two groups. RESULTS: The mean values of severity, extent, and ratio were significantly lower in the SNAP group than in the AD group (P = 0.024, P = 0.044, and P = 0.045, respectively). The AUC values for severity, extent, and ratio were 0.668, 0.683, and 0.692, respectively. CONCLUSIONS: The present study suggests that SNAP shows milder reduction of rCBF in the PCC, precuneus, and parietal lobe as compared to AD. However, it may be difficult to distinguish between SNAP and AD with the degrees of decrease in rCBF in these regions.

Relation of reproductive disturbance in sheep and Leptospira interrogans serovar Icterohaemorrhagiae infection: Impacts on cellular oxidation status.

This study evaluated the seropositivity of Brucella abortus and Leptospira interrogans in ewes with reproductive disturbances in southern Brazil and verified the creatine kinase (CK) activity and oxidation status via assessment of superoxide dismutase, glutathione peroxidase and glutathione transferase in serum of seropositive animals for L. interrogans serovar Icterohaemorrhagiae. For Leptospira infection 381 animals with clinical history of reproductive disturbance from Planalto Serrano de Santa Catarina (Brazil) were analyzed, showing an occurrence for L. interrogans of 20.2% from which 81.8% were seropositive for L. interrogans Icterohaemorrhagiae. Serovars Wolfii, Grippothyphosa, Bratislava, Canicola and Butembo were also identified. In the case of B. abortus, positive cases were identified by buffered acidified antigen, finding 14 positive samples, but none of them were positive after a second test (2-mercaptoethanol), showing the absence of relationship between infection with B. abortus and abortion in the tested individuals. Serum reactive oxygen species (ROS) levels and CK activity were found higher in animals positive for Leptospira infection, presenting higher titrations (1:320) than non-infected individuals. Serum glutathione peroxidase activity was higher in positive animals with titrations 1:160 and 1:320, while serum glutathione S-transferase was higher in positive individuals only for titrations 1:320. Serum superoxide dismutase showed lower activity in infected animals with titrations of 1:320. Our results show the region of Planalto Serrano de Santa Catarina with a high occurrence levels of sheep infected by L. interrogans serovar Icterohaemorrhagiae, from which animals with high titrations (1:320) present oxidative stress elicited by excessive ROS production, triggering the stimulation of antioxidant systems to counter this excess. In summary, ovine with higher titrations (1:320) present oxidative damage that can contribute to disease pathophysiology.

Oxidative stress and antioxidant responses in Nile tilapia Oreochromis niloticus experimentally infected by Providencia rettgeri.

Bacterial diseases are one of the major problems in freshwater fish culture and have been linked to significant losses and high mortality rate. In this study, Nile tilapia Oreochromis niloticus was infected by Providencia rettgeri to evaluate the oxidative stress and antioxidant responses in the fish tissues. Juvenile Nile tilapia was divided into two groups, as follow: control (uninfected) and experimentally infected with 100 µL of P. rettgeri suspension containing 2.4 × 107 viable cells/fish, and the liver and kidney tissues were collected on days 7 and 14 post-infection (PI). Liver and kidney ROS and lipid peroxidation levels were high in infected fish on day 14 PI compared to control group, while superoxide dismutase activity was lower in liver (days 7 and 14 PI) and kidney (day 14 PI) compared to their respective control groups. Liver and kidney antioxidant capacity against peroxyl radicals, non-proteic, and proteic thiols levels was lower in infected tilapia on day 14 PI compared to control group. Based on these results, P. rettgeri infection may elicit oxidative damage via increased ROS production, decreased ROS elimination and inhibits enzymatic and non-enzymatic antioxidant defense systems; which may contribute directly to disease pathophysiology of infected animals.

Postmortem Findings in Patient with Guillain-Barré Syndrome and Zika Virus Infection.

Postmortem examination results of a patient with Guillain-Barré syndrome and confirmed Zika virus infection revealed demyelination of the sciatic and cranial IV nerves, providing evidence of the acute demyelinating inflammatory polyneuropathy Guillain-Barré syndrome variant. Lack of evidence of Zika virus in nervous tissue suggests that pathophysiology was antibody mediated without neurotropism.

The disturbance of antioxidant/oxidant balance in fish experimentally infected by Aeromonas caviae: Relationship with disease pathophysiology.

Aeromonas caviae is a Gram-negative bacterium rarely found in fish but it can be associated to high mortality of infected animals. The disease pathogenesis in fish associated to liver and kidney lesions directly linked to the initiation and progression of the disease remains poorly understood. Thus, the aim of this study was to evaluate whether A. caviae infection causes oxidative stress in liver and kidney of silver catfish Rhamdia quelen, and its involvement in disease pathogenesis. Reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels increased in liver and kidney of fish experimentally infected by A. caviae compared to the control uninfected group. On the other hand, non-protein sulfhydryl (NPSH) levels decreased in both tissues of infected animals, while the glutathione S-transferase (GST) activity decreased only in the hepatic tissue. No difference was observed between groups in both tissues regarding superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) activities and glutathione (GSH) levels. In summary, the disturbance of hepatic and renal antioxidant/oxidant equilibrium contributes to the pathophysiology of the disease in fish experimentally infected by A. caviae.

Diagnosis of Alzheimer's Disease in Clinical Practice: Time to Incorporate Biomarkers?

Hippocampal dysfunction is associated with early clinical signs of Alzheimer's disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities.

Biomarkers associated with migraine and their potential role in migraine management.

OBJECTIVE: The focus of this review is to review potential diagnostic and therapeutic biomarkers associated with migraine. BACKGROUND: Migraine headache is a common disease that affects millions of individuals worldwide. Although well-accepted diagnostic criteria exist for migraine, it is still a complex disorder that remains both underdiagnosed and misdiagnosed. The causes of migraine are likely a mix of genetic, epigenetic, and environmental factors that, together with the individual's life history, translate into the observed clinical heterogeneity. Inherent clinical heterogeneity is an obstacle in developing more effective treatments. The lack of appropriate biomarkers is also an impediment to developing more effective therapeutic/preventive approaches. Ultimately, biomarkers may facilitate the goal of individualized medicine by enabling clinicians to more accurately diagnose and treat migraine and other types of headache. METHODS: A comprehensive review was conducted of PubMed citations containing the key word "marker" OR "biomarker" combined with "migraine" OR "headache." Other key words included "serum," "saliva," "cerebrospinal fluid," "genes," "blood," and "inflammation." The only restriction was English-language publication. The abstracts of all articles meeting these criteria were reviewed, and full text was retrieved and examined for relevant references. RESULTS: Data from human studies have begun to identify genetic mutations/polymorphisms and altered levels of specific proinflammatory and neuromodulatory molecules that strongly correlate with migraine as well as symptom severity. Results from a smaller number of studies have identified parameters, such as the neuropeptide calcitonin gene-related peptide (CGRP), which are significantly associated with response to specific treatments for acute migraine attacks and prophylaxis. Epigenetic mechanisms may also be involved in the development of migraine, and understanding environmentally induced genetic changes associated with this disease may eventually guide the development of therapies capable of reversing these pathophysiological changes in gene function. CONCLUSIONS: The understanding of the etiology of migraine is incomplete. Although the identification and validation of biomarkers has greatly advanced diagnostic precision and measures of therapeutic efficacy in other diseases, there are no currently accepted biomarkers for chronic or episodic migraine. However, the continued investigation and identification of genetic, epigenetic, and molecular biomarkers is likely to facilitate the goal of individualizing medicine by enabling clinicians to more accurately diagnose and treat migraine and other headache disorders.

Lipoprotein(a) and inflammation- pathophysiological links and clinical implications for cardiovascular disease.

The role of lipoprotein(a) (Lp[a]) as a significant and possibly causal cardiovascular disease (CVD) risk factor has been well established. Many studies, mostly experimental, have supported inflammation as a mediator of Lp(a)-induced increase in CVD risk. Lp(a), mainly through oxidized phospholipids bound to its apolipoprotein(a) part, leads to monocyte activation and endothelial dysfunction. The relationship between Lp(a) and inflammation is bidirectional as Lp(a) levels, besides being associated with inflammatory properties, are regulated by inflammatory stimuli or anti-inflammatory treatment. Reduction of Lp(a) concentration, especially by potent siRNA agents, contributes to partial reversion of the Lp(a) related inflammatory profile. This review aims to present the current pathophysiological and clinical evidence of the relationship between Lp(a) and inflammation.

The natural history of Pelizaeus-Merzbacher disease caused by PLP1 duplication: A multiyear case series.

This study aimed to characterize the clinical features, developmental milestones, and the natural history of Pelizaeus-Merzbacher disease (PMD) associated with PLP1 gene duplications. The study examined 16 PMD Patients ranging in age from 7 to 48 years, who had a documented PLP1 gene duplication. The study examined and analyzed the medical and developmental histories of the subjects utilizing a combination of resources that included medical history questionnaires, medical record reviews, and a 31-point functional disability scale that had been previously validated. The data extracted from the medical records and questionnaires for analysis included information related to medical and developmental histories, level of ambulation and cognition, and degree of functional disability. The summation of findings among the study population demonstrated that the presenting symptoms, developmental milestones achieved, and progression of symptoms reported are consistent with many previous studies of patients with PLP1 duplications. All patients exhibited onset within the first year of life, with nystagmus predominating as the first symptom noticed. All patients exhibited delays in both motor and language development; however, many individuals were able to meet several developmental milestones. They exhibited some degree of continued motor impairment with none having the ability to walk independently. All patients were able to complete at least some of the cognition achievements and although not all were verbal, a number were able to use communication devices to complete these tasks. A critical tool of the study was the functional disability scale which provided a major advantage in helping quantify the clinical course of PMD, and for several, we were able to gather this information at more than one point in time. These reported findings in our cohort contribute important insight into the clinical heterogeneity and potential underlying mechanisms that define the molecular pathogenesis of the disease. This is one of only a small number of natural history studies examining the clinical course of a cohort of patients with PLP1 duplications within the context of a validated functional disability scoring system. This study is unique in that it is limited to subjects with PLP1 gene duplications. This study demonstrated many commonalities to other studies that have characterized the features of PMD and other PLP1-related disorders but also provide significant new insights into the evolving story that marks the natural history.

Towards Improved Clinical Diagnosis of Argyrophilic Grain Disease Using Brain Imaging.

In this issue, Sakurai et al. report on relevant findings for the clinical diagnosis of argyrophilic grain disease (AGD). Their study describes a characteristic atrophy distribution restricted to the limbic lobes, namely the ambient gyrus, in AGD versus Alzheimer's disease (AD), in pathologically confirmed patients using magnetic resonance imaging by voxel- and surface-based morphometry. Here, we discuss the possibility of employing functional or molecular brain imaging to further improvement of diagnosis of AGD. Additional research is required to elucidate the contributions of comorbid AD and transactive response DNA-binding protein 43 kDa pathologies in patients with AGD.

Zebrafish as an Experimental and Preclinical Model for Alzheimer's Disease.

The success rate of novel drug candidates in clinical trials relies on the safety and efficacy data of the preclinical studies. Although cell-based assays are widely used, the complexity of an in vivo system to mimic human disease pathophysiology is essential. Despite the wide usage of rodent models for preclinical drug discovery, increasing the repertoire of animal models that allow the investigation of various pathological mechanisms with a unique operational strength for drug discovery is required. Zebrafish, a teleost vertebrate, with its high similarity to human pathophysiology and unique tissue regenerative ability, emerged as an excellent tool for early drug discovery and preclinical studies.

Single-cell profiling to transform immunotherapy usage and target discovery in immune-mediated inflammatory diseases.

Immunotherapy drugs are transforming the clinical care landscape of major human diseases from cancer, to inflammatory diseases, cardiovascular diseases, neurodegenerative diseases and even aging. In polygenic immune-mediated inflammatory diseases (IMIDs), the clinical benefits of immunotherapy have nevertheless remained limited to a subset of patients. Yet the identification of new actionable molecular candidates has remained challenging, and the use of standard of care imaging and/or histological diagnostic assays has failed to stratify potential responders from non-responders to biotherapies already available. We argue that these limitations partly stem from a poor understanding of disease pathophysiology and insufficient characterization of the roles assumed by candidate targets during disease initiation, progression and treatment. By transforming the resolution and scale of tissue cell mapping, high-resolution profiling strategies offer unprecedented opportunities to the understanding of immunopathogenic events in human IMID lesions. Here we discuss the potential for single-cell technologies to reveal relevant pathogenic cellular programs in IMIDs and to enhance patient stratification to guide biotherapy eligibility and clinical trial design.

Mini-review: The suspected non-Alzheimer's disease pathophysiology.

Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept that underlying etiology has not been completely understood. Refers to a group of individuals that are negative for amyloid biomarkers and positive for p-Tau and/or neurodegeneration. SNAP causes great research interest because it is not clear if they have a different biological basis from Alzheimer's disease (AD), or are in an early stage of AD itself. The pathological processes behind SNAP need to be clarified. This mini-review aims to summarize the main characteristics of SNAP, besides reporting challenges and promising biomarkers related to the concept.

Distinct Brain Functional Impairment Patterns Between Suspected Non-Alzheimer Disease Pathophysiology and Alzheimer's Disease: A Study Combining Static and Dynamic Functional Magnetic Resonance Imaging.

Background: Suspected non-Alzheimer disease pathophysiology (SNAP) refers to the subjects who feature negative ß-amyloid (Aß) but positive tau or neurodegeneration biomarkers. It accounts for a quarter of the elderly population and is associated with cognitive decline. However, the underlying pathophysiology is still unclear. Methods: We included 111 non-demented subjects, then classified them into three groups using cerebrospinal fluid (CSF) Aß 1-42 (A), phosphorylated tau 181 (T), and total tau (N). Specifically, we identified the normal control (NC; subjects with normal biomarkers, A-T-N-), SNAP (subjects with normal amyloid but abnormal tau, A-T+), and predementia Alzheimer's disease (AD; subjects with abnormal amyloid and tau, A+T+). Then, we used the static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance to reflect the intrinsic functional network strength and stability, respectively. Further, we performed a correlation analysis to explore the possible relationship between intrinsic brain activity changes and cognition. Results: SNAP showed decreased sALFF in left superior frontal gyrus (SFG) while increased sALFF in left insula as compared to NC. Regarding the dynamic metric, SNAP showed a similarly decreased dALFF in the left SFG and left paracentral lobule as compared to NC. By contrast, when compared to NC, predementia AD showed decreased sALFF in left inferior parietal gyrus (IPG) and right precuneus, while increased sALFF in the left insula, with more widely distributed decreased dALFF variance across the frontal, parietal and occipital lobe. When directly compared to SNAP, predementia AD showed decreased sALFF in left middle occipital gyrus and IPG, while showing decreased dALFF variance in the left temporal pole. Further correlation analysis showed that increased sALFF in the insula had a negative correlation with the general cognition in the SNAP group. Besides, sALFF and dALFF variance in the right precuneus negatively correlated with attention in the predementia AD group. Conclusion: SNAP and predementia AD show distinct functional impairment patterns. Specifically, SNAP has functional impairments that are confined to the frontal region, which is usually spared in early-stage AD, while predementia AD exhibits widely distributed functional damage involving the frontal, parietal and occipital cortex.

Diagnostic accuracy of CSF neurofilament light chain protein in the biomarker-guided classification system for Alzheimer's disease.

We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) neurofilament light chain (NFL) protein in the classification of patients with Alzheimer's disease (AD) and cognitively healthy control individuals (HCs) and patients with frontotemporal dementia (FTD) as comparisons. Particularly, we tested the performance of CSF NFL concentration in differentiating patient groups stratified by fluid biomarker profiles, independently of the severity of cognitive impairment (mild cognitive impairment (MCI) and AD dementia individuals), using a biomarker-guided descriptive classification system for AD. CSF NFL concentrations were examined in a multicenter cross-sectional study of 108 participants stratified in AD pathophysiology-negative (both CSF tau and the 42-amino acid-long amyloid-beta (Aß) peptide (Aß1-42)) (n = 15), tau pathology-positive only (n = 15), Aß pathology-positive only (n = 13), AD pathophysiology-positive (n = 33), FTD (n = 9) patients, and HCs (n = 23), according to the biomarker-based classification system. The performance of CSF NFL in discriminating AD pathophysiology-positive patients from HCs is fair, whereas the ability in differentiating tau-positive patients from HCs is poor. The classificatory performance in distinguishing AD pathophysiology-positive patients from FTD is unsatisfactory.

Renal Oxygenation in the Pathophysiology of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a significant health problem associated with high morbidity and mortality. Despite significant research into various pathways involved in the pathophysiology of CKD, the therapeutic options are limited in diabetes and hypertension induced CKD to blood pressure control, hyperglycemia management (in diabetic nephropathy) and reduction of proteinuria, mainly with renin-angiotensin blockade therapy. Recently, renal oxygenation in pathophysiology of CKD progression has received a lot of interest. Several advances have been made in our understanding of the determinants and regulators of renal oxygenation in normal and diseased kidneys. The goal of this review is to discuss the alterations in renal oxygenation (delivery, consumption and tissue oxygen tension) in pre-clinical and clinical studies in diabetic and hypertensive CKD along with the underlying mechanisms and potential therapeutic options.