INTRODUCTION: The prevention of Alzheimer’s disease (AD) has become a real challenge due to its rising prevalence and the lack of an effective cure. Diet and nutrients have gained significant ...interest as potentially modifiable protective factors. PURPOSE: The aim of this review is to provide an updated summary of evidence related to the effect of diet and nutritional factors on the risk of AD and cognitive aging, and discuss the potential mechanisms and confounding factors involved. METHODS: A search was conducted in Medline and Web of Knowledge for epidemiological and clinical studies in the international literature from January 2000 to February 2013 using combinations of the following keywords: “Alzheimer’s disease”, “mild cognitive impairment”, “cognitive function”, “dietary factors”, “omega-3”, “antioxidants”, “B vitamins”, “dietary patterns”, and “Mediterranean diet”. RESULTS AND CONCLUSION: Data from observational studies point to a protective role for certain nutrients, such as omega-3 fatty acids, antioxidants or B vitamins, and dietary patterns (Mediterranean diet). However, data from randomized controlled trials do not show a consistent effect. Whether confounding factors such as age, disease stage, other dietary components, cooking processes, and other methodological issues explain the divergent results remains to be established. Moreover, if certain nutrients protect against dementia, it is as yet unknown whether they may have a general effect on brain vascular health or directly interfere with the etiopathogenesis of AD.
Objectives
We studied a sample of cognitively unimpaired individuals, with and without subjective cognitive decline (SCD), in order to investigate accelerated long‐term forgetting (ALF) and to ...explore the relationships between objective and subjective cognitive performance and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers.
Methods
Fifty‐two individuals were included and SCD was quantified through the Subjective Cognitive Decline Questionnaire (SCD‐Q), using its validated cutoff to classify participants as Low SCD‐Q (n = 21) or High SCD‐Q (n = 31). These groups were further subdivided according to the presence or absence of abnormal levels of CSF Aβ42. Objective cognitive performance was assessed with the Ancient Farming Equipment Test (AFE‐T), a new highly‐demanding test that calls for acquisition and retention of novel object/name pairs and allows measuring ALF over a 6‐month period.
Results
The High SCD‐Q group showed a significantly higher free forgetting rate at 3 months compared to the Low SCD‐Q (F 1,44 = 4.72; p < 0.05). When stratifying by amyloid status, High SCD‐Q/Aβ+ showed a significantly lower performance than High SCD‐Q/Aβ–on the final free and cued learning scores (F 1,27 = 6.44, p < 0.05 and F 1,27 = 7.51, p < 0.05, respectively), the 1‐week free and cued recall (F 1,24 = 4.49; p < 0.05 and F 1,24 = 7.10; p < 0.01, respectively), the 1‐week cued forgetting rate (F 1,24 = 5.13; p < 0.05), and the 3‐month cued recall (F 1,24 = 4.27; p < 0.05). Linear regression analyses showed that higher SCD‐Q scores were associated with higher forgetting rates on the AFE‐T (β = −0.212; p < 0.05).
Conclusions
It is possible to detect ALF in individuals with high SCD ratings, appearing especially in those with abnormal CSF Aβ42 levels. Both in research and the clinical field, there is an increasing need of using more demanding cognitive measures, such as the AFE‐T, for identifying and tracking the earliest cognitive changes in these populations.
Key Points
We assessed accelerated long‐term forgetting (ALF) in subjective cognitive decline (SCD)
We found ALF over 3 months in individuals with high SCD ratings
Individuals with high SCD ratings and abnormal Aβ42 levels displayed higher forgetting rates
ALF might be a potential marker of subtle cognitive dysfunction in the AD continuum
Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD).
We included healthy control subjects (N = 254), mild cognitive impairment (N ...= 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum.
Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages.
These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification.
OBJECTIVE:To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with ...suspected non-Alzheimer pathology (SNAP).
METHODS:We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau t-tau, phospho-tau p-tau), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging–Alzheimerʼs Association classificationstage 0, 1, 2, 3, and SNAP.
RESULTS:The median age in the whole cohort was 58.8 years (range 39.8–81.6). Participants in stages 2–3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2–3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42.
CONCLUSIONS:Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.
In the search for biomarkers of synapse loss associated with Alzheimer's disease (AD), we used shotgun proteomics to identify a panel of 9 synaptic proteins detectable in human cerebrospinal fluid ...(CSF). Expression at the human synapse was verified using super resolution microscopy. Using SRM, we monitored the panel in CSF from 3 independent clinical cohorts. We report 6 synaptic biomarkers that demonstrate changes in preclinical AD prior to markers of neurodegeneration, which could have clinical value for assessing disease progression.
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Highlights
•Proteomic analysis of cerebrospinal fluid and identification of synaptic component.•Use of super resolution microscopy to verify synapse-specificity in human tissue.•Selective reaction monitoring MS (SRM) of synaptic panel in 3 cohorts of Alzheimer's disease cerebrospinal fluid.•Synaptic protein changes precede tau in preclinical Alzheimer's disease.
A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsyntenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n = 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p = 0.04) in an independent cohort (n = 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8-fold, p < 0.04), a finding that was replicated (0.7 to 0.8-fold, p < 0.05) for 6 proteins in a third cohort (n = 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.
Alzheimer's disease is a progressive neurodegenerative disorder, the early detection of which is crucial for timely intervention and enrollment in clinical trials. However, the preclinical diagnosis ...of Alzheimer's encounters difficulties with gold-standard methods. The current definitive diagnosis of Alzheimer's still relies on expensive instrumentation and post-mortem histological examinations. Here, we explore label-free Raman spectroscopy with machine learning as an alternative to preclinical Alzheimer's diagnosis. A special feature of this study is the inclusion of patient samples from different cohorts, sampled and measured in different years. To develop reliable classification models, partial least squares discriminant analysis in combination with variable selection methods identified discriminative molecules, including nucleic acids, amino acids, proteins, and carbohydrates such as taurine/hypotaurine and guanine, when applied to Raman spectra taken from dried samples of cerebrospinal fluid. The robustness of the model is remarkable, as the discriminative molecules could be identified in different cohorts and years. A unified model notably classifies preclinical Alzheimer's, which is particularly surprising because of Raman spectroscopy's high sensitivity regarding different measurement conditions. The presented results demonstrate the capability of Raman spectroscopy to detect preclinical Alzheimer's disease for the first time and offer invaluable opportunities for future clinical applications and diagnostic methods.
We 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).
We 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.
Ng 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.
Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.
Abstract Introduction Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory ...clinic populations. Methods We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain. Results A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect. Discussions The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia. It has a complex pathophysiology that is not yet completely understood, where multiple central, ...systemic, and environmental factors play a key role in disease progression. Understanding the multifactorial nature of AD is paramount to formulate new therapies.
The authors reviewed the role of the amyloid-β-binding, antioxidant, and immunomodulatory properties of albumin in AD and the use of therapeutic plasma exchange (PE) in neurology. The results from the Alzheimer Management By Albumin Replacement (AMBAR) trial that combined the use of PE with albumin replacement in patients with mild-to-moderate AD, are also analyzed.
Findings from the AMBAR study provide encouraging results in the treatment of AD with PE and albumin replacement, especially in patients at the moderate stage of the disease, who showed less cognitive decline from baseline compared with placebo in most of the variables analyzed. Further research is warranted to ascertain the possible mechanisms of action underlying these results. Different cohorts of patients that may also benefit from this treatment, such as those with mild cognitive impairment or other types of dementia, could also be the target of additional studies.
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