Accuracy of the Brief Cognitive Screening Battery for diagnosing Alzheimer's disease defined by cerebrospinal fluid biomarkers and AT(N) classification: a case-control study

ABSTRACT Background: Validation of cognitive instruments for detection of Alzheimer's disease (AD) based on correlation with diagnostic biomarkers allows more reliable identification of the disease. Objectives: To investigate the accuracy of the Brief Cognitive Screening Battery (BCSB) in the differential diagnosis between AD, non-AD cognitive impairment (both defined by cerebrospinal fluid [CSF] biomarkers) and healthy cognition, and to correlate CSF biomarker results with cognitive performance. Methods: Overall, 117 individuals were evaluated: 45 patients with mild cognitive impairment (MCI) or mild dementia within the AD continuum defined by the AT(N) classification [A+T+/-(N)+/]; 27 non-AD patients with MCI or mild dementia [A-T+/-(N)+/-]; and 45 cognitively healthy individuals without CSF biomarker results. All participants underwent evaluation using the BCSB. Results: The total BCSB and delayed recall (DR) scores of the BCSB memory test showed high diagnostic accuracy, as indicated by areas under the ROC curve (AUC): 0.89 and 0.87, respectively, for discrimination between AD and non-AD versus cognitively healthy controls. Similarly, total BCSB and DR displayed high accuracy (AUC-ROC curves of 0.89 and 0.91, respectively) for differentiation between AD and controls. BCSB tests displayed low accuracy for differentiation between AD and non-AD. The CSF levels of biomarkers correlated significantly, though weakly, with DR. Conclusions: Total BCSB and DR scores presented good accuracy for differentiation between patients with a biological AD diagnosis and cognitively healthy individuals, but low accuracy for differentiating AD from non-AD patients.

Characteristics of Bipolar Patients with Cognitive Impairment of Suspected Neurodegenerative Origin: A Multicenter Cohort

Bipolar disorder is associated with an increased risk of dementia with aging. Little is known regarding this association, limiting appropriate diagnosis and management. We aimed to describe the characteristics of bipolar patients with late cognitive impairment for whom the hypothesis of an underlying neurodegenerative disease had been raised. We performed a retrospective multicenter study, recruiting bipolar patients over 50 years old from five French tertiary memory centers who had undergone cerebrospinal fluid (CSF) biomarker assessment for Alzheimer’s disease (AD). Clinical, neuropsychological, and paraclinical characteristics were analyzed and 78 patients were included. The mean age at the onset of cognitive impairment was 62.4 years (±9.2). The mean MMSE score was 22.8 (±4.5), the mean FAB was 11.7 (±3.9), and the mean FCRST was 15.8 (±7.4)/36.8 (±9.7) (free/total recall). A total of 48.6% of the patients displayed cognitive fluctuations, and 38.2% showed cognitive improvement during follow-ups; and 56.3% of the patients showed Parkinsonism, of which 12.7% had never received antipsychotics. Among patients who underwent DAT-scans, 35.3% displayed dopaminergic denervation; 10.3% of patients had CSF AD biological signature (“A+ T+” profile), while 56.4% had other abnormal CSF profiles. Thus, clinical presentation was dominated by executive dysfunction, episodic memory impairment, fluctuating cognition, and a high frequency of Parkinsonism. Specifically, high frequency of delusional episodes suggests limited tolerance of psychotropic drugs. Most patients had abnormal CSF biomarker profiles, but only a minority displayed AD’s specific biomarker signature. Therefore, while our results unveil shared common neurocognitive features in bipolar patients with cognitive impairment of suspected neurodegenerative origin they suggest a participation of various underlying pathologies rather than a common degenerative mechanism in the pathophysiology of this condition.

Genotyping and Plasma/Cerebrospinal Fluid Profiling of a Cohort of Frontotemporal Dementia–Amyotrophic Lateral Sclerosis Patients

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same pathophysiological spectrum and have common genetic and cerebrospinal fluid (CSF) biomarkers. Our aim here was to identify causative gene variants in a cohort of Greek patients with FTD, ALS and FTD-ALS, to measure levels of CSF biomarkers and to investigate genotype-phenotype/CSF biomarker associations. In this cohort of 130 patients (56 FTD, 58 ALS and 16 FTD-ALS), we performed C9orf72 hexanucleotide repeat expansion analysis, whole exome sequencing and measurement of “classical” (Aβ42, total tau and phospho-tau) and novel (TDP-43) CSF biomarkers and plasma progranulin. Through these analyses, we identified 14 patients with C9orf72 repeat expansion and 11 patients with causative variants in other genes (three in TARDBP, three in GRN, three in VCP, one in FUS, one in SOD1). In ALS patients, we found that levels of phospho-tau were lower in C9orf72 repeat expansion and MAPT c.855C>T (p.Asp285Asp) carriers compared to non-carriers. Additionally, carriers of rare C9orf72 and APP variants had lower levels of total tau and Aβ42, respectively. Plasma progranulin levels were decreased in patients carrying GRN pathogenic variants. This study expands the genotypic and phenotypic spectrum of FTD/ALS and offers insights in possible genotypic/CSF biomarker associations.

Cerebrospinal Fluid Alzheimer’s Biomarkers and Neurofilament Light Profile of Idiopathic Normal Pressure Hydrocephalus in China: A PUMCH Cohort Study

<b><i>Introduction:</i></b> Idiopathic normal pressure hydrocephalus (iNPH) is one of the potentially reversible dementias. Early and accurate diagnosis is important for patients’ prognosis. Emerging evidence shows fluid biomarkers are useful in diagnosis and pathophysiological research of iNPH. <b><i>Methods:</i></b> Probable iNPH and Alzheimer’s disease (AD) patients were recruited. Clinical diagnosis was performed according to international guidelines. CSF collection complied with a standard protocol. Commercial accessible ELISA kits were introduced for measurement of CSF <i>t</i>-tau, <i>p</i>-tau₁₈₁, Aβ₄₂, and NfL. <b><i>Results:</i></b> Twenty-seven iNPH, 27 AD, and 18 controls were included. The profiles of CSF <i>t</i>-tau, <i>p</i>-tau₁₈₁, and <i>t</i>-tau/Aβ₄₂ in the iNPH and AD were significantly different (<i>p</i> &#x3c; 0.0001). The profiles of CSF <i>t</i>-tau, <i>p</i>-tau₁₈₁, and <i>t</i>-tau/Aβ₄₂ in the iNPH and control were not different (<i>p</i> &#x3e; 0.05). Level of CSF Aβ₄₂ in iNPH was significantly lower than control (<i>p</i> &#x3c; 0.0001) and also significantly higher than AD (<i>p</i> &#x3c; 0.05). NfL level in iNPH and AD was increased, but its level in iNPH was significantly lower than that in AD (<i>p</i> = 0.005). NfL and <i>t</i>-tau level in the iNPH group was significantly correlated (coefficient = 0.649, <i>p</i> = 0.005), but not in AD (coefficient = 0.298, <i>p</i> = 0.157). <b><i>Conclusion:</i></b> Alzheimer’s CSF biomarker profile of iNPH subjects showed moderately decreased Aβ₄₂ and normal <i>t</i>-tau, <i>p</i>-tau₁₈₁, and <i>t</i>-tau/Aβ₄₂, which was distinguishable from AD. The different profiles and correlation of <i>t</i>-tau and NfL suggested different pathophysiology of AD and iNPH. <i>t</i>-tau was relatively an AD-specific neurodegenerative biomarker compared to NfL.

A neurologist’s perspective on serum neurofilament light in the memory clinic: a prospective implementation study

Background Neurofilament light in serum (sNfL) is a biomarker for axonal damage with elevated levels in many neurological disorders, including neurodegenerative dementias. Since within-group variation of sNfL is large and concentrations increase with aging, sNfL’s clinical use in memory clinic practice remains to be established. The objective of the current study was to evaluate the clinical use of serum neurofilament light (sNfL), a cross-disease biomarker for axonal damage, in a tertiary memory clinic cohort. Methods Six neurologists completed questionnaires regarding the usefulness of sNfL (n = 5–42 questionnaires/neurologist). Patients that visited the Alzheimer Center Amsterdam for the first time between May and October 2019 (n = 109) were prospectively included in this single-center implementation study. SNfL levels were analyzed on Simoa and reported together with normal values in relation to age, as part of routine diagnostic work-up and in addition to cerebrospinal fluid (CSF) biomarker analysis. Results SNfL was perceived as useful in 53% (n = 58) of the cases. SNfL was more often perceived as useful in patients < 62 years (29/48, 60%, p = 0.05) and males (41/65, 63%, p < 0.01). Availability of CSF biomarker results at time of result discussion had no influence. We observed non-significant trends for increased perceived usefulness of sNfL for patients with the diagnosis subjective cognitive decline (64%), psychiatric disorder (71%), or uncertain diagnosis (67%). SNfL was mostly helpful to neurologists in confirming or excluding neurodegeneration. Whether sNfL was regarded as useful strongly depended on which neurologist filled out the questionnaire (ranging from 0 to 73% of useful cases/neurologist). Discussion Regardless of the availability of CSF biomarker results, sNfL was perceived as a useful tool in more than half of the evaluated cases in a tertiary memory clinic practice. Based on our results, we recommend the analysis of the biomarker sNfL to confirm or exclude neurodegeneration in patients below 62 years old and in males.

Decorin is an early CSF biomarker of Alzheimer’s Aβ amyloidosis

Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-beta (Aβ) amyloidosis. Here, we show that autophagy is similarly inhibited in AD brains and App knock-in AD mouse models. To determine how pathologies translate to cerebrospinal fluid (CSF), label-free mass spectrometry of mouse CSF was used. This identified autophagy-related extracellular matrix (ECM) protein decorin as significantly and similarly increased in App knock-in mice and cognitively normal human subjects with abnormal CSF-amyloid. Notably, a switch from negative to positive correlation of CSF-decorin and CSF-amyloid occurs in cognitively normal subjects when CSF-amyloid becomes abnormal, indicating an early change in CSF-decorin induced by Aβ amyloidosis. In App knock-in mice increased CSF-decorin correlated with accentuated decorin expression in choroid plexus and decreased interneuronal decorin. Furthermore, decorin activates neuronal autophagy-lysosomal system by enhancing lysosomal degradation. Therefore, decorin is a potential CSF biomarker that reflects ECM and autophagy alterations in early AD Aβ amyloidosis.

Alzheimer’s cerebrospinal biomarkers from Lumipulse fully automated immunoassay: concordance with amyloid-beta PET and manual immunoassay in Koreans

Background Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on β-amyloid (Aβ) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans. Methods Among 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n = 128 with overlapping CSF and Aβ-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. Aβ42, Aβ40, total-tau, and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Aβ-PET, was evaluated. Results Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the Aβ-PET status in a subgroup without CSF (n = 143), and then when we applied CSF biomarker cutoffs determined based on the Aβ-PET status, the CSF biomarkers (cutoffs of 642.1 pg/mL for Aβ42, 0.060 for Aβ42/Aβ40, 0.315 for t-tau/Aβ42, and 0.051 for p-tau/Aβ42, respectively) showed good agreement with Aβ-PET (overall AUC ranges of 0.840–0.898). Use of the Aβ-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (Aβ42, Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42) with overall AUC ranges of 0.876–0.952. During follow-up, participants with AD-like CSF signature determined by Aβ-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature. Conclusion CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Aβ-PET in Koreans. The Korean-specific Aβ-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.