CSF Alzheimer's Disease Biomarkers Research Articles

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology. We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid1-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes. Patients with LBD + AD performed worse on BNT than patients with LBD - AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28, p < 0.05) and p-tau (ρ = -0.26, p = 0.05) but not Aβ42 (p > 0.1). Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

Epilepsy in early onset Alzheimer’s disease

AbstractBackgroundEpilepsy seems to be an important comorbidity in patients with Alzheimer’s disease (AD), especially in young onset AD (&lt;65 years old). At this time epileptic seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline and early institutionalization. Seizures may also be a marker of a more aggressive subtype of AD.This study aims to determine the prevalence of the epileptic comorbidity in patients with early onset AD. Secondly, it will investigate the temporal relationship between AD and epilepsy and extract specific characteristics of AD patients at higher risk of epilepsy.MethodAll patients diagnosed as early‐onset Alzheimer disease between 2013 and 2019, with abnormal CSF biomarkers for Alzheimer disease, and followed at the University Hospital of Nancy (AD regional center) were selected. Patients with cortical focal lesion or old history of epilepsy were excluded. The usual clinical follow‐up was extended with a prolonged EEG and a specific consultation with an epilepsy expert. Based on this dedicated interrogation and EEG results, patients were then classified as epileptic or non‐epileptic. We collected demographic data and information on epilepsy and AD disorders.ResultAmong the 22 included patients, 10 were classified as epileptic with a prevalence of 45%. Considering seizure types, patients presented generalized seizures (n=4), typical temporal seizures (n=4), myoclonus (n=1) and extratemporal seizures (n=1). EEG recordings were not useful in our population. Epileptic patients presented a more severe cognitive decline than patients without seizures (MMSE 8.4+/‐6.9 versus MMSE non epileptic 20.9 +/‐ 5.45). 100% of patients with a MMSE &lt;10 had epileptic comorbidity. In our population, epilepsy never occurred before AD diagnosis.ConclusionEpilepsy appears to be a frequent comorbidity in early onset AD patients, with a prevalence of 45% in our study. This comorbidity seems to be a marker for severe AD. The role of the epileptic disorder in the acceleration of cognitive decline as the positive impact of antiepileptic drugs still need to be determined.

Lower CSF amyloid level is associated with sooner anti‐psychotic use in Alzheimer disease: A survival analysis

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) are a common feature of Alzheimer disease (AD). Antipsychotics (AP) remain a mainstay of BPSD treatment but have serious adverse effects and may serve as a proxy for BPSD in retrospective studies. Alzheimer biomarkers have been associated with neuropsychiatric symptoms and risk of post‐operative delirium. Potential associations between CSF markers of Alzheimer disease and antipsychotic use have not been explored. Here we used a survival analysis approach to probe the relationship between CSF AD biomarkers and BPSD by looking at AP use.MethodA retrospective cohort of 86 patients(average 72 y/o +/‐5, 46.5 %M) over the age of 65 with AD confirmed on CSF testing between December 2010 and March 2018 and no premorbid primary psychiatric diagnosis was identified using Northwestern Memorial Hospital’s Enterprise Data Warehouse. Patients were stratified by levels of amyloid‐Beta 42(AB42), phosphorylated tau, total tau, and amyloid to tau index(ATI) with a median split. We looked at time‐to‐AP use for each group using a Kaplan‐Meier analysis. A log rank test was used to calculate statistical significance. Chi‐square was used to compare nominal and Mann‐Whitney U for quantitative features of each group.ResultAltogether 11 patients received APs following CSF testing. There was no difference in AP use if groups were stratified by total tau, phosphorylated tau, or ATI. Nine (20.0%) of patients in the lower AB42 group compared with only 2 (4.5%) in the higher AB42 group received an AP. Patients in the lower AB42 group had sooner time‐to‐AP use on Kaplan‐Meier analysis, confirmed with a log‐rank test (p=0.04) (Figure 1). Comparing the two groups of 43 patients stratified by AB42 level, we did not detect a significant difference in demographics, MMSE scores, AD specific medication use, and comorbidities by the Charlson Comorbidity Index (Table 1).ConclusionThese results suggest a relationship between lower CSF amyloid levels and sooner AP use. This study supports prior work showing a relationship between amyloid deposition on PET imaging and neuropsychiatric symptoms. CSF AB42 appears important towards developing a biological framework of neuropsychiatric symptoms in Alzheimer dementia and may help with BPSD prognostication.

Peripheral markers of vascular endothelial dysfunction show independent but additive relationships with brain‐based biomarkers in association with functional impairment in Alzheimer’s disease

AbstractBackgroundCurrent epidemiologic evidence suggests that potentially modifiable midlife vascular risk factors specifically influence propensity for later‐life Alzheimer's disease (AD)‐associated cognitive decline. Despite this, a large knowledge gap still exists with respect to characterization of the biological overlap of highly co‐morbid vascular and AD pathologies in clinical AD. Prior studies focusing on contributions of co‐existing imaging‐based white matter disease and amyloid burden have found independent and/or additive rather than interactive associations to risk for cognitive decline, however recent studies utilizing sensitive measures of vascular dysfunction or expanded panels of AD pathology indicate that more nuanced synergistic associations between these pathologies may exist in AD. We hypothesized that elevated plasma cell adhesion molecule (CAM) levels would correlate with severity of diagnosis and functional impairment in AD dementia and be concomitantly lower in mild cognitive impairment (MCI) and normal controls, respectively, and would act synergistically rather than independently with CSF AD biomarkers in this regard.MethodUsing generalized linear regression models, we examined cross‐sectional relationships of plasma vascular cell adhesion molecule‐1 (VCAM‐1), intercellular adhesion molecule‐1 (ICAM‐1), and E‐Selectin to baseline diagnosis and functional impairment staging (clinical dementia rating sum‐of‐boxes, CDR‐SB) in the Alzheimer's Disease Neuroimaging (ADNI) cohort (n=564). We also assessed for modifying effects of AD risk factors including ApoE‐ε4 genotype, and then tested for interactive association by combining CAMs with CSF biomarkers into CDR‐SB models in a subset with available CSF data (n=351).ResultHigher mean VCAM‐1 (p=0.0026) and ICAM‐1 (p=0.0189) levels were found in AD versus MCI groups, however not in MCI versus cognitively normal groups. Only VCAM‐1 was linked with CDR‐SB scores (p=0.0157), and ApoE‐ε4 genotype modified this effect (p &lt; 0.0001). Contrary to our expectation, we observed independent and additive rather than interactive associations of VCAM‐1 and CSF Aβ42, total tau, phosphorylated tau (P‐tau), and P‐tau/Aβ42 (all &lt; p=0.01) in a combined CDR‐SB model (and ICAM‐1 to a lesser extent).ConclusionOur findings indicate independent rather than synergistic associations of plasma‐based biomarkers of vascular endothelial dysfunction and CSF biomarkers of AD pathology and neurodegeneration with AD‐related clinical impairment. Future longitudinal studies will be needed to validate these findings.

Differential associations between PET and CSF Alzheimer's disease biomarkers and cognition among cognitively normal older adults

AbstractBackgroundThe presence of brain β‐amyloid (Aβ) plaques among cognitively normal older adults has been related to steeper cognitive decline and an increased risk of Alzheimer’s disease (AD). The co‐presence of tau pathology in these individuals, however, makes it challenging to link AD pathologies to changes in specific cognitive function and brain structure. In addition, it remains unclear whether AD pathologies in the brain and their increased concentration in the cerebrospinal fluid (CSF) have similar effects on cognition.MethodWe assessed the relationship between Aβ and tau pathology, gray matter atrophy, and cognition among cognitively normal older adults in the Alzheimer's disease neuroimaging initiative whose brain Aβ deposition and tau‐protein neurofibrillary tangles were detected by 18F‐Florbetapir and 18F‐Flortaucipir, respectively. Within a subset of the sample, CSF measures of amyloid (Aβ40 and Aβ42) and tau (t‐tau and p‐tau) pathologies were assessed in relation to cognition and cortical thickness. Multiple regression models were applied to assess the relationships between AD pathologies, gray matter atrophy, and cognition using region‐of‐interest and whole‐brain surface‐based approaches.ResultHigher entorhinal tau PET counts corresponded to greater gray matter atrophy in the entorhinal cortex and hippocampus and poorer executive function performance, controlling for age, sex, and whole‐brain amyloid load. In the subset of the sample, whole‐brain amyloid load related to poorer memory and executive function performance, controlling for age, sex, and CSF total tau. Age was associated with memory and executive function performance, independent of entorhinal tau PET counts, CSF total tau, and whole‐brain amyloid load. Entorhinal tau PET counts did not correlate with CSF total tau or p‐tau among cognitively normal older adults.ConclusionAmyloid and tau pathology differentially influence cognition and brain structure. A low correlation between tau PET and CSF total tau measures in cognitively normal older adults may warrant further investigation on the source of discordance in these measures.

Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline.

To determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time. At baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of β-amyloid (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aβ1-42 and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years). There was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate -0.022, 95% confidence interval [CI] -0.043 to -0.002, p = 0.03) and AD biomarkers (estimate -0.060, 95% CI -0.096 to -0.024, p = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aβ1-42, t-tau, or p-tau. The results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline.

Alzheimer's disease biomarkers as predictors of trajectories of depression and apathy in cognitively normal individuals, mild cognitive impairment, and Alzheimer's disease dementia.

To examine trajectories of depression and apathy over a 5-year follow-up period in (prodromal) Alzheimer's disease (AD), and to relate these trajectories to AD biomarkers. The trajectories of depression and apathy (measured with the Neuropsychiatric Inventory or its questionnaire) were separately modeled using growth mixture models for two cohorts (National Alzheimer's Coordinating Center, NACC, n = 22 760 and Alzheimer's Disease Neuroimaging Initiative, ADNI, n = 1 733). The trajectories in ADNI were associated with baseline CSF AD biomarkers (Aβ42, t-tau, and p-tau) using bias-corrected multinomial logistic regression. Multiple classes were identified, with the largest classes having no symptoms over time. Lower Aβ42 and higher tau (ie, more AD pathology) was associated with increased probability of depression and apathy over time, compared to classes without symptoms. Lower Aβ42 (but not tau) was associated with a steep increase of apathy, whereas higher tau (but not Aβ42 ) was associated with a steep decrease of apathy. The trajectories of depression and apathy in individuals on the AD spectrum are associated with AD biomarkers.

Practices and opinions about disclosure of the diagnosis of Alzheimer's disease to patients with MCI or dementia: a survey among Belgian medical experts in the field of dementia.

Previous surveys revealed that only a minority of clinicians routinely disclosed the diagnosis of Alzheimer's disease (AD) to their patients. Many health professionals fear that the disclosure could be harmful to the patient. Recent advances in the development of biomarkers and new diagnostic criteria allow for an earlier diagnosis of AD at the mild cognitive impairment (MCI) stage. The Belgian Dementia Council, a group of Belgian experts in the field of dementia, performed a survey among its 44 members about their opinions and practices regarding disclosure of the diagnosis of AD, including MCI due to AD, and its consequences. Twenty-six respondents declared that they often or always disclose the diagnosis of AD to patients with dementia and to patients with MCI when AD CSF biomarkers are abnormal. The majority observed that the disclosure of AD is rarely or never harmful to the patients. Their patients and their caregivers rarely or never demonstrated animosity towards the clinicians following disclosure of the diagnosis of AD. These results should reassure clinicians about the safety of AD diagnosis disclosure in most cases whether the patient is at the MCI or the dementia stage.

Increased Cerebrospinal Fluid S100B and NSE Reflect Neuronal and Glial Damage in Parkinson's Disease.

Introduction: The diagnosis of Parkinson’s disease (PD) mainly relies on clinical manifestation, but may be difficult to make in very early stages of the disease, especially in pre-motor PD. Thus, there is great interest in finding a biomarker for PD. Among diagnostic biomarkers, the most promising molecules are those which reflect the pathophysiological mechanisms of the disease. Until now, only α-synuclein, a classical CSF Alzheimer’s disease biomarker, and neurofilament light (NFL) chains have turned out to be helpful in differential diagnosis between PD and healthy control subjects.Aim: To assess whether CSF molecules related to some pathological processes present in PD might be of interest in the diagnosis of PD and whether they correlate with disease severity.Methods: CSF levels of S100B and neuron-specific enolase (NSE) were measured in 58 PD patients and in 28 healthy control subjects. Correlations were determined between the levels of these CSF molecules and measures of disease severity (Hoehn–Yahr scale and UPDRS part III), as well as disease duration and levodopa dose.Results: CSF S100B and CSF NSE were both significantly increased in PD subjects vs. healthy controls (p = 0.007 and p = 0.00035, respectively). CSF S100B was significantly positively correlated with measures of disease severity (H-Y score and UPDRS part III), as well as disease duration (p < 0.05). No correlation was found between CSF NSE levels and disease severity or disease duration (p > 0.05). CSF S100B levels alone provided a relatively high discrimination (AUC 0.77) between PD and healthy controls, with 60.7% sensitivity and 88.5% specificity (p < 0.001) at a cut-off value of 123.22 pg/ml. Similarly, CSF NSE levels alone provided a relatively high discrimination (AUC 0.775) between PD and healthy controls, with 78.6% sensitivity and 74.1% specificity at a cut-off value of 51.56 ng/ml (p < 0.001).Conclusions: Our results show that both CSF S100B and CSF NSE seem to be promising markers of the axonal and glial degeneration present in PD. Additionally CSF S100B may be a promising marker of PD progression.

Minor neuropsychological deficits in patients with subjective cognitive decline.

To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD). We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology. We observed worse performance (Cohen d = ≈0.25-0.5, adjusted for age, sex differences with analysis of covariance) in global performance, memory, executive functions, and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately (r = ≈0.3) associated with lower CSF β-amyloid42/40 and CSF β-amyloid42/phosphorylated tau181 in the whole sample and specifically in the SCD subgroup. Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.

Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer disease.

To assess the ability of a combination of synaptic CSF biomarkers to separate Alzheimer disease (AD) and non-AD disorders and to help in the differential diagnosis between neurocognitive diseases. This was a retrospective cross-sectional monocentric study. All participants explored with CSF assessments for neurocognitive decline were invited to participate. After complete clinical and imaging evaluations, 243 patients were included. CSF synaptic (GAP-43, neurogranin, SNAP-25 total, SNAP-25aa40, synaptotagmin-1) and AD biomarkers were blindly quantified with ELISA or mass spectrometry. Statistical analysis compared CSF levels between the various groups of AD dementias (n = 81), mild cognitive impairment (MCI)-AD (n = 30), other MCI (n = 49), other dementias (OD) (n = 49), and neurologic controls (n = 35) and their discriminatory powers. All synaptic biomarkers were significantly increased in patients with MCI-AD and AD-dementia compared to the other groups. All synaptic biomarkers could efficiently discriminate AD dementias from OD (AUC ≥0.80). All but synaptotagmin were also able to discriminate patients with MCI-AD from controls (area under the curve [AUC] ≥0.85) and those with AD dementias from controls (AUC ≥0.80). Overall, CSF SNAP-25aa40 had the highest discriminative power (AUC 0.93 between patients with AD dementias and controls or OD, AUC 0.90 between those with MCI-AD and controls). Higher levels were associated with 2 alleles of APOE ε4. All synaptic biomarkers tested had a good discriminatory power to distinguish patients with AD abnormal CSF from those with non-AD disorders. SNAP25aa40 demonstrated the highest power to discriminate AD CSF-positive patients from patients without AD and neurologic controls in this cohort. This retrospective study provides Class II evidence that CSF synaptic biomarkers discriminate patients with AD from those without AD.

White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease.

Recent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI). Two sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated. Baseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes. These results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

Connected Speech Deficit as an Early Hallmark of CSF-defined Alzheimer's Disease and Correlation with Cerebral Hypoperfusion Pattern.

Diagnosis of prodromal Alzheimer's disease (AD) still represents a hot topic and there is a growing interest for the detection of early and non-invasive biomarkers. Although progressive episodic memory impairment is the typical predominant feature of AD, communicative difficulties can be already present at the early stages of the disease. This study investigated the narrative discourse production deficit as a hallmark of CSFdefined prodromal AD and its correlation with cerebral hypoperfusion pattern. Narrative assessment with a multilevel procedure for discourse analysis was conducted on 28 subjects with Mild Cognitive Impairment (15 MCI due to AD; 13 MCI non-AD) and 28 healthy controls. The diagnostic workup included CSF AD biomarkers. Cerebral hypoperfusion pattern was identified by SPECT image processing. The results showed that the discourse analysis of global coherence and lexical informativeness indexes allowed to identify MCI due to AD from MCI non-AD and healthy subjects. These findings allow to hypothesize that the loss of narrative efficacy could be a possible early clinical hallmark of Alzheimer's disease. Furthermore, a significant correlation of global coherence and lexical informativeness reduction with the SPECT hypoperfusion was found in the dorsal aspect of the anterior part of the left inferior frontal gyrus, supporting the hypothesis that this area has a significant role in communicative efficacy, and in particular, in semantic selection executive control. This study contributes to the understanding of the neural networks for language processing and their involvement in prodromal Alzheimer's disease. It also suggests an easy and sensitive tool for clinical practice that can help identifying individuals with prodromal 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.

Moral Emotions in Frontotemporal Dementia.

Emotions, with or without moral valence, appear to be altered in the behavioral variant of frontotemporal dementia (bvFTD) but the relative degree of moral emotion breakdown, which could be a marker of bvFTD diagnosis, remains unexplored. To assess moral emotions in bvFTD, to differentiate bvFTD from typical Alzheimer's disease (AD) based on moral emotion processing, and to provide a sensitive and specific assessment tool contributing to bvFTD diagnosis. We investigated moral emotions in 22 bvFTD patients, 15 patients with typical AD having positive CSF AD biomarkers, and 45 healthy controls. The 'Moral Emotions Assessment' task consisted in 42 scenarios exploring positive and negative moral emotions. To control for moral-specificity, we contrasted the 42 moral scenarios with 18 extra-moral scenarios eliciting the emotions without involving any inter-human moral context. bvFTD patients were more impaired in emotion processing than AD patients and healthy controls and had significantly poorer performance in the processing of moral emotions than of emotions without moral valence. ROC analyses of data on moral scenarios showed a high area under the curve (83%), and indicated a cut-off score (< 37/42) for differentiating bvFTD from AD with a sensitivity of 82% and specificity of 73%. Our findings demonstrate that bvFTD patients have disorders in emotion processing which is mainly related to failure regarding moral emotions. They also show that this deficit is reliably detected by the 'Moral Emotions Assessment' which represents a sensitive and specific diagnostic tool detecting bvFTD and differentiating it from AD.

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation.

The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer's disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-based navigation is impaired in pre-dementia Alzheimer's disease. Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer's disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-based navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer's disease. Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration performance correlated with Alzheimer's disease molecular pathology, with levels of CSF amyloid-β and total tau contributing independently to distance error. Path integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57). This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer's disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer's disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer's drugs.

Clinical, neuropsychological and imaging characteristics of Alzheimer's disease patients presenting as corticobasal syndrome

BackgroundCorticobasal syndrome (CBS) can harbor diverse pathologies, such as corticobasal degeneration (CBD) and Alzheimer's disease (AD). CSF biochemical analysis in CBS patients can confidently distinguish between an AD (CBS-AD) and a non-AD (CBS-nAD) pathology. ObjectiveWe utilized classical CSF biomarkers to make a distinction between the two groups and examine their clinical, neuropsychological, neuropsychiatric and imaging differences. MethodsSeventeen patients with a CBS phenotype were included. Detailed clinical history, and neurological examination data were recorded. A thorough neuropsychological and neuropsychiatric test battery was performed, including Goldenberg apraxia test. Simple linear MRI measurements and planimetry data were utilized. CSF biomarkers for AD were ascertained. ResultsFive of seventeen CBS patients had a CSF AD profile. Patients with a CSF AD profile (CBS-AD; n = 5) were older and had a greater age at disease onset compared to CBS-nAD. CBS-AD patients had more frequently alien hand phenomena at examination and greater hippocampi surface asymmetry at MRI. CBS-nAD patients (n = 12) had lower superior colliculi width values. ConclusionClinical, neuropsychological and imaging data cannot confidently differentiate CBS-AD from CBS-nAD patients.

A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort

IntroductionMachine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers. MethodsThis study analyzed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV). ResultsOn the test data, DL produced the AUC of 0.85 (0.80–0.89), XGBoost produced 0.88 (0.86–0.89) and RF produced 0.85 (0.83–0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively. DiscussionThis study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.

Alzheimer's disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology.

Although amyloid pathology plays a role in epilepsy, little is known about the relationship between beta amyloid and progression to Alzheimer's disease (AD) among patients with late-onset epilepsy of unknown origin (LOEU). This multicenter, observational, prospective study enrolled 40 consecutive nondemented adults diagnosed with LOEU, together with 43 age- and sex-matched healthy controls. All patients completed neuropsychological tests, core CSF AD biomarkers assessment (Aβ1-42, total tau, and phosphorylated tau), and follow-up for a mean of 3years to verify cognitive decline. Despite age and baseline cognitive performance were similar to healthy controls, patients with LOEU had significant prevalence of CSF pathological Aβ1-42 (<500 pg/mL; 37.5%), 7.5% displaying an AD-like CSF pattern. Moreover, 17.5% of patients with LOEU converted to AD dementia, versus none among healthy controls (p < 0.005). Patients with LOEU with pathological Aβ1-42 had a hazard ratio 3.4 (CI 0.665-17.73) for progression to AD dementia at follow-up. Patients with LOEU have a high prevalence of abnormal CSF Aβ1-42 and progression to AD dementia compared with healthy controls, and therefore should be monitored for cognitive decline.

The hippocampal longitudinal axis-relevance for underlying tau and TDP-43 pathology.

Recent studies suggest that hippocampus has different cortical connectivity and functionality along its longitudinal axis. We sought to elucidate the possible different pattern of atrophy in longitudinal axis of hippocampus between Amyloid/Tau pathology and TDP-43-pathies. Seventy-three presenile subjects were included: Amyloid/Tau group (33 Alzheimer's disease with confirmed cerebrospinal fluid [CSF] biomarkers), probable TDP-43 group (7 semantic variant progressive primary aphasia, 5 GRN and 2 C9orf72 mutation carriers) and 26 healthy controls. We conducted a region-of-interest voxel-based morphometry analysis on the hippocampal longitudinal axis, by contrasting the groups, covarying with CSF biomarkers (Aβ42, total tau, p-tau) and covarying with episodic memory scores. Amyloid/Tau pathology affected mainly posterior hippocampus while anterior left hippocampus was more atrophied in probable TDP-43-pathies. We also observed a significant correlation of posterior hippocampal atrophy with Alzheimer's disease CSF biomarkers and visual memory scores. Taken together, these data suggest that there is a potential differentiation along the hippocampal longitudinal axis based on the underlying pathology, which could be used as a potential biomarker to identify the underlying pathology in different neurodegenerative diseases.