CSF Tau Levels Research Articles

Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer's disease.

Melanopsin-expressing retinal ganglion cells (mRGCs), intrinsically photosensitive RGCs, mediate the light-based pupil response and the light entrainment of the body's circadian rhythms through their connection to the pretectal nucleus and hypothalamus, respectively. Increased awareness of circadian rhythm dysfunction in neurological conditions including Alzheimer's disease (AD), has led to a wave of research focusing on the role of mRGCs in these diseases. Postmortem retinal analyses in AD patients demonstrated a significant loss of mRGCs, and in vivo measurements of mRGC function with chromatic pupillometry may be a potential biomarker for early diagnosis and progression of AD. We performed a prospective case-control study in 20 cognitively healthy study participants: 10 individuals with pre-symptomatic AD pathology (pre-AD), identified by the presence of abnormal levels of amyloid β42 and total Tau proteins in the cerebrospinal fluid, and 10 age-matched controls with normal CSF amyloid β42 and Tau levels. To evaluate mRGC function, we used a standardized protocol of chromatic pupillometry on a Ganzfeld system using red (640 nm) and blue (450 nm) light stimuli and measured the pupillary light response (PLR). Non-invasive wrist actigraphy and standardized sleep questionnaires were also completed to evaluate rest-activity circadian rhythm. Our results did not demonstrate a significant difference of the PLR between pre-AD and controls but showed a variability of the PLR in the pre-AD group compared with controls on chromatic pupillometry. Wrist actigraphy showed variable sleep-wake patterns and irregular circadian rhythms in the pre-AD group compared with controls. The variability seen in measurements of mRGC function and sleep-wake cycle in the pre-AD group suggests that mRGC dysfunction occurs in the pre-symptomatic AD stages, preceding cognitive decline. Future longitudinal studies following progression of these participants can help in elucidating the relationship between mRGCs and circadian rhythm dysfunction in AD.

Higher CSF Tau Levels Are Related to Hippocampal Hyperactivity and Object Mnemonic Discrimination in Older Adults

Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.SIGNIFICANCE STATEMENT Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.

Incremental value of amyloid-PET versus CSF in the diagnosis of Alzheimer's disease.

To compare the incremental diagnostic value of amyloid-PET and CSF (Aβ42, tau, and phospho-tau) in AD diagnosis in patients with mild cognitive impairment (MCI) or mild dementia, in order to improve the definition of diagnostic algorithm. Two independent dementia experts provided etiological diagnosis and relative diagnostic confidence in 71 patients on 3 rounds, based on (1) clinical, neuropsychological, and structural MRI information alone; (2) adding one biomarker (CSF amyloid and tau levels or amyloid-PET with a balanced randomized design); and (3) adding the other biomarker. Among patients with a pre-biomarker diagnosis of AD, negative PET induced significantly more diagnostic changes than amyloid-negative CSF at both rounds 2 (CSF 67%, PET 100%, P = 0.028) and 3 (CSF 0%; PET 78%, P < 0.001); PET induced a diagnostic confidence increase significantly higher than CSF on both rounds 2 and 3. Amyloid-PET should be prioritized over CSF biomarkers in the diagnostic workup of patients investigated for suspected AD, as it provides greater changes in diagnosis and diagnostic confidence. EudraCT no.: 2014-005389-31.

P1‐479: RELATIONSHIPS BETWEEN ALZHEIMER'S DISEASE BIOMARKERS ON SEMANTIC CUEING AND TOTAL RECALL IN THE FREE AND CUED SELECTIVE REMINDING TEST (FSCRT)

Semantic cueing (SC) can enhance performance on learning and recall tasks. SC may be a sensitive measure for detecting early neurocognitive changes in individuals with preclinical Alzheimer's disease (pAD). While free delayed recall is dependent on both the Papez circuit and distributed cortical networks, SC is especially sensitive to deficits in the Papez circuit that is affected early in AD. The present study examined SC in a series of cognitively normal subjects that had undergone structural MRI and CSF analyses for Aβ and tau in order to test the hypothesis that SC deficits can predict pAD. Inclusion/exclusion criteria included Mini-Mental Status Exam (MMSE) score of ≥26 (indicating intact global cognition), a Hachinski Ischemic Scale (HIS) score <4 (indicating low cerebrovascular risk), and no significant medical or neurologic disease that could cause cognitive deficits. The Free and Cued Selective Reminding Test (FCSRT), 3D-MPRAGE T1 sequences on MRI, and CSF were collected on 66 cognitively normal participants seen at the University of Kentucky Alzheimer's Disease Center. Linear regression was used to examine relationships between SC recall, cortical thickness, and CSF. Participants had a mean MMSE score of 28.7 ± 1.8, age of 73.9 ± 5.7 years, an education of 16.6 ± 2.5 years, and were 52.9% female. None of these variables were significant predictors of pAD. While higher CSF Aβ levels were significantly associated with free recall (β=0.025, p=0.01), they showed no association with SC. In contrast, increased levels of CSF tau were significantly associated with decreased SC recall performance (β=0.001, p=0.002). The association of decreased CSF Aβ with free delayed recall but not SC suggests dysfunction in cortical and other brain regions, with relative sparing of the Papez circuit. In contrast, the present data demonstrates that SC is associated with both the presence of tau abnormalities in CSF and entorhinal cortex atrophy, which is indicative of active neurofibrillary tangle pathology. While SC recall does not appear to predict amyloid positivity, it appears to be associated with neuropsychological change early in the neurofibrillary tangle cascade. These results allow for the development of more effective neuropsychological assessments for individuals with preclinical Alzheimer's disease.

P2‐257: BIOTINIDASE AS A NOVEL BIOMARKER OF NEURAL CHANGES AND AD CSF BIOMARKERS ACROSS THE ALZHEIMER'S DISEASE SPECTRUM

Biotinidase (BTD) is an enzyme in the biotin cycle that is critical for releasing free biotin from biotinylated peptides. Biotin is an essential cofactor in various carboxylases involved in metabolism. Consequently, since Alzheimer's disease (AD) is linked to metabolic dysfunction, BTD may be a useful biomarker to track AD-related etiopathogenesis. CSF BTD was assayed from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in 287 participants: 86 cognitively normal (CN), 135 with mild cognitive impairment (MCI) and 66 AD participants. Through voxel-wise analysis, BTD levels were regressed against regional grey matter (GM) volume and fluorodeoxyglucose (FDG) metabolism (p<.05, family-wise corrected). Linear mixed models in SPSS 25 determined the relationship between CSF BTD and cognitive measures, as well as AD CSF biomarkers (total tau, p-tau-181, Aβ1-42). Covariates included age, sex, baseline diagnosis, Apolipoprotein E ε4 (APOE4) status, and BMI, with education added and diagnosis removed in cognitive models. Increased levels of BTD were significantly correlated with less GM volume and FDG metabolism in a large cluster spanning the left paracentral lobule. Higher levels of BTD were also associated with greater levels of total tau (β±SE= 52.44 ±7.27, p<.001) and p-tau-181 (β±SE= 9.70 ±2.51, p<.001). Conversely, there was also a significant CSF Aβ1-42* APOE4 Status interaction, where higher BTD reflected more CSF Aβ1-42 only among APOE4- participants (β±SE= 28.03 ±13.82, p=0.44). Higher BTD levels were associated with more GM and FDG metabolism in smaller regions, in the cingulum and inferior temporal gyrus, respectively, as well as better CDR- SOB ratings (β±SE= −0.65 ±0.29, p=0.27). These results indicate that higher CSF BTD may reflect central dysmetabolism. Higher BTD was related to AD-induced neurodegeneration and hypometabolism in paracentral lobule, which occurs early in the disease process. BTD also tracked CSF tau levels, where APOE4+ subjects would continue to show these associations regardless of presumed amyloid deposition.

Age-related hearing loss accelerates cerebrospinal fluid tau levels and brain atrophy: a longitudinal study.

Age-related hearing loss (ARHL) has been considered as a promising modifiable risk factor for cognitive impairment and dementia. Nonetheless, it is still unclear whether age-related hearing loss associates with neurodegenerative biomarkers of Alzheimer’s disease (AD). Participants with ARHL were selected from the established Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. In multivariable models, the cross-sectional and longitudinal associations of ARHL with CSF β-amyloid (Aβ) and tau measurements, brain Aβ load, and cortical structural measures were explored. ARHL was associated with higher CSF levels of tau (p < 0.001) or ptau181 (p < 0.05) at baseline as well as faster elevation rates of these two types of biomarkers (p < 0.05). Although the baseline volume/thickness of hippocampus (p < 0.05) and entorhinal cortex (p < 0.0005) were higher in individuals with ARHL, these two regions (p < 0.01 for hippocampus, p < 0.05 for entorhinal cortex) displayed significantly accelerated atrophy in individuals with ARHL. No association of ARHL with CSF or brain Aβ levels was found. Subgroup analyses indicated that the above effects of ARHL were more significant in non-demented stage. Age-related hearing loss was associated with elevated cerebrospinal fluid tau levels and atrophy of entorhinal cortex.

18F‐Florbetaben PET/CT to Assess Alzheimer's Disease: A new Analysis Method for Regional Amyloid Quantification

While AD can be definitively confirmed by postmortem histopathologic examination, in vivo imaging may improve the clinician's ability to identify AD at the earliest stage. The aim of the study was to test the performance of amyloid PET using new processing imaging algorithm for more precise diagnosis of AD. Amyloid PET results using a new processing imaging algorithm (MRI-Less and AAL Atlas) were correlated with clinical, cognitive status, CSF analysis, and other imaging. The regional SUVR using the white matter of cerebellum as reference region and scores from clinical and cognitive tests were used to create ROC curves. Leave-one-out cross-validation was carried out to validate the results. Forty-four consecutive patients with clinical evidence of dementia, were retrospectively evaluated. Amyloid PET scan was positive in 26/44 patients with dementia. After integration with 18F-FDG PET, clinical data and CSF protein levels, 22 of them were classified as AD, the remaining 4 as vascular or frontotemporal dementia. Amyloid and FDG PET, CDR 1, CSF Tau, and p-tau levels showed the best true positive and true negative rates (amyloid PET: AUC = .85, sensitivity .91, specificity .79). A SUVR value of 1.006 in the inferior frontal cortex and of 1.03 in the precuneus region was the best cutoff SUVR value and showed a good correlation with the diagnosis of AD. Thirteen of 44 amyloid PET positive patients have been enrolled in clinical trials using antiamyloid approaches. Amyloid PET using SPM-normalized SUVR analysis showed high predictive power for the differential diagnosis of AD.

Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer\u2019s disease

PurposeStudies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau181p) and mid-domain tau (i.e. total tau, T-tau). Moreover, these studies did not examine CSF tau levels in relation to cerebral glucose metabolism. We thus aimed to examine CSF tau measures, using both commercial and novel assays, in relation to [18F]THK5317 (tau) and [18F]FDG PET (glucose metabolism).MethodsFourteen Alzheimer’s disease (AD) patients (seven prodromal, seven dementia) underwent [18F]THK5317 and [18F]FDG PET studies, with follow-up performed in ten subjects (six prodromal, four dementia) after 17 months. In addition to commercial assays, novel measures capturing N-terminus+mid-domain (tau N-Mid) and C-terminally truncated (tau-368) fragments were included.ResultsWhile the levels of all forms of CSF tau were found to be inversely associated with baseline [18F]FDG uptake, associations with baseline [18F]THK5317 uptake varied in relation to the degree of isocortical hypometabolism ([18F]FDG SUVR). Changes in the levels of the novel CSF markers tracked longitudinal changes in tracer uptake better than changes in P-tau181p and T-tau levels, and improved concordance with dichotomized regional [18F]THK5317 measures.ConclusionOur findings suggest that neurodegeneration may modulate the relationship between CSF and PET tau biomarkers, and that, by comparison to P-tau181p and T-tau, tau-368 and tau N-Mid may better capture tau pathology and synaptic impairment.

Plasma Biomarkers of AD Emerging as Essential Tools for Drug Development: An EU/US CTAD Task Force Report.

There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer's disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.

Correction: Abnormal CSF amyloid-β42 and tau levels in hip fracture patients without dementia.

[This corrects the article DOI: 10.1371/journal.pone.0204695.].

Atrophy subtypes in prodromal Alzheimer's disease are associated with cognitive decline.

Alzheimer's disease is a heterogeneous disorder. Understanding the biological basis for this heterogeneity is key for developing personalized medicine. We identified atrophy subtypes in Alzheimer's disease dementia and tested whether these subtypes are already present in prodromal Alzheimer's disease and could explain interindividual differences in cognitive decline. First we retrospectively identified atrophy subtypes from structural MRI with a data-driven cluster analysis in three datasets of patients with Alzheimer's disease dementia: discovery data (dataset 1: n = 299, age = 67 ± 8, 50% female), and two independent external validation datasets (dataset 2: n = 181, age = 66 ± 7, 52% female; dataset 3: n = 227, age = 74 ± 8, 44% female). Subtypes were compared on clinical, cognitive and biological characteristics. Next, we classified prodromal Alzheimer's disease participants (n = 603, age = 72 ± 8, 43% female) according to the best matching subtype to their atrophy pattern, and we tested whether subtypes showed cognitive decline in specific domains. In all Alzheimer's disease dementia datasets we consistently identified four atrophy subtypes: (i) medial-temporal predominant atrophy with worst memory and language function, older age, lowest CSF tau levels and highest amount of vascular lesions; (ii) parieto-occipital atrophy with poor executive/attention and visuospatial functioning and high CSF tau; (iii) mild atrophy with best cognitive performance, young age, but highest CSF tau levels; and (iv) diffuse cortical atrophy with intermediate clinical, cognitive and biological features. Prodromal Alzheimer's disease participants classified into one of these subtypes showed similar subtype characteristics at baseline as Alzheimer's disease dementia subtypes. Compared across subtypes in prodromal Alzheimer's disease, the medial-temporal subtype showed fastest decline in memory and language over time; the parieto-occipital subtype declined fastest on executive/attention domain; the diffuse subtype in visuospatial functioning; and the mild subtype showed intermediate decline in all domains. Robust atrophy subtypes exist in Alzheimer's disease with distinct clinical and biological disease expression. Here we observe that these subtypes can already be detected in prodromal Alzheimer's disease, and that these may inform on expected trajectories of cognitive decline.

Abnormal CSF amyloid-β42 and tau levels in hip fracture patients without dementia.

BackgroundThere is strong association of Alzheimer’s disease (AD) pathology with gait disorder and falls in older adults without dementia. The goal of the study was to examine the prevalence and severity of AD pathology in older adults without dementia who fall and sustain hip fracture.MethodsCerebrospinal fluid (CSF) was obtained from 168 hip fracture patients. CSF Aβ42/40 ratio, p-tau, and t-tau measures were dichotomized into normal vs. abnormal, and categorized according to the A/T/N classification.ResultsAmong the hip fracture patients, 88.6% of the cognitively normal (Clinical Dementia Rating-CDR 0; n = 70) and 98.8% with mild cognitive impairment (CDR 0.5; n = 81) fell in the abnormal biomarker categories by the A/T/N classification.ConclusionsA large proportion of older hip fracture patients have CSF evidence of AD pathology. Preoperative determination of AD biomarkers may play a crucial role in identifying persons without dementia who have underlying AD pathology in perioperative settings.

APOE ε4 is associated with higher levels of CSF SNAP-25 in prodromal Alzheimer’s disease

The underlying mechanism of apolipoprotein E ε4 (APOE ε4) in the pathogenesis of Alzheimer’s disease (AD) remains elusive. We hypothesize that synaptic function is differentially affected by APOE isoforms. Levels of CSF SNAP-25 were compared between APOE ε4 carriers and noncarriers in 55 participants with normal cognition, 75 patients with mild cognitive impairment (MCI), and 16 patients with mild AD dementia. We investigated relationships between SNAP-25 levels and age, gender, education, CSF Aβ42, and tau protein. We found that levels of SNAP-25 in CSF were substantially greater in APOE ε4 carriers compared to noncarriers with MCI. There was no significant difference in SNAP-25 levels between APOE ε4 carriers and noncarriers with normal cognition or AD. CSF SNAP-25 levels were associated with MMSE and CSF Aβ and tau levels. In summary, APOE ε4 may affect CSF SNAP levels in MCI patients, suggesting an important role of APOE ε4 in synaptic dysfunction leading to AD.

Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share a couple of clinical similarities that is often a source of diagnostic pitfalls. We evaluated the discriminatory potential of brain-derived CSF markers [tau, p-tau (181P), Aβ1-42, NSE and S100B] across the spectrum of Lewy body disorders and assessed whether particular markers are associated with cognitive status in investigated patients. The tau CSF level, amyloid β1-42 and p-tau/tau ratio were helpful in the distinction between DLB and PDD (p = 0.04, p = 0.002 and p = 0.02, respectively) as well as from PD patients (p < 0.001, p = 0.001 and p = 0.002, respectively). Furthermore, the p-tau/tau ratio enabled the differentiation of DLB with mild dementia from PDD patients (p = 0.02). The CSF tau and p-tau levels in DLB and CSF tau and p-tau/tau ratio in PDD patients reflected the severity of dementia. Rapid disease course was associated with the decrease of Aβ1-42 in DLB but not in PDD. Elevation of S100B in DLB (p < 0.0001) as well as in PDD patients (p = 0.002) in comparison to controls was estimated. Hence, with the appropriate clinical context; the CSF marker profile could be helpful in distinguishing DLB from PDD patients even in early stages of dementia.

Diabetes mellitus and Parkinson disease.

To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease. We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline. The presence of diabetes mellitus was associated with higher motor scores (p < 0.01), lower striatal dopamine transporter binding (p < 0.05), and higher tau CSF levels (p < 0.05) in patients with Parkinson disease. In patients with diabetes but without Parkinson disease, the presence of diabetes mellitus was associated with lower striatal dopamine transporter binding (p < 0.05) and higher tau (p < 0.05) and α-synuclein (p < 0.05) CSF levels compared to healthy controls. At the Cox survival analysis in the population of patients with Parkinson disease, the presence of diabetes mellitus was associated with faster motor progression (hazard ratio = 4.521, 95% confidence interval = 1.468-13.926; p < 0.01) and cognitive decline (hazard ratio = 9.314, 95% confidence interval = 1.164-74.519; p < 0.05). Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype.

Relationship between cerebrospinal fluid biomarkers and structural brain network properties in Parkinson's disease.

Pathological accumulation of α-synuclein, amyloid-β42 , and tau proteins in the brain is considered critical for development of various neurodegenerative diseases. We investigated the association between CSF levels of these biomarkers, brain structural connectivity, and the UPDRS in PD. Diffusion tensor images and CSF biomarkers (α-synuclein, amyloid-β42 , total tau, and phosphorylated tau181) from 132 drug-naïve, nondemented PD patients and 61 healthy controls were obtained from the Parkinson's Progression Markers Initiative database. After network reconstruction of structural connectivity patterns, global interconnectivity measures (including global efficiency, clustering coefficient, and characteristic path length) and local efficiency were calculated. Network properties and CSF biomarkers were compared between PD patients and healthy controls. The association of CSF biomarkers with network properties and UPDRS-III score was investigated. Global measures (but not local efficiency) and CSF α-synuclein were significantly lower in PD patients. Global efficiency and clustering coefficient correlated positively with α-synuclein, Aβ42 , and total tau CSF levels. Furthermore, these CSF biomarkers showed no significant association with the UPDRS-III score. This study examined the association of CSF biomarkers that reflect the brain pathology, with structural brain connectivity and UPDRS-III in PD. Our results revealed an association between the abnormal aggregation of α-synuclein, Aβ42 , and tau proteins and structural connectivity disruption in PD patients. In summary, a combination of structural imaging and measurement of CSF biomarkers provide a better understanding of the pathogenesis of PD. © 2018 International Parkinson and Movement Disorder Society.

FDG-PET and CSF biomarker accuracy in prediction of conversion to different dementias in a large multicentre MCI cohort.

Background/aimsIn this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to Alzheimer's disease (AD) dementia and non-AD dementias.MethodsWe included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as “typical-AD”, “atypical-AD” (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), “non-AD” (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or “negative” patterns. To perform the statistical analyses, the individual patterns were grouped either as “AD dementia vs. non-AD dementia (all diseases)” or as “FTD vs. non-FTD (all diseases)”. Aβ42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated.ResultsThe multivariate logistic model identified FDG-PET “AD” SPM classification (Expβ = 19.35, 95% C.I. 4.8–77.8, p < 0.001) and CSF Aβ42 (Expβ = 6.5, 95% C.I. 1.64–25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The “FTD” SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expβ = 14, 95% C.I. 3.1–63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expβ = 17.9, 95% C.I. 4.55–70.46, p < 0.001).ConclusionsOur results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.

Risk Factors, Neuroanatomical Correlates, and Outcome of Neuropsychiatric Symptoms in Alzheimer's Disease.

An integrative model of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is lacking. In this study, we investigated the risk factors, anatomy, biology, and outcomes of NPS in AD. 181 subjects were included from the Alzheimer's Disease Neuroimaging Study (ADNI). NPS were assessed with the Neuropsychiatric Inventory Questionnaire at baseline and 6 months. NPI >3 was used as a threshold for NPS positivity. Three NPS courses were characterized: 1) minimal/absent (negative at 0 and 6 months, n = 77); 2) fluctuating (positive only at one time point, n = 53); 3) persistent (positive at both time points, n = 51). We examined the association between NPS course and family history of dementia, personal history of psychiatric disorders, cerebrospinal fluid biomarkers, atrophy patterns, as well as longitudinal cognitive and functional measures at 12 and 24 months (MMSE, CDR-SOB, FAQ). AD subjects with absent, fluctuating, or persistent NPS had similar CSF amyloid-β and tau levels. AD subjects with minimal/absent NPS had less personal history of psychiatric disorders (35%) than those with fluctuating (57%; p = 0.015) or persistent NPS (47%, not significant). At 24 months, AD subjects with persistent NPS had worse cognitive (MMSE; p = 0.05) and functional (CDR-SOB; p = 0.016) outcomes. Dorsolateral prefrontal atrophy was seen in persistent NPS, but not in fluctuating NPS. Our results suggest that individuals with personal history of psychiatric disorders might be more vulnerable to develop NPS throughout the course of AD. The worst cognitive and functional outcomes associated with NPS in AD underscores the importance of monitoring NPS early in the disease course.

Association of Cerebrospinal Fluid Tau Protein in Patients with Alzheimer’s and Non Alzheimer’s Dementias in a Tertiary Level Hospital in Bangladesh

Background: Alzheimer’s disease is one of the common causes of dementia in our country. The growth of the elderly population, together with the rising incidence of dementia requires immediate attention. There is very limited data regarding how CSF Tau protein correlates with this group of people’s cognitive function. Objectives: To evaluate association of CSF Tau protein in different types of dementia patients (AD and non-AD) and to find out the correlation of CSF Tau with severity of dementia and duration of disease. Methods: This cross sectional analytical study was conducted in dementia clinic (OPD) and inpatient department of Neurology, BSMMU from March’2013 to September’2015. 48 both male and female adult subjects were included in this study. Then they were divided into 3 groups: Alzheimer’s disease (AD) group (n=15), non-AD other dementias (OD) group (n=18) and subjects having neither AD and/or OD were included as control (n=15). CSF Tau protein was measured and compared between 3 groups. Results: Mean age of dementia in AD group was 68.2±9.33 years and in OD group was 67.72±12.74 years. Mean MMSE score in AD group was 13.47± 4.72, in OD group 15.83±3.31 and in control group 28.60±1.12. This study showed that CSF Tau protein was highly elevated in AD group (315.30±279.68 pg/ml) than in OD (57.08±27.41pg/ml) and control (39.23±12.21) groups. Conclusion: The study found that CSF Tau levels are elevated in AD patients in comparison to non AD other dementias. So, CSF Tau protein can be an early biomarker of Alzheimer’s disease.

DEVELOPMENT OF A 3-PLEX DIGITAL IMMUNOASSAY FOR DETECTION OF AMYLOID BETA1-42, AMYLOID BETA1-40 AND TAU IN BLOOD AND CSF SAMPLES

Multiplexed measurement of Amyloid beta1–42 (Ab42), amyloid beta1–40 (Ab40) and total tau in serum, plasma and CSF continues to be challenging, especially for normal healthy individuals. A multiplex sandwich immunoassay was developed for Ab42, Ab40 and total tau for the Simoa HD-1 Analyzer. The Analyzer performs a 2-step sandwich immunoassay, transfers labeled capture beads to an array of microwells, and interrogates the wells for presence of enzyme label. A single labeled analyte molecule provides sufficient fluorescence in 30 seconds to be detected. The concentration of target is then interpolated from a calibration curve. The multiplex was evaluated for sensitivity, precision, linearity, spike/recovery, reproducibility and between-assay-cross activity. Serum, plasma and CSF from healthy donors were evaluated. We measured plasma samples from individuals that showed elevated tau levels and decreased Ab42 levels in CSF previously. Limit of detection (2.5 SD) was 0.019 pg/mL(tau), 0.045 pg/mL(Ab42), 0.196 pg/mL(Ab40). Limit of quantification was 0.063 pg/mL(tau), 0.142 pg/ml (Ab42), 0.675 pg/mL (Ab40). Spike/recovery, linearity, and dilution linearity were within the 80–120% range. Inter lot CV was 3.5% and inter instrument CV was 4.1% based on pooled CV using 2 lots reagents, 3 instruments and 6 samples. Within run, between run, between day CVs were below 10% based on triplicates, 5 days, 10 runs of six samples. Plasma, serum and CSF from healthy donors were measured. The median [tau] were 1.43pg/ml, 0.561pg/ml and 82.5pg/ml; median [Ab42] were 11.1pg/mL 10.6pg/mL and 592pg/mL; median [Ab40] were 209pg/mL, 183 pg/mL and 6898 pg/mL respectively. All samples were quantifiable. Individuals that previously demonstrated higher tau levels in CSF did not show similar trend for plasma tau levels. Similarly, individuals with lower Ab42 levels in CSF did not show same trend in plasma either. The Simoa Neurology 3-plex assay is the first to reliably measure all 3 biomarkers simultaneously in plasma, serum and CSF samples from healthy individuals. It provides a new tool for the quantification of Ab42, Ab40and total tau in both normal and diseased samples. Plasma levels of these biomarkers did not correlate with CSF levels in this study.