Neuropathological Markers Research Articles

Alteration of metabolic profile and potential biomarkers in the plasma of Alzheimer's disease

AbstractBackgroundThe expending of elderly population worldwide leads to a dramatical rising in the incidence of chronic diseases including Alzheimer’s Disease (AD) in the elderly. The inadequate understanding of the mechanisms underlying AD is deemed the greatest stumbling block against progress in definitive diagnosis and curative intervention of this disease. Efforts have been made towards the discovery of reliable AD biomarkers, but they are either invasive based on neuropathological markers in cerebrospinal fluid (CSF) or expensive using emission tomography scanning or magnetic resonance imaging techniques. With the emergence of high‐throughput technology that could detect and catalogue larger numbers of small metabolites, metabolomics offers hope for a better understanding of AD and subsequent identification of biomarkers.MethodHerein, using untargeted ultra‐performance liquid chromatography‐mass spectrometry we firstly measured concentrations of plasma metabolites in a cohort of AD subjects (n=44) and cognitively normal controls (Ctrl, n=94).ResultWe found remarkable reductions of polyunsaturated fatty acids (PUFAs), acyl‐carnitines, tryptophan degradation related metabolites and elevated levels of bile acids in AD compared to Ctrl. Followed by repeated validation in an independent cohort including AD (n=30), mild cognitive impairment (MCI, n=13), Ctrl (n=43) and non‐AD neurological disease controls (NDC, n=31), we further identified a metabolite panel consisting of five metabolites including cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid and tryptophan that can distinguish AD from both Ctrl and NDC with satisfactory sensitivity and specificity.ConclusionNotably, the concentrations of these metabolites are significantly correlated with disease severity. Our results also suggested the altered bile acid profiles in AD and MCI might provide clues for early risk of AD. Following further validation in larger cohorts, these findings are expected to provide new approaches for diagnosis of AD and offer novel insights into AD pathogenesis.

Polygenic hazard scores in superagers: Supergenes or superresilience?

AbstractBackgroundUnusually successful cognitive aging (e.g. SuperAging) may reflect underlying resistance to age‐associated cognitive decline and the neuropathologic markers of Alzheimer’s disease (AD). However, it is unknown whether these individuals vary in their genetic protection from AD relative to other clinically normal elderly individuals.MethodThe Northwestern SuperAgers cohort (n=41) was limited to clinically normal individuals who were at least 80 years old but performed at or above normative values for average 50 to 65‐year‐olds on delayed recall of the Rey Auditory Verbal Learning Test and within one standard deviation of the average normative range for their age, or better, on non‐episodic memory tests including the 30‐item Boston Naming Test, Trail Making Test Part‐B and Category Fluency Test (Animals). The UC San Diego (UCSD) Shiley Marcos Alzheimer’s Disease Research Center and Alzheimer’s Disease Neuroimaging Initiative (ADNI) comparison cohorts (n=17 and 46, respectively) included all clinically normal individuals with available genetic data who were at least 80 years old but did not meet the criteria for SuperAgers outlined above. Polygenic hazard scores (PHS) were downloaded from ADNI and calculated for each participant as described (Desikan et al., 2017) for the Northwestern and UCSD cohorts. Briefly, the PHS combines an individual’s genotype for 31 AD‐associated SNPs in addition to APOE.ResultAll three cohorts were similar in age (range: 80‐101) and years of education (range: 12‐20). However, there were significantly more women in the Northwestern SuperAgers cohort (p < 0.001). The mean PHS in each cohort was negative, indicating that these individuals had less than average population risk for AD. However, there were no significant differences in PHS between cohorts.ConclusionAs a group, SuperAgers did not have lower polygenic risk for AD than clinically normal elderly individuals, suggesting determinants of superior memory performance in older age cannot be solely explained by having unusually low risk for AD as assessed by common genetic variants. Given the sex differences in these cohorts, future work should consider whether sex‐specific polygenic risk for AD contributes to the superior memory performance of SuperAgers.

Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study.

Objective. In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer’s disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods. Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results. Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions. The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.

Association of PET-based stages of amyloid deposition with neuropathological markers of Aβ pathology.

ObjectiveTo determine if PET‐based stages of regional amyloid deposition are associated with neuropathological phases of Aβ pathology.MethodsWe applied data‐driven regional frequency‐based and a‐priori striatum‐based PET staging approaches to ante‐mortem 18F‐Florbetapir‐PET scans of 30 cases from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort, and used Bayesian regression analysis to study the associations of these in vivo amyloid stages with neuropathological Thal phases of regional Aβ plaque distribution and with semi‐quantitative ratings of neocortical and striatal plaque densities.ResultsBayesian regression revealed extreme evidence for an association of both PET‐based staging approaches with Thal phases, and these associations were about 44 times more likely for frequency‐based stages and 89 times more likely for striatum‐based stages than for global cortical 18F‐Florbetapir‐PET signal. Early (i.e., neocortical‐only) PET‐based amyloid stages also predicted the absence of striatal/diencephalic cored plaques. Receiver operating characteristics curves revealed highly accurate discrimination between low/high Thal phases and the presence/absence of regional plaques. The median areas under the curve were 0.99 for frequency‐based staging (95% credibility interval 0.97–1.00), 0.93 for striatum‐based staging (0.83–1.00), and 0.87 for global 18F‐Florbetapir‐PET signal (0.72–0.98).InterpretationOur data indicate that both regional frequency‐ and striatum‐based amyloid‐PET staging approaches were superior to standard global amyloid‐PET signal for differentiating between low and high degrees of regional amyloid pathology spread. Despite this, we found no evidence for the ability of either staging scheme to differentiate between low and moderate degrees of amyloid pathology which may be particularly relevant for early, preclinical stages of Alzheimer’s disease.

Disorder- and Emotional Context-Specific Neurofunctional Alterations During Inhibitory Control in Generalized Anxiety Disorder and Major Depressive Disorder

Background: Major Depressive (MDD) and Generalized Anxiety Disorder (GAD) are highly debilitating and often co-morbid disorders. The disorders exhibit partly overlapping dysregulations on the behavioral and neurofunctional level, and the determination of disorder-specific alterations may promote neuro-mechanistic and diagnostic specificity. Methods: In order to determine disorder-specific alterations in the domain of emotion-cognition interactions the present study examined emotional context-specific inhibitory control in treatment-naive, first-episode MDD (n = 37) and GAD (n = 35) patients and healthy controls (n = 35) by employing a validated affective go/no-go fMRI paradigm. Findings: On the behavioral level MDD but not GAD patients exhibited impaired inhibitory control irrespective of emotional context. On the neural level, no alterations were observed during the positive context, yet specifically MDD patients demonstrated attenuated recruitment of a broad bilateral network encompassing inferior/medial parietal, posterior frontal, and mid-cingulate regions during inhibitory control in the negative context. GAD patients exhibited a stronger engagement of the left dorsolateral prefrontal cortex relative to MDD patients and within the GAD group better inhibitory control in negative contexts was associated with higher recruitment of this region. Interpretation: Findings from the present study suggest disorder- and emotional context-specific behavioral and neurofunctional deficits in inhibitory control in MDD in negative emotional contexts and may point to a depression-specific neuropathological and diagnostic marker. In contrast, GAD patients may maintain intact inhibitory performance via compensatory recruitment of prefrontal regulatory regions. Funding Statement: This study was funded by the National Key Research and Development Program of China (2018YFA0701400) and Science & Technology Department of Sichuan Province, China (2017JY0031, JD). Declaration of Interests: There are no conflicts of interest. Ethics Approval Statement: The study was approved by the local ethics committee at the UESTC and adhered to the latest revision of the Declaration of Helsinki. Written informed consent and agreement to experimental procedures was obtained from all participants before enrollment.

Upregulation of Cellular Palmitoylation Mitigates α-Synuclein Accumulation and Neurotoxicity.

Synucleinopathies, including Parkinson's disease (PD), are characterized by α-synuclein (αS) cytoplasmic inclusions. αS-dependent vesicle-trafficking defects are important in PD pathogenesis, but their mechanisms are not well understood. Protein palmitoylation, post-translational addition of the fatty acid palmitate to cysteines, promotes trafficking by anchoring specific proteins to the vesicle membrane. αS itself cannot be palmitoylated as it lacks cysteines, but it binds to membranes, where palmitoylation occurs, via an amphipathic helix. We hypothesized that abnormal αS membrane-binding impairs trafficking by disrupting palmitoylation. Accordingly, we investigated the therapeutic potential of increasing cellular palmitoylation. We asked whether upregulating palmitoylation by inhibiting the depalmitoylase acyl-protein-thioesterase-1 (APT1) ameliorates pathologic αS-mediated cellular phenotypes and sought to identify the mechanism. Using human neuroblastoma cells, rat neurons, and iPSC-derived PD patient neurons, we examined the effects of pharmacologic and genetic downregulation of APT1 on αS-associated phenotypes. APT1 inhibition or knockdown decreased αS cytoplasmic inclusions, reduced αS serine-129 phosphorylation (a PD neuropathological marker), and protected against αS-dependent neurotoxicity. We identified the APT1 substrate microtubule-associated-protein-6 (MAP6), which binds to vesicles in a palmitoylation-dependent manner, as a key mediator of these effects. Mechanistically, we found that pathologic αS accelerated palmitate turnover on MAP6, suggesting that APT1 inhibition corrects a pathological αS-dependent palmitoylation deficit. We confirmed the disease relevance of this mechanism by demonstrating decreased MAP6 palmitoylation in neurons from αS gene triplication patients. Our findings demonstrate a novel link between the fundamental process of palmitoylation and αS pathophysiology. Upregulating palmitoylation represents an unexplored therapeutic strategy for synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.

T2 heterogeneity: a novel marker of microstructural integrity associated with cognitive decline in people with mild cognitive impairment

BackgroundEarly Alzheimer’s disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take place as a result of Alzheimer’s pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. We propose that different microstructural changes affect T2 in opposing ways, such that average ‘midpoint’ measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology.MethodsIn this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ).ResultsWe show an increase in T2 heterogeneity (T2σ; p < .0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ; p = .149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over 1 year in MCI participants (p = .018), but midpoint (p = .132) and volume (p = .315) did not. Age affects T2, but the effects described here are significant even after correcting for age.ConclusionsWe show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.

Roles of glutamate receptors in a novel in vitro model of early, comorbid cerebrovascular, and Alzheimer's diseases.

Systemic multimorbidity is highly prevalent in the elderly and, remarkably, coexisting neuropathological markers of Alzheimer's (AD) and cerebrovascular (CVD) diseases are found at autopsy in most brains of patients clinically diagnosed as AD. Little is known on neurodegeneration peculiar to comorbidities, especially at early stages when pathogenesis may propagate at subclinical levels. We developed a novel in vitro model of comorbid CVD/AD in organotypic hippocampal cultures, by combining oxygen-glucose deprivation (OGD) and exposure to amyloid-Aβ oligomers (AβOs), both applied at levels subtoxic to neurons when used in isolation. We focused on synaptic proteins and the roles of glutamate receptors, which have been implicated in many basic and clinical approaches to either CVD or AD. Subtoxic insults by OGD and AβOs synergized to reduce levels of synaptophysin (SYP) and PSD-95 without cell death, while effects of antagonists of either metabotropic or ionotropic glutamate receptors were distinct from reports in models of isolated CVD or AD. In particular, modulation of glutamate receptors differentially impacted SYP and PSD-95, and antagonists of a single receptor subtype had distinct effects when either isolated or combined. Our findings highlight the complexity of CVD/AD comorbidity, help understand variable responses to glutamate receptor antagonists in patients diagnosed with AD and may contribute to future development of therapeutics based on investigation of the pattern of progressive comorbidity.

Neuropathological profile of long-duration amyotrophic lateral sclerosis in military Veterans.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5years after initial symptom onset, approximately 10% of patients with ALS live more than 10years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n=179), dichotomized into standard duration (<10years) and long-duration (≥10years). The ALS Functional Rating Scale-Revised (ALSFRS-R) was administered at study entry and semi-annually thereafter until death. Microglial density was determined in a subset of participants. long-duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3years (min/max=10.1/42.2). Participants with long-duration ALS were younger at disease onset (P=0.002), had a slower initial ALS symptom progression on the ALSFRS-R (P<0.001) and took longer to diagnose (P<0.002) than standard duration ALS. Pathologically, long-duration ALS was associated with less frequent TDP-43 pathology (P<0.001). Upper motor neuron degeneration was similar; however, long-duration ALS participants had less severe lower motor neuron degeneration at death (P<0.001). In addition, the density of microglia was decreased in the corticospinal tract (P=0.017) and spinal cord anterior horn (P=0.009) in long-duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long-duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long-duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.

Transglutaminase 2 Depletion Attenuates α-Synuclein Mediated Toxicity in Mice

α-Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of α-Syn is believed to be deleterious and a critical step leading to neuronal dysfunction and death. One of the factors that may contribute to the initial steps of this aggregation is crosslinking through transglutaminase 2 (TG2). We previously demonstrated that overexpression of TG2 exacerbates α-Syn toxicity in mice and yeast by increasing the higher-order species of α-Syn. Herein, we investigated whether deletion of the TG2 encoding gene could mitigate the toxicity of α-Syn in vivo. Compared with α-Syn transgenic (SynTg) mice, TG2 null /α-Syn transgenic mice (TG2KO/SynTg) exhibited a reduced amount of phosphorylated α-Syn aggregates and fewer proteinase K-resistant α-Syn aggregates in sections of brain tissue. Neuritic processes that are depleted in SynTg mice compared to wild-type mice were preserved in double TG2KO/SynTg mice. Additionally, the neuroinflammatory reaction to α-Syn was attenuated in TG2KO/SynTg animals. These neuropathological markers of diminished α-Syn toxicity in the absence of TG2 were associated with better motor performance on the rotarod and balance beam. These results suggest that deleting TG2 reduces the toxicity of α-Syn in vivo and improves the behavioral performance of SynTg mice. Accordingly, these findings collectively support pharmacological inhibition of TG2 as a potential disease modifying therapeutic strategy for α-synucleinopathies.

Pathway Analysis for Plasma β-Amyloid, Tau and Neurofilament Light (ATN) in World Trade Center Responders at Midlife.

IntroductionWorld Trade Center (WTC) responders who aided in the search and rescue efforts are now at midlife, and evidence has demonstrated that many are experiencing early-onset cognitive impairment and are at risk of developing dementia, such as Alzheimer’s disease (AD). According to the recent NIA-AA framework, AD is characterized by a neuropathological cascade commencing with β-amyloid deposition (A), followed by tauopathy (T) and neurodegeneration (N). However, the ATN model has not been replicated utilizing recently validated plasma-based biomarkers, and the role of the Aβ40 subtype in A is not well understood. This study examined plasma-based neuropathological markers of Aβ42 and Aβ40 for A, total tau for T, and NfL for N in a cohort of World Trade Center responders at midlife in order to determine the role for the two β-amyloid subtypes in the ATN model.MethodsUltrasensitive Simoa technology was utilized to measure neuropathology in plasma collected from a consecutive clinical sample (n =398). Generalized structural equation modeling was utilized for modeling linkages between pathological markers. Model fit was utilized to determine proposed directions of association.ResultsOur findings support the ATN neuropathological cascade model of AD and further identify an associative role for Aβ40 in A as playing a central role linking T to N. A strong correlation was found between CI and age, and it was found that women may be at increased risk of elevated T levels, with plasma NfL levels higher in responders with CI. Notably, our model reported associations between: Aβ42, CI and N; Aβ40, T and N; T and CI; Aβ42 and Aβ40.ConclusionsThe current ATN model of AD does not specify the subtype of β-amyloid to be considered, which may be overlooking the differential roles that these two subtypes serve in the pathogenesis of AD.

Mitochondrial respiratory chain deficiency correlates with the severity of neuropathology in sporadic Creutzfeldt-Jakob disease

Mitochondrial dysfunction has been implicated in multiple neurodegenerative diseases but remains largely unexplored in Creutzfeldt-Jakob disease. Here, we characterize the mitochondrial respiratory chain at the individual neuron level in the MM1 and VV2 common molecular subtypes of sporadic Creutzfeldt-Jakob disease. Moreover, we investigate the associations between the mitochondrial respiratory chain and neuropathological markers of the disease.Brain tissue from individuals with sporadic Creutzfeldt-Jakob disease and age-matched controls were obtained from the brain collection of the Austrian Creutzfeldt-Jakob Surveillance. The mitochondrial respiratory chain was studied through a dichotomous approach of immunoreactivities in the temporal cortex and the hippocampal subregions of CA4 and CA3.We show that profound deficiency of all mitochondrial respiratory complexes (I-V) occurs in neurons of the severely affected temporal cortex of patients with Creutzfeldt-Jakob disease. This deficiency correlates strongly with the severity of neuropathological changes, including vacuolation of the neuropil, gliosis and disease associated prion protein load. Respiratory chain deficiency is less pronounced in hippocampal CA4 and CA3 regions compared to the temporal cortex. In both areas respiratory chain deficiency shows a predilection for the MM1 molecular subtype of Creutzfeldt-Jakob disease.Our findings indicate that aberrant mitochondrial respiration could be involved early in the pathogenesis of sporadic Creutzfeldt-Jakob disease and contributes to neuronal death, most likely via ATP depletion. Based on these results, we propose that the restricted MRI diffusion profile seen in the brain of patients with sporadic Creutzfeldt-Jakob disease might reflect cytotoxic changes due to neuronal respiratory chain failure and ATP loss.

Somatostatin, Olfaction, and Neurodegeneration.

Alzheimer’s and Parkinson’s diseases are the most prevalent neurodegenerative disorders in aging. Hyposmia has been described as an early symptom that can precede cognitive and motor deficits by decades. Certain regions within the olfactory system, such as the anterior olfactory nucleus, display the neuropathological markers tau and amyloid-β or α-synuclein from the earliest stages of disease progression in a preferential manner. Specific neuronal subpopulations, namely those expressing somatostatin (SST), are preferentially affected throughout the olfactory and limbic systems. SST is a neuropeptide present in a subpopulation of GABAergic interneurons throughout the brain and its main function is to inhibit principal neurons and/or other interneurons. It has been reported that SST expression is reduced by 50% in Alzheimer’s disease and that it is related to the formation of Aβ oligomers. The mechanisms underlying the preferential vulnerability of SST-expressing neurons in Alzheimer’s disease (and, to a minor extent, in Parkinson’s disease) are not known but analysis of the available data could shed light on their etiology. This short review aims to update the knowledge of functional features of somatostatin within the olfactory system and its role in olfactory deficits during neurodegeneration.

Schizophrenia in a genomic era: a review from the pathogenesis, genetic and environmental etiology to diagnosis and treatment insights.

Schizophrenia is a common multigenic and debilitating neurological disorder characterized by chronic psychotic symptoms and psychosocial impairment. Complex interactions of genetics and environmental factors have been implicated in etiology of schizophrenia. There is no central pathophysiology mechanism, diagnostic neuropathology, or biological markers have been defined for schizophrenia. However, a number of different hypotheses including neurodevelopmental and neurochemical hypotheses have been proposed to explain the neuropathology of schizophrenia. This review provides an overview of pathogenesis, genetic and environmental etiologies to diagnosis and treatment insights in clinical management of schizophrenia in light of the recent discoveries of genetic loci associated with susceptibility to schizophrenia.

Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer's Disease.

The expending of elderly population worldwide has resulted in a dramatic rise in the incidence of chronic diseases such as Alzheimer’s disease (AD). Inadequate understanding of the mechanisms underlying AD has hampered the development of efficient tools for definitive diagnosis and curative interventions. Previous studies have attempted to discover reliable biomarkers of AD, but these biomarkers can only be measured through invasive (neuropathological markers in cerebrospinal fluid) or expensive (positron emission tomography scanning or magnetic resonance imaging) techniques. Metabolomics is a high-throughput technology that can detect and catalog large numbers of small metabolites and may be a useful tool for characterization of AD and identification of biomarkers. In this study, we used ultra-performance liquid chromatography-mass spectrometry based untargeted metabolomics to measure the concentrations of plasma metabolites in a cohort of subjects with AD (n=44) and cognitively normal controls (Ctrl, n=94). The AD group showed marked reductions in levels of polyunsaturated fatty acids, acyl-carnitines, degradation products of tryptophan, and elevated levels of bile acids compared to the Ctrl group. We then validated the results using an independent cohort that included subjects with AD (n=30), mild cognitive impairment (MCI, n=13), healthy controls (n=43), and non-AD neurological disease controls (NDC, n=31). We identified five metabolites comprising cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid, and tryptophan that were able to distinguish patients with AD from both Ctrl and NDC with satisfactory sensitivity and specificity. The concentrations of these metabolites were significantly correlated with disease severity. Our results also suggested that altered bile acid profiles in AD and MCI might indicate early risk for the development of AD. These findings may allow for development of new approaches for diagnosis of AD and may provide novel insights into AD pathogenesis.

Neurophysiological Markers of Alzheimer's Disease: Quantitative EEG Approach.

Currently established and employed biomarkers of Alzheimer's disease (AD) predominantly mirror AD-associated molecular and structural brain changes. While they are necessary for identifying disease-specific neuropathology, they lack a clear and robust relationship with the clinical presentation of dementia; they can be altered in healthy individuals, while they often inadequately mirror the degree of cognitive and functional deficits in affected subjects. There is growing evidence that synaptic loss and dysfunction are early events during the trajectory of AD pathogenesis that best correlate with the clinical symptoms, suggesting measures of brain functional deficits as candidate early markers of AD. Resting-state electroencephalography (EEG) is a widely available and noninvasive diagnostic method that provides direct insight into brain synaptic activity in real time. Quantitative EEG (qEEG) analysis additionally provides information on physiologically meaningful frequency components, dynamic alterations and topography of EEG signal generators, i.e. neuronal signaling. Numerous studies have shown that qEEG measures can detect disruptions in activity, topographical distribution and synchronization of neuronal (synaptic) activity such as generalized EEG slowing, reduced global synchronization and anteriorization of neuronal generators of fast-frequency resting-state EEG activity in patients along the AD continuum. Moreover, qEEG measures appear to correlate well with surrogate markers of AD neuropathology and discriminate between different types of dementia, making them promising low-cost and noninvasive markers of AD. Future large-scale longitudinal clinical studies are needed to elucidate the diagnostic and prognostic potential of qEEG measures as early functional markers of AD on an individual subject level.

NEUROPATHOLOGY AND GAIT SPEED DECLINE IN OLDER ADULTS: THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY

Neuropathological markers including amyloid-beta (Aβ) have been implicated in mobility decline in older adults, but no studies have examined the relationship between these markers and longitudinal change in gait speed in a racially diverse community-based sample. In the multi-site prospective ARIC study, a subsample of participants (n=1,978, mean age=76.3, 28.5% black) underwent brain MRI at Visit 5 (2011-13). Of these, 343 participants (mean age=75.9, 42.6% black) completed PET scans using the tracer florbetapir to estimate global brain Aβ. We investigated the relationship between four neuropathological markers [white matter hyperintensities (WMH; log2cm3), infarcts (present/absent), brain atrophy (log2cm3), and global Aβ (log2SUVR)] with cross-sectional usual pace gait speed (cm/s) over 4 meters, and change in gait speed through Visits 6 (2016-17) and 7 (2018-19). Linear regression models were adjusted for age, site, sex, education, BMI, intracranial volume, and all race interactions. Cross-sectionally, slower gait was associated with higher WMH volume (β=-2.16, 95%CI: -2.92, -1.39), infarcts (β=-5.81, 95%CI: -7.86, -3.76), and brain atrophy (β=-16.39, 95%CI: -21.07, -11.71). Longitudinally, only higher WMH volume was statistically associated with gait speed decline (β=-0.14, 95%CI: -0.28, -0.01). Global Aβ was not statistically associated with gait speed cross-sectionally (β=-.269, 95%CI: -8.11, 7.57) or longitudinally (β=-1.16, 95%CI: -2.94, 0.62). There were no significant interactions with race. Detrimental relations of cerebral small vessel disease to mobility and mobility decline were observed across race in this diverse sample. The magnitude of the Aβ association with gait speed decline was high, although not statistically significant in the smaller PET subsample.

Andrographolide Reduces Neuroinflammation and Oxidative Stress in Aged Octodon degus.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder in which superior brain functions, such as memory and cognition, are impaired. Currently, no effective treatment is available for AD. Although andrographolide (ANDRO), a compound extracted from the herb Andrographis paniculata, has shown interesting effects in models of several diseases, including AD, its effects on other molecular changes observed in AD, such as neuroinflammation and oxidative stress, have not yet been studied. To evaluate the impact of ANDRO-based intervention on the levels of amyloid-β (Aβ) and neuroinflammatory and oxidative stress markers in the brains of aged Octodon degus, a Chilean rodent, fifty-six-month-old O. degus were treated intraperitoneally with 2 or 4mg/kg ANDRO. Vehicle-injected and 12-month-old O. degus were used as positive controls. Then, the protein levels of selected markers were assessed via immunohistochemistry and immunoblotting. ANDRO significantly reduced the total Aβ burden as well as astrogliosis and interleukin-6 levels. Moreover, ANDRO significantly reduced the levels of 4-hydroxynonenal and N-tyrosine adducts, suggesting a relevant reduction in oxidative stress within aged O. degus brain. Considering that O. degus has been proposed as a potential "natural" model for sporadic AD due to the development of neuropathological markers that resemble this pathology, our results suggest that ANDRO should be further studied to establish its potential as a therapeutic drug for AD.

Hospitalization, Alzheimer's Disease and Related Neuropathologies, and Cognitive Decline

ObjectiveTo test the hypothesis that Alzheimer's disease and related neuropathologies contribute to the association between hospitalization and cognitive decline in old age.MethodsAs part of a longitudinal clinical–pathologic cohort study, 526 older persons (mean age at death = 90.9 years, 71% female) without dementia at baseline completed annual cognitive testing and were autopsied at death. Hospitalization information was obtained from linked Medicare claims records. Neuropathologic examination assessed β‐amyloid burden, tau tangle density, neocortical Lewy bodies, hippocampal sclerosis, chronic gross and microscopic cerebral infarcts, and transactive response DNA binding protein 43 kDa.ResultsOver a mean of 5.1 years, a total of 1,383 hospitalizations occurred, and the mean annual rate of hospitalization was 0.5 (standard deviation = 0.6, median = 0.4). Higher rate of hospitalization was not directly related to higher burden for any of the neuropathologic markers. Higher rate of hospitalization was associated with more rapid cognitive decline (estimate = −0.042, standard error [SE] = 0.012, p < 0.001), and after controlling for all 7 neuropathologic markers, the association was essentially the same (estimate = −0.040, SE = 0.013, p = 0.002). In a multivariable model with 3‐way interactions of neuropathologic markers with hospitalization rate and time, the association between hospitalization rate and faster cognitive decline was greater in persons with more tangle pathology (estimate for interaction = −0.007, SE = 0.002, p = 0.002) and in persons with neocortical Lewy bodies (estimate for interaction = −0.117, SE = 0.042, p = 0.005).InterpretationOlder persons with more hospitalizations experienced faster rates of cognitive decline, and this association was more pronounced in persons with more tau tangle density and with neocortical Lewy body pathologies. ANN NEUROL 2019;86:844–852

Neuroimaging Studies in Patients With Mental Disorder and Co-occurring Substance Use Disorder: Summary of Findings.

Introduction: More than half of psychiatric patients have comorbid substance use disorder (dual diagnosis) and this rate, confirmed by many epidemiological studies, is substantially higher compared to general population. Combined operation of self-medication mechanisms, common etiological factors, and mutually causative influences most likely accounts for comorbidity, which, despite its clinical prevalence, remains underrepresented in psychiatric research, especially in terms of neuroimaging. The current paper attempts to review and discuss all existing methodologically sustainable structural and functional neuroimaging studies in comorbid subjects published in the last 20 years. Methods: Performing a systematic PubMed/MEDLINE, Web of Science, and Cochrane databases search with predefined key-words and selection criteria, 43 structural and functional neuroimaging studies were analyzed. Results: Although markedly inconsistent and confounded by a variety of sources, available data suggest that structural brain changes are slightly more pronounced, yet not qualitatively different in comorbid patients compared to non-comorbid ones. In schizophrenia (SZ) patients, somewhat greater gray matter reduction is seen in cingulate cortex, dorsolateral prefrontal and frontotemporal cortex, limbic structures (hippocampus), and basal ganglia (striatum). The magnitude of structural changes is positively correlated to duration and severity of substance use, but it is important to note that at least in the beginning of the disease, dual diagnosis subjects tend to show less brain abnormalities and better cognitive functioning than pure SZ ones suggesting lower preexisting neuropathological burden. When analysing neuroimaging findings in SZ and bipolar disorder subjects, dorsolateral prefrontal, cingular, and insular cortex emerge as common affected areas in both groups which might indicate a shared endophenotypic (i.e., transdiagnostic) disruption of brain networks involved in executive functioning, emotional processing, and social cognition, rendering affected individuals susceptible to both mental disorder and substance misuse. In patients with anxiety disorders and substance misuse, a common neuroimaging finding is reduced volume of limbic structures (n. accumbens, hippocampus and amygdala). Whether this is a neuropathological marker of common predisposition to specific behavioral symptoms and drug addiction or a result from neuroadaptation changes secondary to substance misuse is unknown. Future neuroimaging studies with larger samples, longitudinal design, and genetic subtyping are warranted to enhance current knowledge on comorbidity.