Cerebrospinal fluid biomarkers of neurodegeneration,synaptic integrity,and astroglial activation across the clinical Alzheimer's disease spectrum

IntroductionWe investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).MethodsWe included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ− vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.ResultsNg and T-tau distinguished between Aβ+ from Aβ− individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.DiscussionAxonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.     

Applications of amyloid,tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease for which there is no cure. Mild cognitive impairment (MCI) is considered a prodromal stage of the disease. Molecular imaging with positron emission tomography (PET) allows for the in vivo visualisation and tracking of pathophysiological changes in AD and MCI. PET is a very promising methodology for differential diagnosis and novel targets of PET imaging might also serve as biomarkers for disease‐modifying therapeutic interventions. This review provides an overview of the current status and applications of in vivo molecular imaging of AD pathology, specifically amyloid, tau, and microglial activation. PET imaging studies were included and evaluated as potential biomarkers and for monitoring disease progression. Although the majority of radiotracers showed the ability to discriminate AD and MCI patients from healthy controls, they had various limitations that prevent the recommendation of a single technique or tracer as an optimal biomarker. Newer research examining amyloid, tau, and microglial PET imaging in combination suggest an alternative approach in studying the disease process.     

Relations between personality changes and cerebrospinal fluid biomarkers of Alzheimer's disease pathology

Specific changes in personality profiles may represent early non-cognitive symptoms of Alzheimer's disease (AD). Evaluating the subject's personality changes may add significant clinical information, as well as help to better understand the interaction between personality change, cognitive decline, and cerebral pathology. With this study we aimed to describe the relationship between personality changes and cerebrospinal fluid (CSF) markers of AD pathology at early clinical stages of the disease. One hundred and ten subjects, of whom 66 cognitively impaired patients (57 with mild cognitive impairment (MCI), and 9 with mild dementia) and 44 healthy controls, had neuropsychological examination as well as lumbar puncture to determine concentrations of CSF biomarkers of AD pathology (amyloid beta_1-42 (Aβ_1-42), phosphorylated tau (ptau-181), and total-tau (tau)). The Revised NEO Personality Inventory (NEO-PI-R) was administered twice, once to evaluate subjects' current personality and once to assess personality traits retrospectively 5 years before evaluation. Subjects with an AD CSF biomarker profile showed significant increase in neuroticism and decrease in conscientiousness over time as compared to non-AD CSF biomarker group. In regression analysis controlling for global cognition as measured by the MMSE score, increasing neuroticism and decreasing extraversion, openness to experience and conscientiousness were associated with lower Aβ_1-42 concentrations but not with tau and ptau-181 concentrations. Our findings suggest that early and specific changes in personality are associated with cerebral AD pathology. Concentrations of CSF biomarkers, additionally to severity of the cognitive impairment, significantly contribute in predicting specific personality changes.     

Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens

Using immunocytochemistry we have shown that there is a population of macrophages within the stroma of the choroid plexus of rats and mice which expresses high levels of major histocompatibility complex Class II antigens. In whole mount preparations of the choroid plexus, the morphology and regular distribution of these cells is similar to the Langerhans cells of the skin. These cells reside at an important interface between the central nervous system and the peripheral immune system and their possible role in immune-mediated diseases of the central nervous system is discussed.     

The amyloid hypothesis,time to move on: Amyloid is the downstream result,not cause,of Alzheimer's disease

The “amyloid hypothesis” has dominated Alzheimer research for more than 20 years, and proposes that amyloid is the toxic cause of neural/synaptic damage and dementia. If correct, decreasing the formation or removing amyloid should be therapeutic. Despite discrepancies in the proposed mechanism, and failed clinical trials, amyloid continues to be considered the cause of a degenerative cascade. Alternative hypotheses must explain three features: (i) why amyloid toxicity is not the etiology of Alzheimer's disease (AD), (ii) what alternative mechanisms cause the degeneration and dementia of AD, and (iii) why increased amyloid accumulates in the brain in AD. We propose that AD, which occurs in elderly, already vulnerable brains, with multiple age-related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch-related angiogenesis. With impaired microvasculature, a lack of vascular endothelial-derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures. Therapeutic strategies should focus on supporting normal angiogenesis.     

The clinical use of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers Standardization Initiative

BackgroundCerebrospinal fluid (CSF) biomarkers β-amyloid 1-42 (Aβ_1-42), also expressed as Aβ_1-42:Aβ_1-40 ratio, T-tau, and P-tau_181P, have proven diagnostic accuracy for mild cognitive impairment and Alzheimer's disease (AD). How to use, interpret, and disclose biomarker results drives the need for standardization.MethodsPrevious Alzheimer's Biomarkers Standardization Initiative meetings discussed preanalytical issues affecting Aβ_1-42 and tau in CSF. This second round of consensus meetings focused on issues related to clinical use of AD CSF biomarkers.ResultsConsensus was reached that lumbar puncture for AD CSF biomarker analysis be considered as a routine clinical test in patients with early-onset dementia, at the prodromal stage or with atypical AD. Moreover, consensus was reached on which biomarkers to use, how results should be interpreted, and potential confounding factors.ConclusionsChanges in Aβ_1-42, T-tau, and P-tau_181P allow diagnosis of AD in its prodromal stage. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up.     

Immune system-associated antigens on the surface of peripheral blood lymphocytes in patients with Alzheimer's disease.

We investigated the immune-associated antigens of peripheral lymphocytes from 13 patients with Alzheimer's disease (AD) and 13 age-matched healthy control subjects using two-color analysis with flow cytometry. Four ratios of immune-related antigens, T/B lymphocytes, CD4/CD8, CD4/CD45R and CD4/HLA-DR, were compared for the AD and control groups. The T/B and CD4/CD8 ratios did not differ between the groups, the ratio of CD4+CD45R+ subset in the AD group was lower than the ratio in the control group, and the ratios of CD4+ CD45R- and CD4+HLA-DR+ subsets in the AD group were significantly higher. Further, in the AD group, the CD4+ CD45R+/CD4+ ratio was lower and the CD4+ CD45R- CD4+ ratio was higher than in the control group.     

Relationship between physical activity,cognition, and Alzheimer pathology in autosomal dominant Alzheimer's disease

Introduction

Little is known about effects of physical activity (PA) in genetically driven early-onset autosomal dominant Alzheimer's disease (AD).

Tau–amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid‐induced disruption of axonal projections and exacerbated axonal pathology

Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimer's disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle‐bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimer's disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex) and mutant APP/PS1 (in a widespread distribution) to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau‐expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau‐containing axons. Moreover, human P301L tau‐containing axons appear to increase the extent of dystrophic axons around plaques. Thus, the presence of amyloid deposits in the axonal terminal zone of pathological tau‐containing neurons profoundly impacts their normal connectivity. J. Comp. Neurol. 521:4236–4248, 2013. © 2013 Wiley Periodicals, Inc.     

The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis

Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-analysis. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm.     

Managing the burden of Alzheimer's disease: a partnership between caregiver and physician

Alzheimer's disease is a progressive, neurodegenerative disease that preferentially afflicts the elderly. Its clinical features include impairment of cognitive function and decline in activities of daily living, as well as emotional and personality changes. The effective management of Alzheimer's disease requires a partnership between physician and caregiver. Caregivers play a crucial role in the long-term care of demented patients. The demonstration that home-based care is a more economically viable solution than institutional care has led to the realization that community-based care must be supported and preserved if society is to cope with the burgeoning number of patients with Alzheimer's disease. Physicians depend upon caregivers to impart information concerning a patient's cognitive, functional and behavioural symptoms, whether for diagnosis, to assess the efficacy of a particular treatment, or to ascertain the staging of the disease. Caregivers suffer an enormous physical, emotional, financial and psychological burden as a consequence of the demands of caring. They are frequently at risk of ill-health and depression themselves, jeopardizing their ability to care. These problems can be alleviated through support, information, education, counselling, and various treatment programmes, which the physician can provide either directly to the caregivers, or can arrange for them. Where caregivers have a more realistic expectation of their caregiving role, and of the patient's capabilities, they are invariably better able to cope. They can be taught to manage effectively the troublesome behavioural symptoms of Alzheimer's disease, which are the most distressing features for the caregiver. The result of a strong and effective alliance between caregiver and physician is a carer who is more accepting and realistic about the caregiving role, and therefore better able to rise to the demands of caring. In turn, the physician is fully informed about the patient and in the best possible position to prescribe treatment, whether pharmacological or non-pharmacological, for the patient and/or caregiver. The patient whose behavioural symptoms are better managed, thereby reducing anxiety and aggression, receives an optimal level of care, both from the Caregiver and physician.     

Biomarkers of Alzheimer's disease: The present and the future

A paradigm shift has occurred in the last ten years in the diagnostic field of Alzheimer's disease (AD). Scientific thought has enriched the concept of AD as a pathophysiological continuum and emphasized contribution of biological, morphological and functional brain imaging biomarkers for diagnosis, in particular during the early stages of the disease. We address here the present and the future of these biological biomarkers. Most of them are linked to the pathophysiological lesions of the Alzheimer process: aggregates of hyperphosphorylated tau proteins, also called neurofibrillary tangles (NFT), and extracellular deposit of amyloid-beta peptides (Aβ), also called senile plaques. The detection in the cerebrospinal fluid (CSF) of tau and Aβ represents the current diagnostic practice of AD. Improvement for a more accurate and earlier biological diagnosis is however expected using a new generation of biomarkers, mostly in relation with tau and Aβ metabolism.     

Relationship between alcohol intake,age of onset and duration of Alzheimer's disease: A pilot survey of 84 autopsy-confirmed cases

Little is known about the drinking habits of individuals who develop Alzheimer's disease. A pilot survey of 84 autopsy-confirmed Alzheimer cases was carried out to explore a possible role of alcohol consumption in the onset and duration of Alzheimer's disease. Information on the drinking habits of deceased patients for a 15-year period prior to the onset of the disease was obtained from a surrogate respondent (next of kin) and from the patients' medical records. Alzheimer patients' drinking patterns were comparable to those of the general population. Patients with a history of alcohol abuse did not develop Alzeimer's disease at an earlier age than abstainers or occasional, light or moderate drinkers. Although not statistically significant, duration of survival in Alzheimer's disease was a few years shorter in patients with a history of alcohol abuse.     

Coexistence of Creutzfeldt‐Jakob disease,Lewy body disease,and Alzheimer's disease pathology: An autopsy case showing typical clinical features of Creutzfeldt‐Jakob disease

We report here an autopsy case of sporadic Creutzfeldt‐Jakob disease (CJD) without hereditary burden and with a clinical course typical of sporadic CJD. A 77‐year old man developed memory disturbance, followed by gait disturbance and myoclonus. He died of bronchopneumonia 5 months after the disease onset. Post‐mortem examination revealed neuronal loss, astrocytosis, and patchy spongiosis in the cerebral cortex and lenticular nuclei. Synaptic‐type deposits of prion protein were present in the cerebral cortex. Additionally, Lewy bodies were observed in the cerebral cortex and substantia nigra. Furthermore, senile plaques compatible with definite Alzheimer's disease according to Consortium to Establish a Registry for Alzheimer's disease criteria and neurofibrillary changes of the limbic system consistent with Braak stage IV were found. Based on a review of the published literature, this autopsy case is very rare, and we suppose that the incidence of CJD accompanied by Lewy body disease and Alzheimer's disease is very low.     

The diagnostic accuracy of an incidental memory modification of the Boston Naming Test (memo-BNT) in differentiating between normal aging and mild Alzheimer's disease

Early Alzheimer's disease (AD) is associated with deficits in episodic memory. Semantic memory and naming have also been found to be affected, although to a lesser degree than episodic memory. Most episodic memory tests used in clinical settings assess intentional memory. The aim of the present paper was to present an incidental memory modification of the Boston Naming Test (memo-BNT) and to study the diagnostic accuracy of the BNT and the memo-BNT in differentiating between healthy old controls and AD patients. There were three groups in the study: 22 young controls (mean age 21.7), 23 normally aged old controls (mean age 70.6), and 23 patients with mild AD (mean age 74.0). There were no differences in the memo-BNT test scores between the old and young control participants. There were, however, significant differences between the AD patients and both control groups in several of the memo-BNT measures. Incidental free recall was the best measure in discriminating between the healthy aged controls and the AD patients (AUC?=?.939) and it had a better diagnostic accuracy than naming (AUC?=?880). The results indicate that the memo-BNT could be used in clinical settings especially to differentiate between normal aging and mild AD.