Cerebrospinal Fluid Biomarker Profile Research Articles

Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer’s disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer’s disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aβ42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer’s disease who do not have HIV infection.

The relation of a cerebrospinal fluid profile associated with Alzheimer’s disease with cognitive function and neuropsychiatric symptoms in sporadic cerebral amyloid angiopathy

BackgroundPatients with sporadic cerebral amyloid angiopathy (sCAA) frequently report cognitive or neuropsychiatric symptoms. The aim of this study is to investigate whether in patients with sCAA, cognitive impairment and neuropsychiatric symptoms are associated with a cerebrospinal fluid (CSF) biomarker profile associated with Alzheimer’s disease (AD).MethodsIn this cross-sectional study, we included participants with sCAA and dementia- and stroke-free, age- and sex-matched controls, who underwent a lumbar puncture, brain MRI, cognitive assessments, and self-administered and informant-based-questionnaires on neuropsychiatric symptoms. CSF phosphorylated tau, total tau and Aβ42 levels were used to divide sCAA patients in two groups: CAA with (CAA-AD+) or without a CSF biomarker profile associated with AD (CAA-AD-). Performance on global cognition, specific cognitive domains (episodic memory, working memory, processing speed, verbal fluency, visuoconstruction, and executive functioning), presence and severity of neuropsychiatric symptoms, were compared between groups.ResultssCAA-AD+ (n=31; mean age: 72 ± 6; 42%, 61% female) and sCAA-AD- (n=23; 70 ± 5; 42% female) participants did not differ with respect to global cognition or type of affected cognitive domain(s). The number or severity of neuropsychiatric symptoms also did not differ between sCAA-AD+ and sCAA-AD- participants. These results did not change after exclusion of patients without prior ICH.ConclusionsIn participants with sCAA, a CSF biomarker profile associated with AD does not impact global cognition or specific cognitive domains, or the presence of neuropsychiatric symptoms.

Clinical value of Alzheimer's disease biomarker testing.

In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

AT(N) Classification and Clinical Characterization by CSF Biomarkers in Patients with Corticobasal Syndrome

AbstractBackgroundCorticobasal syndrome (CBS) is clinically characterized by asymmetric cortical and extrapyramidal deficits. CBS is caused by various pathological conditions including primary tauopathy and Alzheimer’s disease (AD). To clarify whether there are differences in clinical features of CBS between AD pathology and non‐AD pathology, we classified CBS patients based on AT(N) system by cerebrospinal fluid (CSF) biomarkers and assessed the clinical characteristics of the classified groups.MethodWe assessed retrospectively 19 CBS patients (7 males and 12 females) diagnosed by neurologists at our hospital between 2014 to 2021. They all fulfilled the clinical symptoms of probable or possible CBS according to the Armstrong criteria of corticobasal degeneration. CSF AT(N) biomarkers, A marker: Aβ42 and Aβ42/Aβ40 ratio, T marker: phosphorylated tau (Thr181) [p‐tau], N marker: total tau [t‐tau] and neurofilament light chain [NfL], were evaluated. The positive/negative of each biomarker was judged according to the cutoff value calculated in a cohort independent of this study. We used Aβ42/Aβ40 ratio as the A marker and NfL as the N marker in this study. Each patient was classified AT(N) group. Clinical characteristics were compared between biological AD (i.e., A+T+) group and non‐AD group.ResultThe concordance of A markers (Aβ42 and Aβ42/Aβ40 ratio) was 68.4%, and that of N markers (t‐tau and NfL) was 15.8% in patients with CBS. NfL had more positive rates than t‐tau in CBS patients. Based on CSF biomarker profile, CBS patients were classified as AD group (n = 4, 21%), Alzhehimer’s and concomitant suspected non‐Alzheimer’s pathologic change group (n = 2, 11%) and non‐AD pathologic change group (n = 13, 68%). AD group showed lower scores of MMSE (p = 0.037), more frequent presence of Gerstmann syndrome (p = 0.007), predominance of right limb symptoms (p = 0.015), and more common in non‐motor symptoms onset (p = 0.029) than non‐AD group.ConclusionBy applying the AT(N) classification to CBS patients, we found that 21% of patients exhibited AD pattern by CSF biomarkers. The clinical differences between AD group and non‐AD group may reflect the different pathological backgrounds. NfL could be more sensitive than t‐tau as the N marker in detecting neurodegeneration of CBS.

The cerebrospinal fluid A‐T+ Alzheimer disease biomarker profile: prevalence and clinical relevance

AbstractBackgroundThe cerebrospinal fluid (CSF) amyloid β‐negative and tau‐positive (A‐T+) biomarker profile, as defined by normal amyloid β42/40 ratio (Aβ42/40) and increased phosphorylated tau (p‐tau), is sometimes seen in daily clinical practice. However, knowledge is lacking on its prevalence and whether patients with this profile are at risk for biological disease progression and cognitive decline.MethodIn this study, data from four cohorts were included: UGOT (the clinical laboratory database at Sahlgrenska University Hospital, Gothenburg), Alzheimer’s Disease Neuroimaging Initiative (ADNI; cognitively unimpaired [CU] and mild cognitive impairment [MCI] individuals), Wisconsin Registry for Alzheimer’s Prevention, and Wisconsin ADRC cohorts (latter two analyzed jointly, “WISC”; predominantly CU individuals). Repeated measures of cognitive decline (modified preclinical Alzheimer’s composite [mPACC] in ADNI, and PACC‐3 in the WISC sample), amyloid accumulation (only in ADNI: [18F]‐florbetapir amyloid positron emission tomography [PET]) neurodegeneration (only in ADNI: magnetic resonance imaging [MRI], [18F]‐fluorodeoxyglucose PET [FDG‐PET]), and cross‐sectional tau PET ([F18]‐flortaucipir in ADNI and [F18]‐MK6240 in WISC) were used as exposures.ResultIn the UGOT cohort, a total of 7679 individuals were included (46Conclusions6% women; mean [SD] age, 71.0 [8.3] years). Further, 970 individuals from ADNI (45.8% women, mean [SD] age, 72.8 [7.0]), and n = 519 individuals from WISC (66.7% women, mean [SD] age, 59.7 [7.3]) cohorts were included. The prevalence of the A‐T+ profile in the UGOT cohort was 4.1%, compared with A+T+ that constituted 36%, A‐T‐ 42%, and A+T‐ 17%. In ADNI and UGOT, A‐T+ had higher concentrations of Aβ42 and Aβ40 compared to A‐T‐ individuals. The prognosis of CSF biomarker profiles was determined with linear mixed effects models (ADNI and WISC). The A‐T+ profile, compared with A‐T‐, presented no statistically significant rates of cognitive worsening (ADNI and WISC p>0.05), or in longitudinal changes in Aβ‐PET, FDG‐PET, and hippocampal atrophy (all p>0.05), within the ADNI subsample. Cross‐sectionally, A‐T+ individuals had similar tau‐PET uptake to A‐T‐ individuals (p>0.05).ConclusionThe CSF A‐T+ profile is to be considered clinically benign, as individuals with this profile do not have a higher rate of cognitive decline compared with biomarker‐negative individuals and do not display signs of amyloid accumulation or progressive neurodegeneration.

Cerebrospinal fluid biomarkers profile in scans without evidence of dopaminergic deficits (SWEDD)

BackgroundA small proportion of patients with clinical parkinsonism have normal transporter-single photon emission computed tomography (DaTSPECT) which is commonly defined as scans without evidence of dopaminergic deficits (SWEDD). A better understanding of SWEDD can improve the current therapeutic options and appropriate disease monitoring. AimWe aimed to assess CSF biomarkers levels including α-synuclein (α-syn), amyloid βeta (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) in SWEDD and investigate the longitudinal alteration in the CSF profile. MethodsIn total, 406 early-stage PD, 58 SWEDD, and 187 healthy controls (HCs) were entered into our study from PPMI. We compared the level of CSF biomarkers at baseline, six months, one year, and two years. Furthermore, the longitudinal alteration of CSF biomarkers was explored in each group using linear mixed models. ResultsThere was no significant difference in the level of CSF α-syn Aβ1–42, t-tau, and p-tau between HCs and SWEDD at different time points. Investigating the level of CSF α-syn in PD and SWEDD showed a significant difference at one (p = 0.016) and two years (p = 0.006). Also, we observed a significant difference in the level of CSF Aβ1–42 between SWEDD and PD at one year (p = 0.012). Moreover, there was a significant difference in the level of CSF t-tau between SWEDD and PD subjects at one (p = 0.013) and two years (p = 0.017). Furthermore, there was a significant difference in the level of CSF p-tau between SWEDD and PD groups at two years visits (p = 0.030). Longitudinal analysis showed a significant decrease after one (p = 0.029) and two years (p = 0.002) from baseline in the level of CSF α-syn only in the PD group. Also, we observed that the level of CSF Aβ1–42 significantly increased after one year in SWEDD (p = 0.031) and decreased after two years from baseline in PD subjects (p = 0.005). Moreover, there was a significant increase in the level of CSF t-tau after two years (p = 0.036) and CSF p-tau after six months from baseline in SWEDD subjects (p = 0.011). ConclusionThis finding suggests a faster neurodegeneration process in PD patients compared to SWEDD at least based on these biomarkers. Future studies with longer follow-up duration and more sample sizes are necessary to validate our results.

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

BackgroundGenome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.MethodsWe performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.ResultsFive loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.ConclusionsThese results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Clinical Characteristics, Neuroimaging Markers, and Outcomes in Patients with Cerebral Amyloid Angiopathy: A Prospective Cohort Study.

Background and purpose: Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease, resulting from progressive amyloid-β deposition in the media/adventitia of cortical and leptomeningeal arterioles. We sought to assess the prevalence of baseline characteristics, clinical and radiological findings, as well as outcomes among patients with CAA, in the largest study to date conducted in Greece. Methods: Sixty-eight patients fulfilling the Boston Criteria v1.5 for probable/possible CAA were enrolled and followed for at least twelve months. Magnetic Resonance Imaging was used to assess specific neuroimaging markers. Data regarding cerebrospinal fluid biomarker profile and Apolipoprotein-E genotype were collected. Multiple logistic regression analyses were performed to identify predictors of clinical phenotypes. Cox-proportional hazard regression models were used to calculate associations with the risk of recurrent intracerebral hemorrhage (ICH). Results: Focal neurological deficits (75%), cognitive decline (57%), and transient focal neurological episodes (TFNEs; 21%) were the most common clinical manifestations. Hemorrhagic lesions, including lobar cerebral microbleeds (CMBs; 93%), cortical superficial siderosis (cSS; 48%), and lobar ICH (43%) were the most prevalent neuroimaging findings. cSS was independently associated with the likelihood of TFNEs at presentation (OR: 4.504, 95%CI:1.258-19.088), while multiple (>10) lobar CMBs were independently associated with cognitive decline at presentation (OR:5.418, 95%CI:1.316-28.497). cSS emerged as the only risk factor of recurrent ICH (HR:4.238, 95%CI:1.509-11.900) during a median follow-up of 20 months. Conclusions: cSS was independently associated with TFNEs at presentation and ICH recurrence at follow-up, while a higher burden of lobar CMBs with cognitive decline at baseline. These findings highlight the prognostic value of neuroimaging markers, which may influence clinical decision-making.

Prevalence and Clinical Implications of a β-Amyloid–Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease

Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile. To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications. This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023. Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240). Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET. A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile. Results suggest that the CSF A-T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.

Increased Cerebrospinal Fluid Levels of Soluble Triggering Receptor Expressed on Myeloid Cells 2 and Chitinase-3-Like Protein 1 in Idiopathic Normal-Pressure Hydrocephalus.

Neurodegenerative disease pathology is associated with neuroinflammation, but evidence on idiopathic normal pressure hydrocephalus (iNPH) remains limited and cerebrospinal fluid (CSF) biomarker profiles need to be elucidated. To investigate whether iNPH pathological mechanisms are associated with greater CSF markers of core Alzheimer's disease pathology (amyloid-β42 (Aβ42), phosphorylated tau (P-tau)), neurodegeneration (total tau (T-tau)), and neuroinflammation (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40)). The study analyzed lumbar CSF samples from 63 patients with iNPH and 20 age-matched orthopedic surgery patients who had no preoperative gait or cognitive impairment (control group). Aβ42, T-tau, P-tau, sTREM2, and YKL-40 in different subgroups were investigated. CSF sTREM2 levels were significantly higher in the iNPH group than in the control group, but no significant between-group difference was noted in YKL-40. Moreover, YKL-40 levels were significantly higher in the tap test non-responders than in the tap test responders (p = 0.021). At the 1-year follow-up after shunt surgery, the CSF P-tau levels were significantly lower (p = 0.020) in those with gait improvement and the CSF sTREM2 levels were significantly lower (p = 0.041) in those with cognitive improvement. In subgroup analysis, CSF sTREM2 levels were strongly correlated with CSF YKL-40 in the iNPH group (r = 0.443, p < 0.001), especially in the tap test non-responders (r = 0.653, p = 0.002). YKL-40 and sTREM2 are disease-specific markers of neuroinflammation, showing higher CSF levels in iNPH. In addition, sTREM2 is positively associated with YKL-40, indicating that interactions of glial cells play an important role in iNPH pathogenesis.

Reactive astrocytes as imaged with 11C‐DED in patients with different dementia disorders

AbstractBackgroundNeuroinflammation, which receives ever increasing interest in neurodegenerative diseases, comprises a heterogeneous cascade of events that are thought to be related to the downstream neurodegeneration. The aim of this study was to evaluate the binding of 11C‐Deuterium‐L‐Deprenyl PET (DED) as a measure of reactive astrocytes in patients with different dementia disorders, and to assess its association with other disease biomarkers.MethodEleven patients with a clinical diagnosis of semantic variant of primary progressive aphasia (svPPA, n = 5) and behavioral variant of frontotemporal dementia (bvFTD, n = 6) were recruited. All patients had a cerebrospinal fluid biomarker profile that was inconsistent with Alzheimer’s disease (AD) or a negative amyloid‐β PET scan. The imaging protocol included 11C‐DED‐PET, 18F‐FDG‐PET, and a 3D T1 MRI. A group of amyloid‐beta positive patients with AD (n = 20) that underwent similar investigations were used for comparison. Z‐scores were created for 11C‐DED binding (Patlak slopes) and tracer relative delivery (R1 parameter) relative to that of healthy controls (HC; n = 20), for assessing the load of reactive astrocytes and cerebral perfusion, respectively.ResultThe patients with svPPA and bvFTD showed significantly higher 11C‐DED binding in frontotemporal areas, compared to HC. Patients with AD showed significantly higher 11C‐DED binding in temporo‐occipital areas, compared to HC. The regional distribution of 11C‐DED binding in the patients with svPPA and bvFTD was consistent with the expected underlying pattern of neurodegeneration in those disorders, although the load of binding was heterogeneous across patients with the same clinical diagnosis.ConclusionReactive astrocytes appear to be a common feature of different dementia disorders, although the regional pattern of reactivity differs. Ongoing work evaluates the relationship between patterns of reactive astrocyte activation, cerebral perfusion, glucose metabolism, atrophy, and cognitive performance.

Prognostic value of cerebrospinal fluid biomarkers in mild cognitive impairment due to Alzheimer disease

We performed a retrospective analysis of the patients assessed at our memory unit for whom Alzheimer disease (AD) cerebrospinal fluid biomarker results were available. We selected patients diagnosed with mild cognitive impairment due to AD (National Institute on Aging-Alzheimer’s Association clinical criteria), confirmed neuropsychological deficit, a Global Deterioration Scale score of 3, and an abnormal profile of cerebrospinal fluid biomarkers. Of the 588 cases reviewed, 110 met the inclusion criteria. During follow-up, 50 cases (45.45%) progressed to dementia due to AD. Baseline levels of total and phosphorylated tau were higher in the group of patients that progressed to dementia than in those remaining with mild cognitive impairment. After adjusting for age, sex, history of hypertension, diabetes, and educational level, a 10% increase in total tau protein values was associated with a 7.60% increase in the risk of progression to dementia (hazard ratio: 2.22; 95% confidence interval, 1.28–3.84]; P = .004). Among patients with mild cognitive impairment due to AD and abnormal cerebrospinal fluid biomarker profiles, progressively higher concentrations of total or phosphorylated tau were associated with increased risk of progression to dementia.

Exploring the role of sleep in Alzheimer’s disease: The AlfaSleep project

AbstractBackgroundSleep disruption is prevalent in the aging population and increasingly recognized as a risk factor and an early sign of Alzheimer’s disease (AD). Emerging data suggest that dysregulated orexin signaling may play a role in this association. The AlfaSleep study aims to characterize sleep patterns with objective measurements, and determine CSF orexin‐A levels in cognitively unimpaired middle‐aged adults at increased risk of AD.MethodTwo‐hundred cognitively unimpaired middle‐aged adults from the prospective observational ALFA+ study have been invited to participate in this study based on their cerebrospinal fluid (CSF) biomarker profile at the ALFA+ study baseline (100 in the AD continuum and 100 control, non‐altered biomarkers). ALFA+ participants are followed‐up every three years (and currently are undergoing the first follow‐up visit) with neuropsychological testing, blood and CSF sampling, and MRI and PET (with FDG, amyloid and tau tracers) acquisition. Participants included in the AlfaSleep study are additionally characterized with actigraphy (Actiwatch2®, Philips Respironics during two weeks), a nasal flow monitoring device (RUSleeping RTS®, Philips Respironics during one night) and CSF orexin‐A measurements. Furthermore, a subset (n = 90) will undergo overnight polysomnography at the Hospital Clinic Sleep Unit (Figure 1). Sleep‐related outcomes include total sleep time, sleep latency, sleep efficiency, sleep fragmentation, apnea‐hypopnea index and sleep microarchitecture measures (e.g. spectral power analyses). These data, as well as CSF orexin‐A levels will be compared across participants with different AD biomarkers profiles and correlated with cognitive performance, neuroimaging and fluid biomarkers data.ResultTo date, 134 participants (mean age 64.4 years, 67% female) have been included in the AlfaSleep study. Of these, 50 (37.9%) reported poor sleep quality (PSQI&gt;5), 45.5% are APOE‐ε4 carriers and 35.8% had abnormal CSF amyloid levels, as measured at the ALFA+ baseline visit (see Table 1 for a detailed description).ConclusionDue to its multimodal approach, and the profile of the study population (cognitively unimpaired middle‐aged adults in the AD continuum), the present project will make relevant contributions to understand the role of sleep disruption as a risk factor and early clinical manifestation of AD. Preliminary results will be presented at the conference.

Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological syndrome characterized by the clinical triad of gait disorder, cognitive impairment and urinary incontinence. It has attracted interest because of the possible reversibility of symptoms, especially with timely treatment. The main pathophysiological theory is based on a vicious circle of disruption in circulation of cerebrospinal fluid (CSF) that leads to the deceleration of its absorption. Data regarding CSF biomarkers in iNPH are contradictory and no definite CSF biomarker profile has been recognized as in Alzheimer's disease (AD), which often co-exists with iNPH. In this narrative review, we investigated the literature regarding CSF biomarkers in iNPH, both the established biomarkers total tau protein (t-tau), phosphorylated tau protein (p-tau) and amyloid peptide with 42 amino acids (Aβ42), and other molecules, which are being investigated as emerging biomarkers. The majority of studies demonstrate differences in CSF concentrations of Aβ42 and tau-proteins (t-tau and p-tau) among iNPH patients, healthy individuals and patients with AD and vascular dementia. iNPH patients present with lower CSF Aβ42 and p-tau concentrations than healthy individuals and lower t-tau and p-tau concentrations than AD patients. This could prove helpful for improving diagnosis, differential diagnosis and possibly prognosis of iNPH patients.

Differences in CSF Biomarkers Profile of Patients with Parkinson's Disease Treated with MAO-B Inhibitors in Add-On.

Monoamine oxidase type B inhibitors (iMAO-Bs) are a class of largely-used antiparkinsonian agents that, based on experimental evidence, are supposed to exert different degrees of neuroprotection in Parkinson's disease (PD). However, clinical proofs on this regard are very scarce. Since cerebrospinal fluid (CSF) reflects pathological changes occurring at brain level, we examined the neurodegeneration-related CSF biomarkers profile of PD patients under chronic treatment with different iMAO-Bs to identify biochemical signatures suggestive for differential neurobiological effects. Thirty-five PD patients under chronic treatment with different iMAO-Bs in add-on to levodopa were enrolled and grouped in rasagiline (n = 13), selegiline (n = 9), safinamide (n = 13). Respective standard clinical scores for motor and non-motor disturbances, together with CSF biomarkers of neurodegeneration levels (amyloid- β -42, amyloid- β -40, total and 181-phosphorylated tau, and lactate) were collected and compared among the three iMAO-B groups. No significant clinical differences emerged among the iMAO-B groups. CSF levels of tau proteins and lactate were instead different, resulting higher in patients under selegiline than in those under rasagiline and safinamide. Although preliminary and limited, this study indicates that patients under different iMAO-Bs may present distinct profiles of CSF neurodegeneration-related biomarkers, probably because of the differential neurobiological effects of the drugs. Larger studies are now needed to confirm and extend these initial observations.

Logogenic Primary Progressive Aphasia or Alzheimer Disease: Contribution of Acoustic Markers in Early Differential Diagnosis.

The logopenic variant of Primary Progressive Aphasia (lvPPA), a syndromic disorder centered on language impairment, often presents variable underlying neurodegenerative pathologies such as Alzheimer Disease (AD). Actual language assessment tests and lumbar puncture, focused on AD diagnosis, cannot precisely distinguish the symptoms, or predict their progression at onset time. We analyzed acoustic markers, aiming to discriminate lvPPA and AD as well as the influence of AD biomarkers on acoustic profiles at the beginning of the disease. We recruited people with AD (n = 8) and with lvPPA (n = 8), with cerebrospinal fluid biomarker profiles determined by lumbar puncture. The participants performed a sentence repetition task that allows assessing potential lvPPA phonological loop deficits. We found that temporal and prosodic markers significantly differentiate the lvPPA and AD group at an early stage of the disease. Biomarker and acoustic profile comparisons discriminated the two lvPPA subgroups according to their biomarkers. For lvPPA with AD biomarkers, acoustic profile equivalent to an atypical AD form with a specific alteration of the phonological loop is shown. However, lvPPA without AD biomarkers has an acoustic profile approximating the one for DLFT. Therefore, these results allow us to classify lvPPA differentially from AD based on acoustic markers from a sentence repetition task. Furthermore, our results suggest that acoustic analysis would constitute a clinically efficient alternative to refused lumbar punctures. It offers the possibility to facilitate early, specific, and accessible neurodegenerative diagnosis and may ease early care with speech therapy, preventing the progression of symptoms.

Changes in Adiposity and Cerebrospinal Fluid Biomarkers Following a Modified Mediterranean Ketogenic Diet in Older Adults at Risk for Alzheimer's Disease.

BackgroundKetogenic diets have been used to treat both obesity and neurological disorders, including epilepsy and more recently Alzheimer’s disease (AD), likely due to favorable effects on both central and peripheral metabolism. Improvements in body composition have also been reported; however, it is unclear if diet-induced changes in adiposity are related to improvements in AD and related neuropathology.PurposeWe examined the effects of a Modified Mediterranean Ketogenic (MMK) diet vs. an American Heart Association (AHA) diet on body weight, body composition, and body fat distribution and their association with cerebrospinal fluid (CSF) biomarkers in older adults at risk for AD.MethodsTwenty adults (mean age: 64.3 ± 6.3 years, 35% Black, 75% female) were randomly assigned to a crossover trial starting with either the MMK or AHA diet for 6 weeks, followed by a 6-week washout and then the opposite diet for 6 weeks. At baseline and after each diet adiposity was assessed by dual-energy x-ray absorptiometry and CSF biomarkers were measured. Linear mixed effect models were used to examine the effect of diet on adiposity. Spearman correlations were examined to assess associations between adiposity and CSF biomarkers.ResultsAt baseline there was a high prevalence of overweight/obesity and central adiposity, and higher visceral fat and lower peripheral fat were associated with an adverse CSF biomarker profile. The MMK and AHA diets led to similar improvements in body composition and body fat distribution. Significant correlations were found between changes in adiposity and changes in CSF biomarkers (r’s = 0.63–0.92, p’s < 0.05), with notable differences by diet. Decreases in body fat on the MMK diet were related to changes in Aβ biomarkers, whereas decreases in body fat on the AHA diet were related to changes in tau biomarkers and cholinesterase activity. Interestingly, increases in CSF Aβ on the MMK diet occurred in those with less fat loss.ConclusionAn MMK diet leads to favorable changes in body composition, body fat distribution, and CSF biomarkers. Our data suggest that modest weight loss that maximizes visceral fat loss and preserves peripheral fat, may have the greatest impact on brain health.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT02984540].

Dopamine transporter SPECT imaging in corticobasal syndrome: A peak into the underlying pathology?

Multiple pathologies may underlie corticobasal syndrome (CBS), including Alzheimer's disease (AD). Dopamine transporter density imaging with Ioflupane 123 I SPECT (DaTscan) may be normal in CBS. No studies to date have examined the relationship between DaTscan status and underlying pathology in CBS. The main objective of the study was to test whether a normal DaTscan in CBS patients is indicative of an underlying AD pathology, as determined by cerebrospinal fluid (CSF) biomarkers. Eighteen CBS patients were included. They were divided into patients with an AD and a non-AD disease pathology, based on their cerebrospinal fluid biochemical profile. A typical AD CSF profile was defined as an increase in total and phosphorylated at threonine 181 tau protein in addition to a decrease in amyloid-beta with 42 amino acids. DaTscan data were compared in these two groups. Eight of the 18 CBS patients (44%) had a normal DaTscan. Seven of the 18 CBS patients (39%) had an AD cerebrospinal fluid biochemical profile. Two of seven CBS patients with AD biomarker profile had abnormal DaTscans. Three of 11 CBS patients with a non-AD biomarker profile had normal DaTscans. A normal DaTscan was indicative of AD pathology with suboptimal (~70%) sensitivity and specificity. Semi-quantitative DaTscan analysis did not differentiate between AD from non-AD CSF biomarker profile in CBS. A normal DaTscan is indicative of AD in CBS, but the sensitivity and specificity of DaTscan as an in vivo marker of AD pathology is suboptimal.

Brain Atrophy and Clinical Characterization of Adults With Mild Cognitive Impairment and Different Cerebrospinal Fluid Biomarker Profiles According to the AT(N) Research Framework of Alzheimer’s Disease

IntroductionThis study aimed to evaluate, in adults with mild cognitive impairment (MCI), the brain atrophy that may distinguish between three AT(N) biomarker-based profiles, and to determine its clinical value.MethodsStructural MRI (sMRI) was employed to evaluate the volume and cortical thickness differences in MCI patients with different AT(N) profiles, namely, A−T−(N)−: normal AD biomarkers; A+T−(N)−: AD pathologic change; and A+T+(N)+: prodromal AD. Sensitivity and specificity of these changes were also estimated.ResultsAn initial atrophy in medial temporal lobe (MTL) areas was found in the A+T−(N)− and A+T+(N)+ groups, spreading toward the parietal and frontal regions in A+T+(N)+ patients. These structural changes allowed distinguishing AT(N) profiles within the AD continuum; however, the profiles and their pattern of neurodegeneration were unsuccessful to determine the current clinical status.ConclusionsMRI is useful in the determination of the specific brain structural changes of AT(N) profiles along the AD continuum, allowing differentiation between MCI adults with or without pathological AD biomarkers.

Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.

The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.