Neuroimmune Dysfunction in Alzheimer's Disease and Other Forms of Dementia.

Alzheimer's disease (AD) is a common form of dementia. Although the causal mechanisms of AD are not fully understood, intracerebral accumulation of amyloid beta (Aß) and tau aggregates seems to play an important role in disease development. Therefore, numerous experimental and clinical studies targeting the Aß and tau proteins have been performed. However, these treatments have not achieved good clinical results. Additionally, recent findings have indicated that immune abnormalities contribute to the pathogenesis of AD. Several immune- and microglia-related genes have been identified as putative causative genes for the disease. Microglia, which are resident immune cells in the central nervous system (CNS), are key players that maintain brain homeostasis by communicating with other cells, such as astrocytes and immune cells, in or around the CNS. Furthermore, dysfunction of microglia and the immune system of the CNS could lead to chronic neuroinflammation and impairment of protective neuroimmune responses, which have been associated with the pathogenesis of AD and other forms of dementia. In this review, we assemble information regarding genetic evidence, imaging and biofluid biomarkers, and the pathophysiology of AD, especially highlighting bilateral (protective or detrimental) microglial functions, thus connecting neuroimmune dysfunction and AD. We also introduce candidate drugs to target neuroimmune dysfunction in AD. Finally, we discuss future therapeutic precision medicine approaches for AD, which could be achieved by identifying and targeting signals critical for AD pathogenesis through analyses of interactions between genetic risk factors, as well as identifying and modulating disease-relevant immune cell populations.

Depression, dementia and immune dysregulation.

Major depression is a prevalent illness that increases the risk of several neurological conditions. These include stroke, cardiovascular disease, and dementia including Alzheimer's disease. In this review we ask whether certain types of depression and associated loneliness may be a harbinger of cognitive decline and possibly even dementia. We propose that chronic stress and inflammation combine to compromise vascular and brain function. The resulting increases in proinflammatory cytokines and microglial activation drive brain pathology leading to depression and mild cognitive impairment, which may progress to dementia. We present evidence that by treating the inflammatory changes, depression can be reversed in many cases. Importantly, there is evidence that anti-inflammatory and antidepressant treatments may reduce or prevent dementia in people with depression. Thus, we propose a model in which chronic stress and inflammation combine to increase brain permeability and cytokine production. This leads to microglial activation, white matter damage, neuronal and glial cell loss. This is first manifest as depression and mild cognitive impairment, but can eventually evolve into dementia. Further research may identify clinical subgroups with inflammatory depression at risk for dementia. It would then be possible to address in clinical trials whether effective treatment of the depression can delay the onset of dementia.

The impact of nutrition on COVID-19 susceptibility and long-term consequences.

While all groups are affected by the COVID-19 pandemic, the elderly, underrepresented minorities, and those with underlying medical conditions are at the greatest risk. The high rate of consumption of diets high in saturated fats, sugars, and refined carbohydrates (collectively called Western diet, WD) worldwide, contribute to the prevalence of obesity and type 2 diabetes, and could place these populations at an increased risk for severe COVID-19 pathology and mortality. WD consumption activates the innate immune system and impairs adaptive immunity, leading to chronic inflammation and impaired host defense against viruses. Furthermore, peripheral inflammation caused by COVID-19 may have long-term consequences in those that recover, leading to chronic medical conditions such as dementia and neurodegenerative disease, likely through neuroinflammatory mechanisms that can be compounded by an unhealthy diet. Thus, now more than ever, wider access to healthy foods should be a top priority and individuals should be mindful of healthy eating habits to reduce susceptibility to and long-term complications from COVID-19.

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1ß replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1ß synthesis. Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1ß but direct hippocampal action of IL-1ß causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

Balance between innate versus adaptive immune system and the risk of dementia: a population-based cohort study.

BACKGROUND: Immunity has been suggested to be important in the pathogenesis of dementia. However, the contribution of innate versus adaptive immunity in the development of dementia is not clear. In this study, we aimed to investigate (1) the association between components of innate immunity (granulocytes and platelets) and adaptive immunity (lymphocytes) with risk of dementia and (2) the association between their derived ratios (granulocyte-to-lymphocyte ratio [GLR], platelet-to-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII]), reflecting the balance between innate and adaptive immunity, with risk of dementia. METHODS: Blood cell counts were measured repeatedly between 2002 and 2015 in dementia-free participants of the prospective population-based Rotterdam Study. Participants were followed-up for dementia until 1 January 2016. Joint models were used to determine the association between granulocyte, platelets, and lymphocyte counts, and their derived ratios with risk of dementia. RESULTS: Of the 8313 participants (mean [standard deviation] age 61.1 [7.4] years, 56.9% women), 664 (8.0%) developed dementia during a median follow-up of 8.6 years. Doubling of granulocyte and platelet counts tended to be associated with an increased risk of dementia (HR [95%CI] 1.22 [0.89-1.67] and 1.45 [1.07-1.95], respectively). Doubling of the derived ratios GLR, PLR, and SII were all associated with an increased dementia risk (HR [95%CI] 1.26 [1.03-1.53], 1.27 [1.05-1.53], and 1.15 [0.98-1.34], respectively). CONCLUSIONS: GLR, PLR, and SII are associated with an increased risk of dementia in the general population. This supports the role of an imbalance in the immune system towards innate immunity in the pathogenesis of dementia.

Autoimmune Encephalitides and Rapidly Progressive Dementias.

Rapidly progressive dementia (RPD) or cognitive decline is a common presenting complaint in neurology. While primary dementia is often a concern, other forms of reversible dementia must be thoroughly considered. This article focuses on the growing field of autoimmune encephalitis (AE) as it pertains to the differential diagnostic considerations in a work-up for RPD. Understanding clues in the history and examination is the first step in identifying patients with a potential autoimmune cause for RPD. While testing for infectious and toxic-metabolic etiologies is commonly preformed, it is necessary to consider early ancillary testing for AE in appropriate cases of RPD. Autoantibody testing in the spinal fluid and serum, brain imaging, and electroencephalography all form the first line of investigations for AE. Treatment options and strategies depend on the AE subtype and a number of individual patient considerations.

Autoimmune Dementia.

Dementia refers to an acquired syndrome of intraindividual cognitive decline that ultimately interferes with an individual's ability to manage their usual duties at work or home. As experience with the diagnosis and management of patients with autoimmune and paraneoplastic encephalitis (AE) has expanded, it has become increasingly apparent that dementia may arise as a subacute or chronic complication of immune-mediated injury to the central nervous system. Progressive memory and thinking problems may represent the first (or only) sign of an underlying autoimmune or paraneoplastic disease. Accordingly, there is a need to routinely consider the diagnosis of AE in patients with dementia, and to evaluate patients recovering from AE for clinically meaningful cognitive impairment. We review and summarize the available evidence concerning the diagnosis and care of AE patients with associated cognitive impairment, herein referred to as autoimmune dementia (AiD). Relevant information is used to propose a novel diagnostic framework that may be applied to improve recognition, and facilitate the expedited evaluation and treatment of patients with AiD.

Dysfunction of the blood-cerebrospinal fluid-barrier and N-methyl-D-aspartate glutamate receptor antibodies in dementias.

N-Methyl-D-aspartate glutamate receptor (NMDA-R) antibodies (Abs) could play a role in neurodegenerative disorders. Since, in these diseases, NMDA-R Abs were detected in serum, but only sporadic in cerebrospinal fluid (CSF), the origin and impact of the Abs are still unresolved. We examined the presence of NMDA-R Abs in serum and CSF using a cell-based immunofluorescence assay as well as the function of the blood-CSF-barrier (B-CSF-B) by determination of Q albumin (ratio of albumin in CSF and serum) in patients with mild cognitive impairment (MCI; N = 59) and different types of dementia, Alzheimer's disease (AD; N = 156), subcortical ischemic vascular dementia (SIVD; N = 61), and frontotemporal dementia (FTD; N = 34). Serum IgA/IgM NMDA-R Abs and/or a disturbed B-CSF-B were sporadically present in all investigated patients' groups. In AD, these Abs often developed during the disease course. Patients with either no hippocampal atrophy and/or no AD-related characteristic changes in CSF, referred to "non-classical" AD, were characterized by seropositivity at diagnosis and loss of function of the B-CSF-B showed a progressive decline in cognitive functions and a poor prognosis. Our data indicate that NMDA-R Abs are present in different types of dementia and elderly healthy individuals. In combination with disturbed B-CSF-B integrity, they seem to promote their pathological potential on cognitive decline, and thus, a subgroup of dementia patients with these unique characteristics might inform clinicians.

Inflammatory markers and the risk of dementia and Alzheimer's disease: A meta-analysis.

INTRODUCTION: Inflammatory markers are often elevated in patients with dementia, including Alzheimer's disease (AD). However, it remains unclear whether inflammatory markers are associated with the risk of developing dementia. METHODS: We searched PubMed, Embase, and Cochrane library for prospective population-based studies reporting associations between inflammatory markers and all-cause dementia or AD. We used random effects meta-analyses to obtain pooled hazard ratios (HRs) and 95% confidence intervals of inflammatory markers (highest vs. lowest quantile) for all-cause dementia and AD. RESULTS: Fifteen articles from 13 studies in six countries reported data that could be meta-analyzed. C-reactive protein (HR = 1.37 [1.05; 1.78]), interleukin-6 (HR = 1.40 [1.13; 1.73]), α1-antichymotrypsin (HR = 1.54 [1.14; 2.80]), lipoprotein-associated phospholipase A2 activity (HR = 1.40 [1.03; 1.90]), and fibrinogen were each associated with all-cause dementia, but neither was significantly associated with AD. DISCUSSION: Several inflammatory markers are associated with an increased risk of all-cause dementia; however, these markers are not specific for AD. Whether inflammatory markers closely involved in AD pathology are associated with the risk of AD remains to be elucidated.

A Role of Cytokine Gene Polymorphisms in Cognitive Functioning.

The changes in cognitive functions that occur with aging and in various pathological conditions are a subject of growing interest. Experimental and clinical data justify the hypothesis about the influence the immune system exerts on cognitive processes. The balance between pro-inflammatory and anti-inflammatory cytokines has been established as a necessary factor for normal cognitive functioning. Cytokine production is under strong genetic control and various single nucleotide polymorphisms (SNPs) in cytokine genes have been described. As cytokine SNPs have been demonstrated to affect the gene expression or the functional activity of the immune protein this logically led to the suggestion about the role of these polymorphisms in cognitive functioning. Studies exploring the association between different genetic variants of cytokine gene polymorphisms and cognitive abilities in healthy subjects and in demented patients show divergent results. The review of relevant literature suggests that SNPs implement their effect on cognition in large interactions with each other, as well as with many other factors, some of which still remain to be identified. This article summarizes the contemporary knowledge about the correlations between SNPs in cytokine genes and cognitive status in humans. Further research is needed to determine the precise role and the molecular mechanisms of action of the SNPs in cognitive processes.

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy.

Disorders with progressive accumulation of α-synuclein (α-syn) are a common cause of dementia and parkinsonism in the aging population. Accumulation and propagation of α-syn play a role in the pathogenesis of these disorders. Previous studies have shown that immunization with antibodies that recognize C-terminus of α-syn reduces the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy. These studies employed antibodies that recognize epitopes within monomeric and aggregated α-syn that were generated through active immunization or administered via passive immunization. However, it is possible that more specific effects might be achieved with antibodies recognizing selective species of the α-syn aggregates. In this respect we recently developed antibodies that differentially recognized various oligomers (Syn-O1, -O2, and -O4) and fibrilar (Syn-F1 and -F2) forms of α-syn. For this purpose wild-type α-syn transgenic (line 61) mice were immunized with these 5 different antibodies and neuropathologically and biochemically analyzed to determine which was most effective at reducing α-syn accumulation and related deficits. We found that Syn-O1, -O4 and -F1 antibodies were most effective at reducing accumulation of α-syn oligomers in multiple brain regions and at preventing neurodegeneration. Together this study supports the notion that selective antibodies against α-syn might be suitable for development new treatments for synucleinopathies such as PD and DLB.

Identification of a conserved gene signature associated with an exacerbated inflammatory environment in the hippocampus of aging rats.

There have been a few descriptive studies in aged rodents about transcriptome changes in the hippocampus, most of them in males. Here, we assessed the age changes in spatial memory performance and hippocampal morphology in female rats and compared those changes with changes in the hippocampal transcriptome. Old rats displayed significant deficits in spatial memory. In both age groups, hole exploration frequency showed a clear peak at hole 0 (escape hole), but the amplitude of the peak was significantly higher in the young than in the old animals. In the hippocampus, there was a dramatic reduction in neurogenesis, whereas reactive microglial infiltrates revealed an inflammatory hippocampal state in the senile rats. Hippocampal RNA-sequencing showed that 210 genes are differentially expressed in the senile rats, most of them being downregulated. Our RNA-Seq data showed that various genes involved in the immune response, including TYROBP, CD11b, C3, CD18, CD4, and CD74, are overexpressed in the hippocampus of aged female rats. Enrichment analysis showed that the pathways overrepresented in the senile rats matched those of an exacerbated inflammatory environment, reinforcing our morphologic findings. After correlating our results with public data of human and mouse hippocampal gene expression, we found an 11-gene signature of overexpressed genes related to inflammatory processes that was conserved across species. We conclude that age-related hippocampal deficits in female rats share commonalities between human and rodents. Interestingly, the 11-gene signature that we identified may represent a cluster of immune and regulatory genes that are deregulated in the hippocampus and possibly other brain regions during aging as well as in some neurodegenerative diseases and low-grade brain tumors. Our study further supports neuroinflammation as a promising target to treat cognitive dysfunction in old individuals and some brain tumors. © 2017 Wiley Periodicals, Inc.

Does B lymphocyte-mediated autoimmunity contribute to post-stroke dementia?

Post-stroke cognitive decline and dementia pose a significant public health problem, with 30% of stroke survivors suffering from dementia. The reason for this high prevalence is not well understood. Pathogenic B cell responses to the damaged CNS are one possible contributing factor. B-lymphocytes and antibodies are present in and around the stroke core of some human subjects who die with stroke and dementia, and mice that develop delayed cognitive dysfunction after stroke have clusters of B-lymphocytes in the stroke lesion, and antibody infiltration in the stroked hemisphere. The ablation of B-lymphocytes prevents post-stroke cognitive impairment in mice. Multiple drugs that target B cells are FDA approved, and so if pathogenic B cell responses are occurring in a subset of stroke patients, this is potentially treatable. However, it has also been demonstrated that regulatory B cells can be beneficial in mouse models of stroke. Consequently, it is important to understand the relative contribution of B-lymphocytes to recovery versus pathogenicity, and if this balance is heterogeneous in different individuals. Therefore, the purpose of this review is to summarize the current state of knowledge with regard to the role of B-lymphocytes in the etiology of post-stroke dementia.

Predictive models in the diagnosis and treatment of autoimmune epilepsy.

OBJECTIVE: To validate predictive models for neural antibody positivity and immunotherapy response in epilepsy. METHODS: We conducted a retrospective study of epilepsy cases at Mayo Clinic (Rochester-MN; Scottsdale-AZ, and Jacksonville-FL) in whom autoimmune encephalopathy/epilepsy/dementia autoantibody testing profiles were requested (06/30/2014-06/30/2016). An Antibody Prevalence in Epilepsy (APE) score, based on clinical characteristics, was assigned to each patient. Among patients who received immunotherapy, a Response to Immunotherapy in Epilepsy (RITE) score was assigned. Favorable seizure outcome was defined as >50% reduction of seizure frequency at the first follow-up. RESULTS: Serum and cerebrospinal fluid (CSF) from 1,736 patients were sent to the Mayo Clinic Neuroimmunology Laboratory for neural autoantibody evaluation. Three hundred eighty-seven of these patients met the diagnostic criteria for epilepsy. Central nervous system (CNS)-specific antibodies were detected in 44 patients. Certain clinical features such as new-onset epilepsy, autonomic dysfunction, viral prodrome, faciobrachial dystonic seizures/oral dyskinesia, inflammatory CSF profile, and mesial temporal magnetic resonance imaging (MRI) abnormalities had a significant association with positive antibody results. A significantly higher proportion of antibody-positive patients had an APE score ≥4 (97.7% vs. 21.6%, p < 0.01). Sensitivity and specificity of an APE score ≥4 to predict presence of specific neural auto-antibody were 97.7% and 77.9%, respectively. In the subset of patients who received immunotherapy (77), autonomic dysfunction, faciobrachial dystonic seizures/oral dyskinesia, early initiation of immunotherapy, and presence of antibodies targeting plasma membrane proteins (cell-surface antigens) were associated with favorable seizure outcome. Sensitivity and specificity of a RITE score ≥7 to predict favorable seizure outcome were 87.5% and 83.8%, respectively. SIGNIFICANCE: APE and RITE scores can aid diagnosis, treatment, and prognostication of autoimmune epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

A human monoclonal IgG that binds aß assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo.

Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aß and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aß and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aß in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aß amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases.

B-lymphocyte-mediated delayed cognitive impairment following stroke.

Each year, 10 million people worldwide survive the neurologic injury associated with a stroke. Importantly, stroke survivors have more than twice the risk of subsequently developing dementia compared with people who have never had a stroke. The link between stroke and the later development of dementia is not understood. There are reports of oligoclonal bands in the CSF of stroke patients, suggesting that in some people a B-lymphocyte response to stroke may occur in the CNS. Therefore, we tested the hypothesis that a B-lymphocyte response to stroke could contribute to the onset of dementia. We discovered that, in mouse models, activated B-lymphocytes infiltrate infarcted tissue in the weeks after stroke. B-lymphocytes undergo isotype switching, and IgM, IgG, and IgA antibodies are found in the neuropil adjacent to the lesion. Concurrently, mice develop delayed deficits in LTP and cognition. Genetic deficiency, and the pharmacologic ablation of B-lymphocytes using an anti-CD20 antibody, prevents the appearance of delayed cognitive deficits. Furthermore, immunostaining of human postmortem tissue revealed that a B-lymphocyte response to stroke also occurs in the brain of some people with stroke and dementia. These data suggest that some stroke patients may develop a B-lymphocyte response to stroke that contributes to dementia, and is potentially treatable with FDA-approved drugs that target B cells.

Enterovirus causes rapidly progressive dementia in a 28-year-old immunosuppressed woman.

Enterovirus in the nervous system can present with protean manifestations, including polio-like paralysis, movement disorders, and seizures. This is a report of a single case of a rapidly progressive dementing illness in a young woman with common variable immunodeficiency (CVID). Over the course of several months, she developed profound aphasia, apraxia, and cerebellar signs. She underwent brain biopsy which was suggestive of toxoplasmosis; despite an adequate course of treatment, she continued to decline and ultimately died. Autopsy and PCR testing revealed diffuse coxsackie B3 infiltration in the meninges and brain parenchyma. To our knowledge, this is the first description of enterovirus causing a dementing illness in a young immunosuppressed adult. We highlight the need for a broad differential diagnosis, especially for immunocompromised individuals, who may present in an atypical fashion.

Imaging neuroinflammation in Alzheimer's disease and other dementias: Recent advances and future directions.

Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia (FTD), and Huntington's disease (HD) are the main neurodegenerative causes of dementia. Causes and mechanisms of these diseases remain elusive. Neuroinflammation is increasingly emerging as an important pathological factor in their development. Positron emission tomography (PET) using [11C]PK11195 represents a method of visualizing the microglial component of neuroinflammation via the translocator protein (TSPO) and we discuss the valuable insights this has yielded in neurodegenerative diseases. We discuss the limitations of this method and the development of second generation TSPO PET ligands which hope to overcome these limitations. We also discuss other methods of visualizing neuroinflammation and review the state of current dementia treatments targeted at neuroinflammation. It is our view that a multimodal investigation into neuroinflammation in AD, Parkinson's disease dementia, FTD and HD will yield valuable pathological insights which will usefully inform development of therapeutic targets and biomarkers.