Herpes simplex virus alters Alzheimer's disease biomarkers - A hypothesis paper.

INTRODUCTION: Human herpes simplex virus 1 (HSV1) is discussed to induce amyloid-ß (Aß) accumulation and neurofibrillary tangles of hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) in cell culture and animal models. Aß appears to be virostatic. We investigated the association between intrathecal antibodies against HSV or cytomegalovirus (CMV) and cerebrospinal fluid (CSF) AD biomarkers. METHODS: Aß42 /Aß40 ratio, pTau, and tTau were measured in CSF of 117 patients with early AD positive for amyloid pathology (A+) and 30 healthy controls (A-). CSF-to-serum anti-HSV1/2-IgG antibody indices (AI-IgGHSV1/2 ) and CMV (AI-IgGCMV ) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Exclusively in HSV1-seropositive AD, pTau was positively and significantly predicted by AI-IgGHSV1/2 and negatively by the Aß42 /Aß40 ratio in both univariate and multivariate regression analyses. Furthermore, a significant and negative interaction between the AI-IgGHSV1/2 and Aß42 /Aß40 ratio on pTau was found. DISCUSSION: The results support the hypothesis that HSV infection contributes to AD. HIGHLIGHTS: HSV antibody index is positively associated with tau pathology in patients with AD. HSV antibody index is negatively associated with cerebral FDG metabolism. Amyloid modulates the association of HSV antibody index with CSF-pTau. HSV in AD offers a pathophysiological model connecting tau and amyloid.

Serum GFAP differentiates Alzheimer's disease from frontotemporal dementia and predicts MCI-to-dementia conversion.

OBJECTIVE: Reactive astrogliosis is a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD). METHODS: This multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple). RESULTS: In total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276-505 pg/mL) compared with controls (167 pg/mL, IQR 108-234 pg/mL) and bvFTD (190 pg/mL, IQR 134-298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232-433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253-414 pg/mL vs 215 pg/mL, IQR 111-266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8). CONCLUSIONS: Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.

Normative brain volume reports may improve differential diagnosis of dementing neurodegenerative diseases in clinical practice.

OBJECTIVES: Normative brain volume reports (NBVRs) are becoming more and more available for the workup of dementia patients in clinical routine. However, it is yet unknown how this information can be used in the radiological decision-making process. The present study investigates the diagnostic value of NBVRs for detection and differential diagnosis of distinct regional brain atrophy in several dementing neurodegenerative disorders. METHODS: NBVRs were obtained for 81 consecutive patients with distinct dementing neurodegenerative diseases and 13 healthy controls (HC). Forty Alzheimer's disease (AD; 18 with dementia, 22 with mild cognitive impairment (MCI), 11 posterior cortical atrophy (PCA)), 20 frontotemporal dementia (FTD), and ten semantic dementia (SD) cases were analyzed, and reports were tested qualitatively for the representation of atrophy patterns. Gold standard diagnoses were based on the patients' clinical course, FDG-PET imaging, and/or cerebrospinal fluid (CSF) biomarkers following established diagnostic criteria. Diagnostic accuracy of pattern representations was calculated. RESULTS: NBVRs improved the correct identification of patients vs. healthy controls based on structural MRI for rater 1 (p < 0.001) whereas the amount of correct classifications was rather unchanged for rater 2. Correct differential diagnosis of dementing neurodegenerative disorders was significantly improved for both rater 1 (p = 0.001) and rater 2 (p = 0.022). Furthermore, interrater reliability was improved from moderate to excellent for both detection and differential diagnosis of neurodegenerative diseases (κ = 0.556/0.894 and κ = 0.403/0.850, respectively). CONCLUSION: NBVRs deliver valuable and observer-independent information, which can improve differential diagnosis of neurodegenerative diseases. KEY POINTS: • Normative brain volume reports increase detection of neurodegenerative atrophy patterns compared to visual reading alone. • Differential diagnosis of regionally distinct atrophy patterns is improved. • Agreement between radiologists is significantly improved from moderate to excellent when using normative brain volume reports.

Correction to: Amyloid PET, FDG-PET or MRI? - the power of different imaging biomarkers to detect progression of early Alzheimer's disease.

Following publication of the original article [1], the authors ask to correct the surname of co-author Dennis Hedderich from from Heddderich to Hedderich.

Development and testing of an informative guide about palliative care for family caregivers of people with advanced dementia.

BACKGROUND: Since people with advanced dementia are usually not able to make complex decisions, it is usually the family caregivers, as proxies, who have to decide on treatments and their termination. However, these decisions are difficult for the caregivers to make, as they are often inadequately informed and cannot properly assess the consequences; moreover, they are concerned about harming the sick person. We aimed to first develop an informative booklet about palliative care issues for caregivers of people with advanced dementia. Secondly, we aimed to investigate a change in family caregivers' knowledge regarding palliative care issues and caregivers' involvement in medical and care decisions before and after studying this booklet. METHODS: A first version of the booklet was drafted by an experienced psychiatrist and palliative care specialist based on existing booklets and guidelines; necessary cultural adaptions were taken into consideration. A nominal group process was conducted to develop the informative guide. In order to investigate the acceptance of the booklet and the possibility to implement it, 38 patient-caregiver dyads were recruited, and caregivers were interviewed both before receiving the booklet and after 3 months of receiving the booklet. RESULTS: Experts from various disciplines collaborated on a German booklet for family caregivers of people with advanced dementia as an information aid regarding issues of palliative care. The subsequent test showed that all caregivers had experienced a personal benefit from the booklet. Caregivers had a significant gain of knowledge after provision of the booklet. A large proportion of caregivers who had not previously considered and/or discussed medical topics reported that they had done so within 3 months after obtaining the booklet, or planned to do so in the near future. CONCLUSIONS: The caregivers valued the comprehensible, concise and well-structured information guide on palliative care issues in advanced dementia. They agreed it increases knowledge and prompts decision making and therefore should be developed in many languages and disseminated among family caregivers of people with dementia. TRIAL REGISTRATION: clinicaltrial.gov, NCT03548142. Retrospectively registered 7 June 2018.

The overnight reduction of amyloid ß 1-42 plasma levels is diminished by the extent of sleep fragmentation, sAPP-ß, and APOE ε4 in psychiatrists on call.

INTRODUCTION: In mice there might be an association between sleep deprivation and amyloid ß plasma levels. Hence, we examined whether amyloid plasma levels are associated with sleep duration or fragmentation in 17 psychiatrists on-call. METHODS: Amyloid ß (Aß)42, Aß40, and soluble amyloid precursor protein ß (sAPP-ß) plasma concentrations were measured at the beginning and end of 90 on-call nights, and analyzed using generalized linear models. RESULTS: In on-call nights, a 10.7% reduction of Aß42 was revealed overnight. Every single short sleep interruption diminished this reduction by 5.4%, as well as every pg/mL of sAPP-ß by 1.2%, each copy of APOE ε4 by 10.6%, and each year of professional experience by 3.0%. DISCUSSION: The extent of sleep fragmentation diminishes the physiological overnight reduction of Aß42 but not Aß40 plasma levels in the same direction as the enzyme for Aß42 production, the genetic risk factor for Alzheimer's disease (AD), and on-call experience. Might on-call duty and sleep fragmentation in general alter the risk for AD?

Amyloid PET, FDG-PET or MRI? - the power of different imaging biomarkers to detect progression of early Alzheimer's disease.

BACKGROUND: As investigations of disease modifying drugs aim to slow down progression of Alzheimer' disease (AD) biomarkers to reliably track disease progression gain more importance. This is especially important as clinical symptoms, including psychometric measures, are only modestly associated with the underlying disease pathology, in particular at the pre-dementia stages. The decision which biomarkers to choose in clinical trials is crucial and depends on effect size. However, longitudinal studies of multiple biomarkers in parallel that allow direct comparison on effect size are scarce. METHODS: We calculated effect size and minimal sample size for three common imaging biomarkers of AD, namely amyloid deposition measured with PiB-PET, neuronal dysfunction measured with FDG-PET and cortical thickness measured with MRI in a prospective 24-month follow-up study in a monocentric cohort of early AD. RESULTS: Post hoc power calculation revealed large effect sizes of Cohen's d for PiB-PET and cortical thickness and a small effect size for FDG-PET (1.315, 0.914, and 0.341, respectively). Accordingly, sample sizes for PiB-PET and cortical thickness required significantly smaller sample sizes than FDG-PET to reliably detect statistically significant changes after 24 months in early AD (n = 7, n = 12, and n = 70, respectively). CONCLUSION: Amyloid imaging with PET and measuring cortical thickness with MRI are suitable biomarkers to detect disease progression in early AD within a small sample.

Associations of Neprilysin Activity in CSF with Biomarkers for Alzheimer's Disease.

BACKGROUND: Neprilysin (NEP) cleaves amyloid-ß 1-42 (Aß42) in the brain. Hence, we aimed to elucidate the effect of NEP on Aß42 in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [11C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. METHODS: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer's disease patients. RESULTS: CSF-NEP was significantly inversely associated with CSF-Aß42 and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. CONCLUSIONS: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer's pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

Fluid biomarker agreement and interrelation in dementia due to Alzheimer's disease.

The cerebrospinal fluid (CSF) levels of ß-amyloid 42, total tau, and phosphorylated tau 181 are supposed to be all continuously abnormal in dementia due to Alzheimer's disease (AD), being the most advanced disease stage. The aim of the present study, which included a monocentric and a multicentric sample (N = 119 and 178, respectively), was to investigate the degree of CSF biomarker agreement and interrelation in AD dementia. Based on previously published cut-off values, biomarker values were categorized as positive or negative for AD (dichotomization strategy) and as either positive, negative, or borderline (trichotomization strategy). The statistical analyses relied on distance correlation analysis and kappa (k) statistics. Poor agreement (k < 0.4) and low interrelations between the studied biomarkers were detected in all cases with the exception of the interrelation between the markers total tau and phosphorylated tau 181, especially in the monocentric sample. Interestingly, lower interrelation and agreement degrees were observed in carriers of the Apolipoprotein E ε4 allele compared to non-carriers. The clinical phenotype currently referred to as "AD dementia" is characterized by an inhomogeneous CSF biomarker profile, possibly mirroring the complex genesis of AD-typical dementia symptoms and pointing to the necessity of shedding more light on the hypothesis of biomarker stability over time in symptomatic AD.

Cerebrospinal Fluid BACE1 Activity and sAßPPß as Biomarker Candidates of Alzheimer's Disease.

BACKGROUND/AIMS: The utility of ß-site amyloid-ß precursor protein (AßPP) cleaving enzyme 1 (BACE1) activity and soluble AßPP ß (sAßPPß) levels in cerebrospinal fluid (CSF) in detecting Alzheimer's disease (AD) is still elusive. METHODS: BACE1 activity and sAßPPß concentration were measured in patients with AD dementia (n = 56) and mild cognitive impairment (MCI) due to AD (n = 76) with abnormal routine AD CSF markers, in patients with MCI with normal CSF markers (n = 39), and in controls without preclinical AD (n = 48). In a subsample with available 18F-fluorodeoxyglucose positron emission tomography (FDG PET) data, ordinal regression models were employed to compare the contribution of BACE1 and sAßPPß to correct diagnostic classification to that of FDG PET. RESULTS: BACE1 activity was significantly higher in patients with MCI due to AD compared to both controls and patients with MCI with normal CSF markers. sAßPPß did not differ between any of the studied groups. Interestingly, BACE1 activity was not found to be inferior to FDG PET as predictive covariate in differentiating between the diagnostic groups. CONCLUSIONS: Further studies using biomarker-underpinned diagnoses are warranted to shed more light on the potential diagnostic utility of BACE1 activity as AD biomarker candidate in MCI.

Neuro-cognitive mechanisms of simultanagnosia in patients with posterior cortical atrophy.

Posterior cortical atrophy is dominated by progressive degradation of parieto-occipital grey and white matter, and represents in most cases a variant of Alzheimer's disease. Patients with posterior cortical atrophy are characterized by increasing higher visual and visuo-spatial impairments. In particular, a key symptom of posterior cortical atrophy is simultanagnosia i.e. the inability to perceive multiple visual objects at the same time. Two neuro-cognitive mechanisms have been suggested to underlie simultanagnosia, either reduced visual short-term memory capacity or decreased visual processing speed possibly resulting from white matter impairments over and above damage to cortical brain areas. To test these distinct hypotheses, we investigated a group of 12 patients suffering from posterior cortical atrophy with homogenous lesion sides in parieto-occipital cortices and varying severity of grey and white matter loss. More specifically, we (i) tested whether impaired short-term memory capacity or processing speed underlie symptoms of simultanagnosia; (ii) assessed the link to grey and white matter damage; and (iii) integrated those findings into a neuro-cognitive model of simultanagnosia in patients with posterior cortical atrophy. To this end, simultaneous perception of multiple visual objects was tested in patients with posterior cortical atrophy mostly with positive Alzheimer's disease biomarkers and healthy age-matched controls. Critical outcome measures were identification of overlapping relative to non-overlapping figures and visuo-spatial performance in tests sensitive to simultanagnosia. Using whole report of briefly presented letter arrays based on the mathematically formulated 'Theory of Visual Attention', we furthermore quantified parameters of visual short-term memory capacity and visual processing speed. Grey and white matter atrophy was assessed by voxel-based morphometry analyses of structural magnetic resonance data. All patients showed severe deficits of simultaneous perception. Compared to controls, we observed a specific slowing of visual processing speed, while visual short-term memory capacity was preserved. In a regression analysis, processing speed was identified as the only significant predictor of simultaneous perception deficits that explained a high degree of variance (70-82%) across simultanagnosia tasks. More severe slowing was also indicative for more severe impairments in reading and scene comprehension. Voxel-based morphometry yielded extensive reductions of grey and white matter in parieto-occipital and thalamic brain areas. Importantly, the degree of individual atrophy of white matter in left superior parietal lobe, but not of any grey matter region, was associated with processing speed. Based on these findings, we propose that atrophy of white matter commonly observed in posterior cortical atrophy leads to slowing of visual processing speed, which underlies the overt clinical symptoms of simultanagnosia.

Mapping CSF biomarker profiles onto NIA-AA guidelines for Alzheimer's disease.

The National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines for Alzheimer's disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA-AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102). The CSF biomarkers ß-amyloid 1-42, total tau, and phosphorylated tau at threonine 181 were measured with commercially available assays. Biomarker values were trichotomized into positive for AD, negative, or borderline. In controls the presence of normal CSF profiles varied between 13.6 and 25.4 % across the studied groups, while up to 8.6 % of them had abnormal CSF biomarkers. In 40.3-52.9 % of patients with AD dementia, a typical CSF profile for AD was detected. Approximately 40 % of the potential biomarker constellations are not considered in the NIA-AA guidelines, and more than 40 % of participants could not be classified into the NIA-AA categories with distinct biomarker constellations. Here, a refined scheme covering all potential biomarker constellations is proposed. These results enrich the discussion on the NIA-AA guidelines and point to a discordance between clinical symptomatology and CSF biomarkers even in patients with full-blown AD dementia, who are supposed to have a clearly positive for AD neurochemical profile.

Within-patient correspondence of amyloid-ß and intrinsic network connectivity in Alzheimer's disease.

There is striking overlap between the spatial distribution of amyloid-ß pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-ß and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-ß plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-ß exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-ß on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-ß and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-ß on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-ß distributions. Here we compared spatial patterns of amyloid-ß-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-ß and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-ß aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-ß-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-ß pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-ß-plaque concentration. The local negative association between amyloid-ß and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-ß on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-ß and intrinsic connectivity, with the distribution of amyloid-ß pathology following functional connectivity gradients within and across intrinsic networks.

Trends of patient referral to a memory clinic and towards earlier diagnosis from 1985-2009.

BACKGROUND: It may be assumed that increased public awareness of dementia due to Alzheimer's disease (AD) together with the availability of efficacious treatment will result in diagnostic evaluation at earlier stages of cognitive decline and diagnosis of dementia due to AD at earlier stages. METHODS: All persons that were examined at a university based memory clinic, in Germany, between 1985 and 2009 were included. RESULTS: In the 3,951 persons identified, linear regression analysis revealed a positive association between Mini Mental State Examination (MMSE) score and year of initial examination (yearIE) (ß = 0.266; p < 0.001). In the 1,821 patients diagnosed with dementia due to AD, a positive association between MMSE score and yearIE (ß = 0.230; p < 0.001) was revealed. MMSE scores were higher (ß = 0.195; p < 0.001) after the introduction of cholinesterase inhibitors in Germany in 1997. CONCLUSIONS: Diagnostic evaluation of individuals occurred at progressively earlier stages of cognitive decline. Dementia due to AD was diagnosed at progressively earlier stages, and this trend was associated with the availability of efficacious treatment. This is the first study on changes in patient referral and diagnosis based on a continuous 25 years period.

Link between hippocampus' raised local and eased global intrinsic connectivity in AD.

BACKGROUND: The hippocampus (HP) is part of the default mode network (DMN), and both are key targets of Alzheimer's disease (AD). Because of widespread network degeneration, it has been suggested that increasing HP disconnection from the DMN may lead to progressive disinhibition of intra-HP synchronized activity. METHODS: To analyze HP local (i.e., within HP) and global (i.e., within DMN) intrinsic functional connectivity (local/global intrinsic functional connectivity [iFC]), healthy controls and patients with mild cognitive impairment and AD dementia were assessed by spatial high and normal resolution resting-state functional magnetic resonance imaging. RESULTS: Although patients' parietal local-iFC was reduced and positively correlated with reduced global-iFC within the DMN, HP local connectivity was progressively increased and negatively correlated with HP decreased global connectivity. Increased intra-HP connectivity was associated with impaired memory. CONCLUSION: Our result demonstrates a link between increased local and reduced global hippocampal connectivity in AD. Increased intra-HP synchrony may contribute to distinct symptoms such as memory impairment or more speculatively epileptic seizure.

Elecsys Cerebrospinal Fluid Immunoassays Accurately Detect Alzheimer's Disease Regardless of Concomitant Small Vessel Disease.

BACKGROUND: Differentiating dementia due to small vessel disease (SVD) from dementia due to Alzheimer's disease (AD) with concomitant SVD is challenging in clinical practice. Accurate and early diagnosis of AD is critical to delivering stratified patient care. OBJECTIVE: We characterized the results of Elecsys® cerebrospinal fluid (CSF) immunoassays (Roche Diagnostics International Ltd) in patients with early AD, diagnosed using core clinical criteria, with varying extent of SVD. METHODS: Frozen CSF samples (n = 84) were measured using Elecsys ß-Amyloid(1-42) (Aß42), Phospho-Tau (181P) (pTau181), and Total-Tau (tTau) CSF immunoassays, adapted for use on the cobas® e 411 analyzer (Roche Diagnostics International Ltd), and a robust prototype ß-Amyloid(1-40) (Aß40) CSF immunoassay. SVD was assessed by extent of white matter hyperintensities (WMH) using the lesion segmentation tool. Interrelations between WMH, biomarkers, fluorodeoxyglucose F18-positron emission tomography (FDG-PET), and other parameters (including age and Mini-Mental State examinations [MMSE]) were assessed using Spearman's correlation, sensitivity/specificity, and logistic/linear regression analyses. RESULTS: The extent of WMH showed significant correlation with Aß42/Aß40 ratio (Rho=-0.250; p = 0.040), tTau (Rho = 0.292; p = 0.016), tTau/Aß42 ratio (Rho = 0.247; p = 0.042), age (Rho = 0.373; p = 0.002), and MMSE (Rho=-0.410; p = 0.001). Sensitivity/specificity point estimates for Elecsys CSF immunoassays versus FDG-PET positivity for underlying AD pathophysiology were mostly comparable or greater in patients with high versus low WMH. WMH were not a significant predictor and did not interact with CSF biomarker positivity but modified the association between pTau181 and tTau. CONCLUSION: Elecsys CSF immunoassays detect AD pathophysiology regardless of concomitant SVD and may help to identify patients with early dementia with underlying AD pathophysiology.

Cerebrospinal fluid lactate levels along the Alzheimer's disease continuum and associations with blood-brain barrier integrity, age, cognition, and biomarkers.

BACKGROUND: Cerebrospinal fluid (CSF) lactate levels have been suggested to be associated with disease severity and progression in several neurological diseases as an indicator of impaired energy metabolism, neuronal death, or microglial activation. Few studies have examined CSF lactate levels in dementia due to Alzheimer's disease (AD) and found higher values in AD patients compared to healthy controls (HC). However, these studies were mostly small in size, the inclusion criteria were not always well defined, and the diagnostic value and pathophysiological significance of CSF lactate in AD remain unclear. METHODS: We examined CSF lactate levels and potentially associated factors in a large (n=312), biologically and clinically well-defined sample of patients with AD at the stage of mild cognitive impairment (MCI-AD) and dementia (ADD), HC, and patients with frontotemporal lobar degeneration (FTLD). RESULTS: Contrary to previous studies, patients with ADD and HC did not differ in CSF lactate levels. However, we found higher values for patients with MCI-AD compared to those with ADD and to HC in univariate analysis, as well as for MCI-AD compared to ADD when controlling for age and blood-brain barrier integrity. CSF lactate levels were associated with age and blood-brain barrier integrity but not with clinical severity or CSF biomarkers of AD. CONCLUSIONS: CSF lactate does not indicate biological or clinical disease severity in AD, nor does it differentiate between patients with AD and HC or patients with FTLD. However, higher CSF lactate levels were found in earlier stages of AD, which might be interpreted in the context of inflammatory processes.

The cerebrospinal fluid biomarker ratio Aß42/40 identifies amyloid positron emission tomography positivity better than Aß42 alone in a heterogeneous memory clinic cohort.

BACKGROUND: Cerebrospinal fluid (CSF) analysis for detecting amyloid positivity may be as reliable as positron emission tomography (PET). We evaluated the performance of the amyloid beta (Aß)42/40 ratio for predicting amyloid positivity by PET, compared with Aß42 alone, and phosphorylated tau 181 (pTau181)/Aß42 and total tau (tTau)/Aß42 ratios, using fully automated CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) in a heterogeneous cohort of patients with a range of cognitive disorders reflecting the typical population of a memory clinic. METHODS: CSF samples from 103 patients with known amyloid PET status (PET positive = 54; PET negative = 49) were retrospectively selected from one site in Germany; 71 patients were undergoing treatment for mild cognitive impairment (n = 44) or mild-to-moderate dementia (n = 27) due to Alzheimer's disease (AD), and 32 patients were undergoing treatment for non-AD-related cognitive disorders. Aß42, pTau181, and tTau concentrations were measured in CSF samples using the respective Elecsys® CSF immunoassays modified for use on the cobas e 411 analyzer; Aß40 concentrations were measured using a non-commercially available robust prototype assay. Sensitivities/specificities for amyloid positivity cut-offs (Youden-derived and pre-defined) were calculated, and receiver operating characteristic analyses determined area under the curve (AUC) versus amyloid PET status. Limitations include a small sample size, use of a pre-analytical protocol not in accordance with the Elecsys CSF immunoassay method sheets, and the lack of a pre-defined cut-off for Aß42/40. RESULTS: Point estimates for sensitivity and specificity of CSF biomarkers and biomarker ratios versus amyloid PET were 0.93 and 0.57 for Aß42, 0.96 and 0.69 for pTau181/Aß42, 0.92 and 0.69 for tTau/Aß42, and 0.94 and 0.82 for Aß42/40. For AUCs, point estimates (95% confidence intervals) versus amyloid PET were 0.78 (0.68-0.88) for Aß42, 0.88 (0.81-0.95) for pTau181/Aß42, 0.87 (0.80-0.95) for tTau/Aß42, and 0.90 (0.83-0.97) for Aß42/40. CONCLUSIONS: CSF Aß42/40 ratio can predict PET amyloid positivity with high accuracy in patients with a range of cognitive disorders when evaluating Aß pathology independent of tau and neurodegeneration for research purposes. The performance of Aß42/40 was comparable with pTau181/Aß42 and tTau/Aß42 used in clinical practice and better than Aß42 alone.

Altered retinal cerebral vessel oscillation frequencies in Alzheimer's disease compatible with impaired amyloid clearance.

Retinal vessels are similar to cerebral vessels in their structure and function. Moderately low oscillation frequencies of around 0.1 Hz have been reported as the driving force for paravascular drainage in gray matter in mice and are known as the frequencies of lymphatic vessels in humans. We aimed to elucidate whether retinal vessel oscillations are altered in Alzheimer's disease (AD) at the stage of dementia or mild cognitive impairment (MCI). Seventeen patients with mild-to-moderate dementia due to AD (ADD); 23 patients with MCI due to AD, and 18 cognitively healthy controls (HC) were examined using Dynamic Retinal Vessel Analyzer. Oscillatory temporal changes of retinal vessel diameters were evaluated using mathematical signal analysis. Especially at moderately low frequencies around 0.1 Hz, arterial oscillations in ADD and MCI significantly prevailed over HC oscillations and correlated with disease severity. The pronounced retinal arterial vasomotion at moderately low frequencies in the ADD and MCI groups would be compatible with the view of a compensatory upregulation of paravascular drainage in AD and strengthen the amyloid clearance hypothesis.

Age-Dependency of Total Tau in the Cerebrospinal Fluid Is Corrected by Amyloid-ß 1-40: A Correlational Study in Healthy Adults.

BACKGROUND: Tau proteins are established biomarkers of neuroaxonal damage in a wide range of neurodegenerative conditions. Although measurement of total-Tau in the cerebrospinal fluid is widely used in research and clinical settings, the relationship between age and total-Tau in the cerebrospinal fluid is yet to be fully understood. While past studies reported a correlation between age and total-Tau in the cerebrospinal fluid of healthy adults, in clinical practice the same cut-off value is used independently of patient's age. OBJECTIVE: To further explore the relationship between age and total-Tau and to disentangle neurodegenerative from drainage-dependent effects. METHODS: We analyzed cerebrospinal fluid samples of 76 carefully selected cognitively healthy adults and included amyloid-ß 1-40 as a potential marker of drainage from the brain's interstitial system. RESULTS: We found a significant correlation of total-Tau and age, which was no longer present when correcting total-Tau for amyloid-ß 1-40 concentrations. These findings were replicated under varied inclusion criteria. CONCLUSION: Results call into question the association of age and total-Tau in the cerebrospinal fluid. Furthermore, they suggest diagnostic utility of amyloid-ß 1-40 as a possible proxy for drainage-mechanisms into the cerebrospinal fluid when interpreting biomarker concentrations for neurodegenerative diseases.