Cerebrospinal Fluid Levels Research Articles

Alzheimer’s disease biomarker profiling in a memory clinic cohort without common comorbidities

AbstractBackgroundComorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to Alzheimer disease (AD) progression. However, their mechanistic contribution to pathology and neurodegeneration has not been clarified. The aim of this study was to investigate cerebrospinal fluid (CSF) levels of markers reflecting brain changes in synaptic integrity, inflammation, oxidative stress, glucose homeostasis and cholesterol metabolism in memory clinic patients without known AD comorbidities.MethodCSF samples from 90 memory clinic patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, were used to investigate 13 molecular markers representing key mechanisms underlying AD pathogenesis. Associations were analyzed by linear regression. Two‐step cluster analysis was used to determine patient clusters. Two key markers were analyzed by immunofluorescence staining in hippocampus from control and AD individuals.ResultCSF angiotensinogen, thioredoxin‐1, and interleukin‐15 had the most prominent associations with AD pathology, synaptic and axonal damage. SNAP‐25 and NFL were increased in MCI and AD cases. Grouping biomarkers by biological function, showed that inflammatory and survival components were associated with AD pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data‐driven analysis, two patient clusters were identified; cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared to cluster 2. Clinical groups were evenly distributed between the clusters. Analysis of post‐mortem hippocampal tissue, showed that, compared to non‐demented controls, angiotensinogen staining was higher in AD and co‐localized with phosphorylated‐tau.ConclusionThe identification of biomarker‐driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of AD and the importance of tailored prevention and treatment strategies.

Developing Topics.

Alzheimer's disease (AD) is associated with the accumulation of neuropathological beta-amyloid (Ab) plaques, which is thought to be caused by an imbalance between Ab overproduction and dysfunctional Ab clearance. Both animal and human studies have shown that increased cerebrospinal fluid (CSF) levels of Ab peptides, especially Ab-40 and Ab-38 due to their high solubility, may be indicative of overall Ab dysregulation in preclinical AD, years before pathological Ab plaques begin to aggregate. The apolipoprotein E (APOE) e4 allele, which is the strongest genetic risk factor for AD, has been linked to impaired Ab clearance and disruption of the amyloid precursor protein (APP) pathway that is responsible for Ab production. However, the association between early Ab dysregulation and other genetic risk variants remains understudied. Thus, we aimed to explore whether genetic risk for AD is related to early markers of Ab overproduction by examining associations between polygenic risk scores (PRS) and CSF Ab-40 and Ab-38 in an AD-vulnerable population. We selected 88 non-demented Veterans (Age: M = 68.22, SD = 3.75 years) from the Alzheimer's Disease Neuroimaging Initiative-Department of Defense (ADNI-DOD) database with available genetic markers and CSF measures for Ab-40 and Ab-38. Genetic propensity for AD was assessed using genome-wide PRS, both with and without the APOE region, employing a p-value threshold < 0.01. CSF Ab concentrations were measured using a 2D-UPLC-tandem mass spectrometry method outlined by ADNI-DOD. Partial spearman's correlations related PRS to CSF Ab-38 and Ab-40 levels adjusting for age. CSF Ab-40 levels were positively associated with PRS for AD (rhopartial = 0.22, p = 0.037). When variants in the APOE region were excluded from the score, the relationship between CSF Ab-40 and PRS remained significant (rhopartial = 0.23, p = 0.035). The relationship between PRS for AD and CSF Ab-38 levels was not significant, regardless of whether APOE regions were included in the score (all p's > 0.1). Genetic risk for AD may lead to early Ab overproduction, as evidenced by elevated CSF Ab levels, particularly Ab-40. Other genetic variants, in addition to APOE, may play an integral role in disrupting the APP pathway and dysregulating Ab production.

Sex‐specific associations of cerebrospinal fluid YKL‐40 with white matter hyperintensities over a 7‐year follow‐up period

AbstractBackgroundWomen have a higher prevalence of Alzheimer’s disease (AD), but the underlying reason remains unknown. White matter damage is common in AD and partially attributed to inflammation. Animal models suggest that neuroinflammation with advanced age may differ between sexes, so we assessed whether sex modified associations between neuroinflammation assessed with cerebrospinal fluid (CSF) chitinase 3‐like 1 protein (YKL‐40) and white matter damage in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 33% female) underwent lumbar puncture at study entry and brain magnetic resonance imaging (MRI) serially over a 7‐year period (mean follow‐up = 5.5 years). CSF YKL‐40 was quantified using an enzyme‐linked immunosorbent assay. MRI T2‐FLAIR was used to quantify total and lobar white matter hyperintensities (WMHs) at each timepoint. Ordinary least squares regression and linear mixed‐effects models related baseline CSF YKL‐40 to baseline and longitudinal WMHs, adjusting for baseline age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐e4 status, and intracranial volume. Longitudinal models adjusted for follow‐up time. Models were repeated with a sex interaction.ResultIn main models, CSF‐YKL‐40 was cross‐sectionally unrelated to total and all lobar WMHs (p‐values&gt;0.20) or longitudinal WMH progression (p‐values&gt;0.06). However, CSF YKL‐40 cross‐sectionally interacted with sex on total, frontal, and parietal lobe WMHs (p‐values&lt;0.05). In stratified models, higher CSF YKL‐40 levels related to greater WMH burden in the frontal (b = 0.005, p = 0.04), parietal (b = 0.005, p = 0.02), temporal (b = 0.003, p = 0.01), and occipital lobes (b = 0.003, p = 0.02) in females only. In longitudinal models, CSF YKL‐40 interacted with sex on temporal lobe WMH progression (p = 0.01), such that higher CSF YKL‐40 at study entry was associated with progression of temporal lobe WMHs over time in females only (b = 0.002, p = 0.003).ConclusionHigher levels of neuroinflammation, reflected by higher levels of CSF YKL‐40, are associated with greater WMHs cross‐sectionally and progression over time in females only. Longitudinally, this effect is specific to the temporal lobe, where AD neuropathology originates. Neuroinflammation may be a key, sex‐specific etiology of temporal lobe white matter damage in females. Additional research is needed to characterize the role of this damage in cognitive decline.FundingIIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082

Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values&gt;0.31) nor p‐tau (p‐values&gt;0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values&gt;0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values&lt;0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082

Circulating cell‐free mitochondrial DNA (ccf‐mtDNA) and memory in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)

AbstractBackgroundCirculating cell‐free mitochondrial DNA (ccf‐mtDNA), a measure of mitochondrial dysfunction, is emerging as a potential biomarker for early Alzheimer’s disease (AD). Decreased levels of cerebrospinal fluid ccf‐mtDNA concentrations have been detected in early AD patients. Few studies have investigated peripheral ccf‐mtDNA in early AD or with cognitive measures, much less evaluating the role of physical activity within the relationships. Considering the hallmark of episodic memory impairment in early AD, we examined the association between serum ccf‐mtDNA and memory, while considering potential contributing factors, physical activity level and age.MethodsParticipants were diagnosed with mild cognitive impairment (MCI) or mild AD using the Diagnostic and Statistical Manual of Mental Disorders criteria for mild or major neurocognitive disorder. Serum ccf‐mtDNA concentration (copies/uL) was measured using quantitative polymerase chain reaction from circulating cell free DNA purified by spin columns with primer for the MT‐ND4 gene. Memory was assessed using the Word Recall Task from the Alzheimer’s Disease Assessment Scale‐Cog (ADAS‐Cog). Physical activity level was assessed by Leisure‐Time Exercise Questionnaire (LTEQ). Linear regression analyses were used to assess the association between ccf‐mtDNA levels and recall memory with a priori covariates, age and LTEQ score. Ccf‐mtDNA levels were log‐transformed prior to analyses due to significant departure from normality in Shapiro‐Wilk tests.ResultsOf 29 participants [17 (59%) male, 21 (72%) MCI], the mean (SD) age was 74.2 (8.7), years of education was 16.2 (2.2), Montreal Cognitive Assessment (MoCA) total score was 22.1 (3.3), LTEQ score was 36.2 (17.4), and ccf‐mtDNA levels were 2545.8 (2223.6) copies/uL. Higher ccf‐mtDNA was associated with worse recall [F(3,25) = 5.21, R2 = .39, p = .006]. Controlling for LTEQ and age, one log ccf‐mtDNA unit was associated with 1.87 (SE = .71) fewer words recalled (p = .01, f2 = .21).ConclusionIn this sample, higher serum ccf‐mtDNA concentrations were associated with worse recall, controlling for age and physical activity level. This relationship supports the potential involvement of mitochondrial dysfunction in cognitive functions and neurodegenerative diseases and suggest the need for further research to explore the role of physical activity and age with mitochondrial dysfunction and memory.

Cerebrospinal fluid metabolome‐wide association study of Alzheimer’s disease provides insight into molecular pathways

AbstractBackgroundMany genetic risk variants have been identified for Alzheimer’s disease (AD), but their functional consequence on molecular pathways are unclear. Quantitative trait loci (QTL) studies help elucidate the functional effect of genetic variance on (neuro)biological processes. The understanding of AD mechanisms has been limited due to the relative inaccessibility of in vivo brain tissue and its surroundings. In this study, we integrated genetic and metabolomics cerebrospinal fluid (CSF) data, to understand how AD risk variants influence neurobiological processes.MethodWe performed a genome‐wide mQTL study on 5,543 CSF metabolite levels using data from 977 subjects (age 52.7±16.6 years, 63.8%female) from the Amsterdam Dementia Cohort (n = 487; 220 controls, 87 mild cognitive impairment, 180 AD‐type dementia) and the Utrecht cohort (n = 490 controls). We measured CSF metabolites with three platforms: GC‐TOF MS (primary metabolism, 393 metabolites), CSH‐QTOF MS/MS (complex lipids, 3,532 metabolites), and HILIC‐QTOF MS/MS (biogenic amines, 1,618 metabolites). Association signals between genetic variants and CSF metabolite levels were tested using linear regression, adjusted for principal components, age, sex and site (Amsterdam/Utrecht) using a Bonferroni‐corrected genome‐wide significance threshold (5.0e−8 /754 independent CSF signals = 6.0e−11). To identify metabolites with predicted CSF levels associated with AD, we integrated metabolite summary statistics with AD summary statistics (Kunkle et al., 2019; Bellenguez et al., 2022), using a metabolome‐wide association study (MWAS) approach (FUSION software).ResultWe identified 89 genome‐wide CSF mQTLs, including 89 independent loci for 62 CSF metabolite levels. Most mQTLs were biogenic amines (81), followed by mQTLs for the primary (5) metabolism and complex lipids (3) (Figure 1). MWAS results included 24 metabolite‐AD associations with P&lt;0.05. The strongest associations included variants proximal to the CANX gene with unannotated CSF metabolite 1.09_397.32 (PBellenguez = 2.4e−6; PKunkle = 3.4e−3), and CCDC124 variants with 8.76_225.06 (PBellenguez = 2.9e−3; PKunkle = 2.8e−5) (Figure 2).ConclusionWe identified novel metabolite‐AD risk associations, including CANX and CCDC124 with unknown CSF metabolites. In future work we aim to identify these CSF metabolites using raw spectra and intensity data. This study shows that the multi‐modal integration of genetics with CSF metabolomics helps in the functional interpretation of genetic variance, and could therefore serve as useful approach for other brain‐related disorders.

Biofluid activity and levels of the angiotensin‐converting enzyme may translate into distinct neuropsychiatric symptoms associated with cerebrospinal fluid amyloid‐beta effects and tauopathy in dementia with Lewy bodies and Alzheimer’s dementia

AbstractBackgroundAmyloid‐β‐degrading enzymes such as the angiotensin‐converting enzyme (ACE‐1) might be surrogates of the amyloid‐β load in the brain potentially triggering tauopathy and behavioral features in dementia.MethodsConsecutive outpatients with probable dementia with Lewy bodies (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset Alzheimer’s dementia (AD, National Institute on Aging – Alzheimer’s Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Behavioral symptoms were assessed by way of the Neuropsychiatric Inventory. APOE genotyping (rs7412&amp;rs429358) was undertaken with TaqMan® Real‐Time PCR technology, while conventional PCR was used for the ACE insertion/deletion polymorphism. Cerebrospinal fluid (CSF) amyloid‐β42, amyloid‐β38, ACE‐1, tau and phospho‐tau Thr181 were quantified with enzyme‐linked immunosorbent assays, whereas CSF and plasma ACE‐1 activities were measured using a fluorescence method. Adjusted general linear models were used to examine relationships between log‐transformed behavioral symptoms and biomarkers of interest at p&lt;0.05.ResultsParticipants with DLB (n = 27;78.48±9.0years‐old;eleven APOE‐ε4 carriers) were paired with participants with AD (n = 27;81.00±5.8years‐old;twelve APOE‐ε4 carriers) and controls (n = 27;78.48±8.7years‐old;four APOE‐ε4 carriers); two thirds were women. CSF ACE‐1 activity was associated with CSF ACE‐1 levels (p&lt;0.0001) and with plasma ACE‐1 activity (p&lt;0.0001), no differences among the participants. Only in DLB, the ACE deletion allele was cumulatively associated with higher plasma ACE‐1 activity (p = 0.049). Use of ACE inhibitors did not affect CSF ACE‐1 levels. For APOE‐ε4 carriers with DLB, agitation was inversely associated with amyloid‐β38, CSF and plasma ACE‐1 activities. For APOE‐ε4 non‐carriers with DLB, appetite and eating abnormalities were associated with CSF ACE‐1 levels and activity, tau and tau/phospho‐tau, and inversely associated with amyloid‐β42/amyloid‐β38. CSF ACE‐1, tau, tau/phospho‐tau, and tau/amyloid‐β42 were associated with disinhibition for APOE‐ε4 carriers with AD, and with aberrant motor behavior for APOE‐ε4 non‐carriers with AD. For APOE‐ε4 carriers with AD, irritability was associated with CSF ACE‐1 and inversely associated with amyloid‐β42. All other behavioral associations with ACE‐1 were independent of measures of amyloidosis or tauopathy.ConclusionsBiofluid activity and CSF levels of ACE‐1 may be surrogates for CSF amyloid‐β levels and tauopathy unevenly associated with behavioral symptoms across dementia syndromes.

Associations of self‐reported psychological stress with memory and cerebrospinal fluid biomarkers of Alzheimer’s disease in middle‐aged adults

AbstractBackgroundSelf‐reported psychological stress is associated with an increased risk of cognitive decline and dementia. However, it remains unclear whether stress is related to key biomarkers of Alzheimer’s disease (AD). This cross‐sectional study examined the relationship of psychological stress with memory and cerebrospinal fluid (CSF) biomarkers of AD in middle‐aged adults without dementia.MethodThe Healthy Brain Project (HBP) is a prospective web‐based study of adults aged between 40 and 70 years. A total of 2208 participants (76% female) completed the Depression, Anxiety, and Stress Scale (DASS) and Paired Associates Learning subtest of the CANTAB unsupervised on the HBP web platform. Additionally, a sub‐group of participants (n = 67; 41% APOE e4 carriers) attended an in‐person assessment where CSF samples were obtained to measure levels of amyloid‐beta (Aβ42), total tau (t‐tau), phosphorylated tau 181 (p‐tau), and neurofilament light chain (NFL). Separate linear regression analyses investigated associations of the DASS‐Stress score with memory performance and AD biomarkers. All analyses were adjusted for age, sex, education, and race.ResultIn the web‐based cohort, higher levels of self‐reported psychological stress were significantly associated with poorer memory (unstandardised β = ‐0.014, standard error [SE] = 0.004, p &lt;.001). However, there were no significant associations between psychological stress and CSF levels of Aβ42, t‐tau, p‐tau, and NFL (all p &gt; .05), with small effect sizes (Cohen’s f2 ≤ 0.05).ConclusionHigher levels of self‐reported psychological stress were associated with poorer memory in a large middle‐aged cohort but were not associated with AD biomarkers in a subset of participants with available CSF. One potential explanation is that non‐AD pathologies may underlie the relationship between stress and poorer memory; for example, poor coping strategies (e.g., smoking, overeating, and physical activity) might increase the risk of vascular cognitive impairment. However, it is also likely that the small sample size of the in‐clinic cohort was insufficient to detect any subtle relationships between stress and AD pathologies. Further research is needed to determine the associations between stress and the development of the clinical and biological manifestations of AD.

Basal forebrain nuclei volume is associated with hematoencephalic barrier dysfunction in early Alzheimer’s disease

AbstractBackgroundHematoencephalic barrier (HEB) is a protective layer of cells that separates the circulatory system from the brain. Its dysfunction is one of the possible mechanisms leading to the development of Alzheimer’s disease (AD), a progressive neurodegenerative disease and a leading cause of dementia worldwide. The albumin quotient (QAlb), the ratio between cerebrospinal fluid (CSF) and serum albumin concentrations, is a frequently used measure of HEB breakdown. Elevated levels of QAlb were previously reported in early AD. Here we explored the relationship between QAlb and volumes of the hippocampus and entorhinal cortex (EC) subregions and basal forebrain (BF) nuclei, the brain structures affected early in the course of AD.Method92 participants, including 20 AD biomarker negative cognitively normal (CN), 42 AD biomarker positive with mild cognitive impairment (AD‐MCI) and 30 AD biomarker positive with mild dementia (AD‐DEM), from the Czech Brain Aging Study underwent structural MRI and CSF sampling. CSF levels of amyloid beta 1‐42, total tau, phosphorylated tau 181 and QAlb, as well as volumes of the hippocampal subregions (i.e., head, body and tail), anterolateral and posteromedial EC and BF nuclei were obtained. Associations between regional brain volumes, normalized to total intracranial volume, and QAlb were assessed using MANOVA controlled for gender and age.ResultIn the AD‐MCI group, volumes of the anterior and posterior parts of the nucleus basalis of Meynert (NBM), one of the BF nuclei, were positively associated with QAlb levels (β = 0.317 and 0.345, p = 0.045 and 0.029, respectively). There were no other significant associations of regional brain volumes with QAlb in CN, AD‐MCI or AD‐DEM groups. All measured volumes, except for BF nuclei of medial septum in AD‐DEM (p = 0.058), were smaller in AD‐MCI and AD‐DEM v.s. CN group (p&lt;0.05). There were no differences in volumes between AD‐MCI and AD‐DEM groups. QAlb did not differ between groups.ConclusionOur results show that severity of HEB dysfunction is associated with increased volume of the NBM in individuals with AD‐MCI, suggesting a link between HEB dysfunction and early pathological changes in the BF nuclei.

Osteopontin exhibits a bidirectional relationship with Alzheimer’s disease pathology in asymptomatic individuals with a parental history of sporadic Alzheimer’s disease

AbstractBackgroundOsteopontin (OPN) is a secreted protein that plays pivotal roles in the recruitment and activation of immune cells, cell survival, and tissue repair following injury. OPN has been demonstrated to be increased in the cerebrospinal fluid (CSF) and brains of individuals with Alzheimer’s disease (AD). However, in order to elucidate the role of OPN in the asymptomatic stage of sporadic AD, we analyzed data from the PREVENT‐AD cohort, which consists of asymptomatic individuals with a parental or multi‐sibling history of AD.MethodThe Olink Proximity Extension Assay was used to measure CSF levels of OPN. CSF levels of amyloid beta (Aβ1‐42), and total Tau (t‐Tau) were measured by enzyme‐linked immunosorbent assay (Fujirebio). Participants were staged as CSF Aβ1‐42 or t‐Tau positive according to specified thresholds of 989 pg/mL and 336 pg/mL, respectively. CSF levels of synaptic proteins, including GAP43, SYT1, SNAP25 and NRGN were measured by immunoprecipitation followed by mass spectrometry. Tau and Aβ positron emission tomography (PET) burdens were measured using 18F‐AV1451 and 18F‐NAV4694.ResultAβ(+)/Tau(‐) individuals displayed a reduction in CSF OPN levels, relative to Aβ(‐)/Tau(‐) individuals (p = 0.001). Furthermore, Aβ(+)/Tau(+) individuals exhibited a significant increase in CSF OPN levels relative to Aβ(+)/Tau(‐) individuals (p &lt; 0.001), and at a trend level, to Aβ(‐)/Tau(‐) individuals (p = 0.069). In addition, CSF OPN levels were positively correlated with synaptic markers in the CSF, including GAP43 (p &lt; 0.001), SYT1 (p = 0.001), SNAP25 (p &lt; 0.001) and NRGN (p = 0.004). Finally, in PET imaging analyses, CSF OPN levels were positively correlated with pTau burden in the entorhinal cortex (p = 0.009), fusiform gyrus (p = 0.030) and lingual gyrus (p = 0.003). However, CSF OPN levels were not correlated with global cortical Aβ burden (p = 0.374).ConclusionOur results suggest that early Aβ pathology dampens OPN levels in asymptomatic individuals with a family history of AD. Furthermore, our data provide compelling evidence that OPN plays a critical role in the compensatory response to neurofibrillary tangle formation, neuronal loss and synaptic dysfunction. Finally, our findings reveal that OPN may be a valuable therapeutic target.

Increase in Matrix Metaloproteinase‐10 is associated with tau, neurodegeneration and reduced brain perfusion in the right temporal lobe

AbstractBackgroundBlood brain barrier dysfunction amplifies neuroinflammation, which may drive Alzheimer’s Dementia (AD) pathology. Regional cerebral blood flow (RCBF), measured by HMPAO SPECT, is an established biomarker for AD diagnosis. Matrix Metalloproteinase‐10 (MMP‐10), an enzyme involved in blood brain barrier function through regulating the breakdown of extracellular matrix, was recently proposed as a biomarker of progression to AD. In this study, we examine the relationship between RCBF and levels of MMP‐10 in the cerebrospinal fluid (CSF).Materials and MethodsDatasets of 91 participants from a heterogenous clinical cohort, investigated for dementia due to cognitive complaints were analysed. CSF levels of MMP‐10 were measured using the OLINK proximity extension array platform. HMPAO SPECT scans were analysed using Statistical Parametric Mapping (SPM). A univariate linear regression model was used in SPM to quantify the impact of MMP‐10 changes on brain perfusion.ResultsSPM results showed that higher levels of MMP‐10 in CSF are associated with significant reduction in RCBF (family‐wise error corrected p&lt;0.05). The neuroimaging signature of changes in RCBF with increasing MMP‐10 is outlined in Figure 1. The main cluster of reduction in perfusion is on the right temporal lobe with an additional cluster on the right medial frontal lobe.ConclusionIncreased levels of MMP‐10 in CSF have been associated with blood brain barrier vulnerability and faster cognitive decline in AD. Here we identified a right sided neuroimaging signature in RCBF with increasing levels MMP‐10. This may indicate that by the time of symptoms onset the right side is the fastest progressing as it is catching up with the left side. Right sided changes have been previously associated with delusions, disinhibition and irritability in AD and linked with increased carer burden. The significant reduction in RCBF of the right temporal lobe identified in our study, further reinforces a role for MMP‐10 as a marker of progression to AD.Acknowledgement: Dr Sofia Michopoulou, is funded through an Integrated Clinical Academic Lectureship by Health Education England (HEE) / NIHR for this research project (NIHR301287). The views expressed in this publication are those of the authors.

High diagnostic performance of plasma and cerebrospinal fluid beta‐synuclein in the differential diagnosis of sporadic Creutzfeldt‐Jakob disease

AbstractBackgroundBeta‐synuclein (beta‐syn) is an emerging biofluid marker for synaptic damage in several neurological diseases. In particular, patients with prion disease showed significantly higher cerebrospinal fluid (CSF) and blood beta‐syn levels compared to controls and subjects with other neurodegenerative disorders. However, to date, no study explored the biomarker distribution and prognostic value across the heterogeneous spectrum of sporadic Creutzfeldt‐Jakob disease (sCJD) as well as its diagnostic performance in the real‐life setting of patients with rapidly progressive dementia (RPD).MethodUsing in house established immunoassays we measured CSF and/or plasma beta‐syn concentrations in 150 patients with sCJD, belonging to the most prevalent molecular subtypes [MM(V)1, VV2 and MV2K], and in 106 subjects with non‐prion RPD. In the same cohort, we assessed CSF levels of total tau (t‐tau) and protein 14‐3‐3. We compared the diagnostic performance of CSF/plasma beta‐syn with that of classic CSF markers and we tested the possible associations of CSF/plasma beta‐syn with survival in patients with sCJD.ResultsCJD patients showed higher CSF and plasma beta‐syn levels compared to non‐prion RPD subjects (p&lt;0.001 for both) (Figure 1A, B). Different CSF and blood profiles of beta‐syn were observed for the most prevalent sCJD molecular subtypes (Figure 1C, D). Concerning the diagnostic value, CSF beta‐syn outperformed 14‐3‐3 (AUC 0.95 vs. 0.89, p = 0.028) but not t‐tau (AUC 0.92, p = 0.212). Further, the discriminative accuracy of plasma beta‐syn (AUC 0.91) was not inferior to that of classic CSF markers (t‐tau, p = 0.765 and 14‐3‐3, p = 0.447) and CSF beta‐syn (p = 0.135). In the whole sCJD cohort, CSF and plasma beta‐syn were significantly associated with survival at univariate analyses but not after accounting for codon 129 genotype or molecular subtype.ConclusionCSF beta‐syn performed similar or better compared to t‐tau and 14‐3‐3, respectively, thus, the marker might represent an alternative first‐level test in patients with suspected sCJD. Most interestingly, the high diagnostic value of beta‐syn in plasma, which was comparable to that of classic CSF surrogate markers, suggests that beta‐syn might be used as highly accurate blood surrogate marker in sCJD for patient screening and monitoring.

Biomarker Profiling for Alzheimer‐like Dementia in Aged Non‐human Primates

AbstractBackgroundAlzheimer’s disease (AD) places increasingly burdens on global healthcare. Non‐human primates (NHPs) have been used in preclinical pharmacology for AD drug discovery and they were mainly based on induction by amyloid plaque. However, previous strategies focused on clearance and prevention of amyloid plaques and neurofibrillary inclusions have mostly yielded discouraging results in clinical trials for AD. More fitting NHP models reflective of natural ageing of brain with an AD‐related clinical profile would be most desirable for translational pharmacology. To address this, the pilot study herein profiled a group of aged NHPs for biomarkers characteristic of AD‐like dementia, including cognitive behavior, diagnostic neuroimaging, EEG, and amyloid beta 42 (Aβ42) in cerebrospinal fluid (CSF).MethodTwo groups of male Macaca fascicularis (adult: 9‐11 years, n = 4; aged: 20‐25 years, n = 10) were trained to perform a delayed response task (DRT) to assess their short term memory. Meanwhile, their CSF levels of Aβ42 were determined. EEG signals at rest were captured with Neuroscan EEG System and data processed with customized Matlab code. The volume of hippocampus in eight selected animals were analyzed through a 3‐D reconstruction with MRI imaging.ResultSix (6) out of 10 aged animals showed lower DRT performance (successful rate &lt; 80%) than the remaining 4 and those in the adult group. The overall DRT performance was positively correlated with the CSF levels of Aβ42 in all animals. Moreover, we observed the slowing of EEG activity (increased δ &amp; θ activity and decreased β activity) in the frontal lobe and smaller average volume of hippocampus in the low DRT performers vis‐à‐vis the rest of the animals.ConclusionWe identified a group of aged NHPs with spontaneous dementia, with cognitive, electrophysiological and brain structural characteristic of mild cognitive impairment in the humans. Their CSF levels of Aβ42 inversely correlated with the memory function. Most notably, EEG and neuroimaging showed promising potential as non‐invasive approaches for the evaluation of aging‐related dementia of NHP in the longitudinal studies. The translational value of such animals could provide important insight to the disease progress and the therapeutic efficacy of AD treatment in the preclinical stages.

Fully Automated Lumipulse Plasma Amyloid and phosphorylated Tau assays for Progression to Alzheimer’s disease in Mild Cognitive Impairment patients

AbstractBackgroundLumipulse G automated immunoassays represent the most widely used method for the quantification of Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF)1. Less invasive blood‐based markers confer a promising tool for AD diagnosis at prodromal stages (Mild Cognitive Impairment‐MCI)2. Highly sensitive assays for the quantification of amyloid‐beta (Aβ) and phosphorylated Tau‐181 (p‐Tau181) in blood are showing promising results3. In this study we evaluated the clinical performance of the available Lumipulse plasma markers for progression to AD.MethodA group of 138 patients (22 neurological controls‐NC, 72 MCI and 44 AD) recruited at the Dementia Clinic of Centro Hospitalar Universitário de Coimbra (CHUC) was included. Data regarding baseline CSF levels of Ab42, Ab40, t‐Tau and p‐Tau181 was available, allowing for characterization into ATN categories4. Baseline Ab42, Ab40 and p‐Tau181 levels were determined in stored plasma samples using high‐throughput fully automated Lumipulse assays. Progression from MCI to AD dementia was assessed at follow‐up (mean 5.9±3.0 years; 36 converted ‐MCI‐AD/36 stable ‐MCI‐St).ResultIn the total cohort, correlations between CSF and plasma were moderate for p‐Tau 181 (r = 0.61, p&lt;0.001), weak for Aβ42 (r = 0.28, p = 0.001) and non‐significant for Aβ40 (r = ‐0.05, p = 0.54). Plasma p‐Tau181 levels were significantly increased while Aβ42, Aβ42/Aβ40 and Aβ42/p‐Tau181 were significantly decreased (p&lt;0.001) in patients classified as MCI‐AD and AD in relation both to NC and MCI‐St. Plasma p‐Tau181 showed a robust performance in differentiating NC+MCI‐St vs. MCI‐AD+AD (AUC = 0.89, 95%CI:0.83‐0.94), MCI‐St vs. MCI‐AD (AUC = 0.89, 95%CI:0.81‐0.96) and CSF A+ vs. A‐ (AUC = 0.84, 95%CI:0.77‐0.91). Plasma Aβ42/p‐Tau181 gave similar AUC results (AUCs = 0.88, 0.84 and 0.83) and showed no significant differences compared to p‐Tau181 alone (p = 0.34, 0.33 and 0.92). For MCI‐St vs. MCI‐AD, when maximizing for sensitivity (0.92, specificity 0.67), baseline plasma p‐Tau181 levels higher than 1.69 pg/mL predicted future AD dementia (HR = 11.5; 95%CI = 10.9‐12.1).ConclusionOur results show that the measurement of p‐Tau181 in peripheral blood has great potential as a non‐invasive prognostic screening tool for AD dementia in MCI patients.1. Delaby C, et al. Alzheimer’s Dement. 2021; 2.Teunissen CE, et al. Lancet Neurol. 2022; 3.Palmqvist S, et al. Nat Med. 2021; 4.Jack CR, et al. Alzheimer’s Dement. 2018

Longitudinal decrements in the sensitivity of cueing in the Free and Cued Selective Reminding Test predict A+T+ status in cognitively unimpaired individuals

AbstractBackgroundThe Index of Sensitivity of Cueing (ISC) from the Free and Cued Selective Reminding Test (FCSRT) memory test evaluates the efficacy of the semantic cues to facilitate retrieval from stored information. Although the ISC has been extensively studied in individuals with prodromal Alzheimer’s disease (AD), its association with AD core pathology, amyloid‐β (A) and p‐tau (T), in cognitively unimpaired (CU) individuals remains unknown. The aim of the present study was to explore the cross‐sectional and longitudinal differences in ISC scores among cerebrospinal fluid (CSF)‐defined AT groups in CU individuals.MethodsWe studied 341 CU participants from the ALFA+ study with available baseline CSF and longitudinal data for the word‐FCSRT‐without‐immediate‐recall version after 3 years. The ISC was computed as: (“total recall”‐“free recall”)/(48‐“free recall”). We defined AT groups (A‐T‐, A+T‐, and A+T+) using baseline CSF levels (Table1) using the cut‐offs defined in Milà‐Alomà et al., 2020. We set independent ANCOVAs to explore the associations between AT status and cross‐sectional and longitudinal (delta) ISC and main FCSRT variables (Table 1). All models were adjusted for age, education and sex, and longitudinal analyses were further adjusted for inter‐visit time and baseline scores. Nominal and FDR‐adjusted p‐values are reported.ResultsNo differences among AT groups were found for baseline FCSRT variables (Table 2). At nominal p‐value levels We observed differences in total recall (TR) and ISC both at visit2 and delta in association with AT status at nominal p‐value levels (Table2), but only the ISC change survived FDR corrections (pFDR = 0.03). Associations were driven by the A+T+ group (Figure1). No differences between A‐T‐ and A+T‐ were found (p&gt;0.05). TR delta was still significant after adjusting for free recall (nominal p = 0.011), suggesting ISC as the main driver of TR decrements.ConclusionDecrements in sensitivity of cueing after 3 years, that in turn diminish FCSRT total recall, were related to concurrent CSF Aβ and p‐tau abnormal levels in CU individuals. No differences between AT groups were observed in free recall, in contrast with other studies using other FCSRT versions that include immediate recall during learning. Further research on secondary memory variables may elucidate the subtle changes related to early AD pathology.

The cerebrospinal fluid soluble TREM‐1 concentration in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI)

AbstractBackgroundThe most prevalent form of dementia in the world is Alzheimer Disease (AD), a common neurodegenerative condition. Amyloid peptides, phosphorylated tau proteins, and neuroinflammation are the disease’s hallmarks. Finding new biomarkers that can assist in early AD detection is crucial due to the late appearance of the disease symptoms. Triggering receptor expressed on myeloid cell 1 (TREM‐1) is hypothesized that may contribute to the development of AD by causing neuroinflammation. Due of its significance in inflammatory responses, it has been regarded as a promising biomarker. Literature data indicate that TREM‐1 could be potential biomarker of AD severity. Therefore the purpose of our research was to measure the concentration of soluble TREM‐1 in cerebrospinal fluid of AD and MCI patients and non‐demented controls and compare it with classical AD biomarkers.MethodThe concentrations of TREM‐1 were measured in cerebrospinal fluid (CSF) of 20 AD patients and 15 MCI patients as well as 11 non‐demented controls using multiplexing method. Classical biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181 were assessed by immunoenzyme assays.ResultTREM‐1 concentrations were significantly higher in AD and MCI patients in comparison to non‐demented controls. Moreover, in MCI patients, the levels of this protein were significantly higher than in AD patients. Additionally, increased CSF levels of TREM‐1 correlated positively with Tau, pTau181 in the whole study group.ConclusionFindings of our research suggest that TREM‐1 could be early indicator of AD pathology. However, follow‐up studies on larger study group are needed.

Examination of plasma YKL‐40 as a clinical biomarker for Alzheimer’s disease

AbstractBackgroundBlood biomarkers represent a potential non‐invasive and cost‐effective strategy for the clinical detection and monitoring of neurodegenerative conditions including Alzheimer’s disease (AD). YKL‐40 is a secreted glycoprotein associated with inflammatory processes, and elevated cerebrospinal fluid levels have been observed in AD and other neurodegenerative conditions. Fewer studies have examined plasma YKL‐40. We examined relationships between plasma YKL‐40 and clinical indices of AD in a large cross‐sectional sample from a clinical cohort registry.MethodThe sample included 569 participants from the Boston University Alzheimer’s Disease Research Center, including participants with normal cognition (NC; n = 235), mild cognitive impairment due to suspected AD (MCI; n = 181), and AD dementia (n = 153). Blood plasma samples were analyzed using standard ELISA methods; values were log transformed and standardized into z‐scores. Cross‐sectional analyses investigated the relationships between YKL‐40 and clinical indices of functioning including diagnostic status, dementia severity (on the Clinical Dementia Rating scale [CDR]), and neuropsychological test performance. Age, sex, education, race, and APOE ε4 carrier status were included as covariates in all analyses.ResultNo significant differences in plasma YKL‐40 were observed between participants with NC, MCI, and AD dementia after accounting for covariates. The comparison between MCI and dementia was marginally significant (p = .07), with an adjusted mean difference of Z = 0.19. For participants with dementia (CDR scores 1‐3), non‐significant trends were observed for relationships between plasma YKL‐40 values and dementia severity, including for Sum of Boxes (Pearson partial correlation: r = .14, p = .10) and Total Score (ordinal logistic regression: OR = 1.38; 95% CI: [0.98,1.93]), p = .06. Modest but significant correlations were observed between YKL‐40 and performance on 4/12 neuropsychological tests including Animal Fluency (r = ‐.10), Vegetable Fluency (r = ‐.09), and Neuropsychological Assessment Battery List Learning Trials 1‐3 (r = ‐.10) and Short Delay (r = ‐.12).ConclusionPlasma YKL‐40 biomarker levels were modestly related to neuropsychological assessments of language and memory but not significantly related to cognitive diagnosis of AD or dementia severity. This biomarker may reflect underlying inflammatory processes in the context of AD. However, the use of plasma YKL‐40 to assess the presence and severity of AD in a larger cross‐sectional sample size, and using a multiple biomarker approach, warrant further study.

Biomarkers of synaptic and neuronal dysfunction in relation to mild behavioral impairment: a study of dementia‐free older adults

AbstractBackgroundMild behavioral impairment (MBI) represents a high‐risk state for incident cognitive decline and dementia, capturing later‐life emergent and persistent neuropsychiatric symptoms in five domains: 1) decreased motivation; 2) affective dysregulation 3) impulse dyscontrol; 4) social inappropriateness; and 5) psychosis. We examined cross‐sectional associations between MBI and cerebrospinal fluid levels of markers of synaptic/neuronal dysfunction including 1) alpha‐synuclein (α‐syn); 2) growth‐associated protein 43 (GAP‐43); 3) neurogranin (NGRN); 4) synaptosomal‐associated protein 25 (SNAP‐25); 5) visinin‐like protein 1 (VILIP‐1); and 6) chitinase‐3‐like protein 1 (YKL‐40). Longitudinally, we determined associations between these biomarkers and incident MBI or dementia.MethodAlzheimer’s Disease Neuroimaging Initiative participants with normal cognition and mild cognitive impairment were included (n = 853). MBI scores were derived from the Neuropsychiatric Inventory using a published algorithm. Participants were classified as MBI+ if MBI symptoms were present at ≥2 consecutive visits.Cross‐sectional associations between MBI total score and each log‐transformed biomarker were modelled using multivariable‐adjusted linear regression. Biomarkers with cross‐sectional associations meeting a pre‐defined p‐value threshold (p&lt;0.1) were then incorporated as exposures into adjusted longitudinal Cox proportional hazard regression models (n = 111) of 1) MBI and 2) dementia as the outcomes, the latter of which also included interactions between MBI status and biomarker levels.ResultDemographics are summarized in Table 1. Cross‐sectionally, only MBI associations with VILIP‐1 (beta = 3.3%, 95%CI:+0.2% to +6.5%, p = 0.04) and SNAP‐25 (beta = 2.0%, 95%CI:‐0.4% to 6.3%, p = 0.09) met the pre‐defined p‐value for inclusion in Cox models. Longitudinally, higher VILIP‐1 levels were associated with a 3.02‐fold greater rate of incident MBI (95%CI:1.43‐6.40, p = 0.004) and a 3.83‐fold greater rate of incident dementia (95%CI:1.22‐12.03, p = 0.021). The relationship between VILIP‐1 and dementia did not depend on participants having MBI. MBI status predicted incident dementia with an HR = 4.75 (95%CI:2.36‐9.55, p&lt;0.001) and HR = 4.06 (95%CI:2.01‐8.21, p&lt;0.001) after adjusting for VILIP‐1.ConclusionElevated VILIP‐1 levels are associated with greater incidence of MBI and greater incidence of dementia, suggesting that synaptic dysfunction traditionally related to cognitive decline and dementia may also contribute to behavioral changes. Treatments aimed to mitigate MBI symptoms and dementia may explore VILIP‐1—a neuronal calcium‐sensor protein—as a therapeutic target, though more research is needed.

Spatial navigation, physical activity, and Alzheimer disease biomarkers

AbstractBackgroundElevated levels of amyloid are associated with worse performance on cognitive mapping (CM), a spatial navigation task reliant on the hippocampus. Prior animal work found that exercise is associated with better learning in CM tasks. Hence, the first goal of the study was to examine whether physical activity moderates the relationship between amyloid deposition and CM. In addition, spatial navigation ability predicts Alzheimer disease (AD) clinical progression but there is a need to examine whether it also predicts subsequent levels of amyloid and tau. Hence, the second goal was to examine whether CM predicts later levels of PET‐Tau and longitudinal trajectories of PET‐Amyloid.MethodCognitively normal individuals (n = 65; age range 50‐84 years) were administered a CM task in a virtual environment and a self‐report measure of physical activity. For cross‐sectional analyses, amyloid deposition was estimated via cerebrospinal fluid levels of Aβ42. One assessment of PET‐Tau (n = 49) and repeated assessments of PET‐Amyloid (n = 59) were obtained following the CM session.ResultConcurrent amyloid deposition was associated with reduced learning (p = 0.002) and retention of the environment (p = 0.002) while greater physical activity was associated with better learning (p = 0.004). There was no moderation by physical activity (all p’s &gt; 0.156). CM performance was not associated with longitudinal trajectories of PET‐Amyloid (all p’s &gt; 0.330) or the subsequent levels of PET‐Tau (all p’s &gt; 0.572).ConclusionThese results suggest that both current physical activity and levels of amyloid can be important predictors of spatial navigation skills. However, CM might be a limited predictor of AD biomarker accumulation. Future studies should use a larger sample size and greater number of assessments to examine these questions.

Alzheimer´s Disease initial cognitive profile in an Argentinian cohort of individuals with Down Syndrome

AbstractBackgroundDown Syndrome [DS] is the most frequent cause of genetic developmental and intellectual disability. The lifetime risk of Alzheimer’s Disease [AD] in people with DS is more than 90%, with an earlier age of onset than the general population. There is ongoing debate whether there are significant differences in dementia presentation in the specific context of DS, with some studies suggesting a predominantly frontal phenotype with behavioural symptoms and others suggesting a more frequent amnestic presentation.The aim of this study was to characterize the initial cognitive profile of AD in a cohort of Argentinian adults with DS.MethodAdults with DS and prodromal or established AD dementia who were part of the IASDA (Argentinian initiative for the study of DS and AD) cohort or spontaneusly attended our Memory Clinic were included. Initial cognitive profile was determined by a semi‐structured interview conducted by a cognitive neurologist with the subject, their family and caregivers.ResultSixteen adults with DS were included. Fifty‐six percent (n = 9) were males. Mean age was 51 yo (42‐59 yo). Sixty‐two percent (n = 10) had premorbid moderate intellectual disability [DI], 25% (n = 4) had severe DI and 13% (n = 2) had mild DI.Fifty‐six percent (n = 9) had a clinical diagnosis of prodromal AD, and the remaining individuals had clinically established AD dementia. Fifty percent (n = 8) had positive amiloid biomarkers (determined by cerebral PiB‐PET or cerebrospinal fluid levels of Aβ42, phosphorylated‐tau and total‐tau), while the remaining subjects did not undergo amiloid biomarker assessment. Due to cognitive impairment, premorbid language impairment and/or premorbid severe DI, only 25% (n = 4) of individuals completed neuropsychological testing (CAMDEX‐DS, Cued Recall Task).Initial cognitive profile was charactirized as amnestic (single‐domain amnestic or multiple‐domain amnestic) in 81% percent (n = 13) of the cohort. Only 13% (n = 2) of the subjects had initial non‐amnestic syndromes, and in one case (6%) the initial cognitive syndrome was uncertain.ConclusionAmnestic cognitive impariment was the most frequent presentation of AD in this small cohort of Latin American adults with DS.