Trajectories of CSF and plasma biomarkers across Alzheimer's disease continuum: disease staging by NF-L, p-tau181, and GFAP.

CSF-to-plasma transition will open new avenues for molecular phenotyping of Alzheimer's disease (AD). Here we evaluated a panel of AD biomarkers in matched CSF and plasma samples across the AD continuum, from preclinical AD to dementia. The aims were to: 1) compare diagnostic performance of the two biofluids, 2) evaluate trajectories of the biomarkers along AD progression. We analyzed CSF and plasma Aß42/40, p-tau181, p-tau231, t-tau, NF-L, GFAP, UCHL-1 and CSF SNAP-25 in a cohort (n = 173) of preclinical AD, MCI-AD, AD dementia, frontotemporal dementia patients, and controls. We found a significant correlation between CSF and plasma levels of Aß42/40, p-tau181, p-tau231, NF-L, and GFAP, while no CSF-plasma correlation was observed for t-tau and UCHL-1. Next to the core CSF biomarkers (Aß42/40, p-tau181, t-tau), those providing the best discrimination between controls and preclinical AD were CSF p-tau231 and SNAP-25 and plasma Aß42/40, p-tau231, and GFAP. Among plasma biomarkers, we found Aß42/Aß40, GFAP, and p-tau231 to show the largest rate of change at the CSF biomarker-defined cut-offs for amyloidosis and tauopathy. Finally, we identified GFAP, NF-L, and p-tau181 as the biomarkers most significantly associated with disease progression in both CSF and plasma. We suggest that a well-standardized and validated panel of selected plasma markers can facilitate early AD diagnosis, even at the asymptomatic disease stage. We propose that both CSF and plasma measurement of NF-L, p-tau181, and GFAP may play a significant role in disease staging and monitoring.

Chronotype is associated with affective temperaments, clinical severity and worse treatment outcomes in bipolar disorders: results from a two-center, cross-sectional study.

OBJECTIVE: The present study was aimed at investigating the clinical correlates of evening chronotype in a population of subjects suffering from bipolar disorders (BD). METHODS: We assessed chronotype using the Morningness-Eveningness Questionnaire. We administered the brief Temperament Evaluation of Memphis, Pisa, and San Diego, the Barratt Impulsiveness Scale, and the Alda Scale to evaluate affective temperaments, impulsiveness, and response to mood stabilisers. We performed bivariate analyses and ran a logistic regression model to analyse clinical variables associated with evening chronotype. RESULTS: In our sample (n = 178), subjects with an evening chronotype (n = 56, 31.5%) more often suffered from BD type I and reported higher prevalence of seasonality, antidepressant-induced mood switches, psychotic, aggressive, mixed, and anxiety features, and substance use disorders. The number of lifetime suicide attempts and mood episodes was higher in this subgroup. Depressive, cyclothymic, irritable, and anxious temperament scores were higher among evening-chronotype subjects, who also displayed greater levels of impulsiveness and worse treatment response. At the logistic regression, evening chronotype was associated with depressive and irritable temperaments. CONCLUSIONS: Subjects with evening chronotype display higher clinical severity and worse BD course. Clinicians should evaluate the presence of evening chronotype in BD subjects, especially in those with irritable or depressive temperament.Key pointsEvening chronotype is a frequent clinical feature in subjects suffering from bipolar disorders (BD);Affective temperaments, particularly depressive and irritable, are associated with evening chronotype in BD;Evening chronotype underpins higher severity of the clinical picture in BD, as well as a worse response to mood stabiliser treatment;Circadian preferences should be systematically assessed in subjects suffering from BD, with particular attention to evening preference.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

Temporal lobe dysfunction in late-onset epilepsy of unknown origin.

OBJECTIVE: Epilepsy with onset in the adulthood is an increasing health problem, due to the progressive aging of the worldwide population. Whether the causes remain undetermined, the disease is defined as Late-Onset Epilepsy of Unknown origin (LOEU). The aim of this study was to evaluate the semiological, electroencephalographic, metabolic, and neuropsychological features of LOEU. METHODS: We selected patients with late-onset epilepsy (LOE) (≥55 years), whose causes of the disease have been excluded with a deep clinical-instrumental characterization, including brain MRI, EEG, 18F-labeled fluoro-2-deoxyglucose positron emission tomography (FDG-PET), and neuropsychological assessment. RESULTS: Twenty-three LOEU cases were retrospectively recruited. Half presented focal-onset seizures (FOS), the others focal to bilateral tonic-clonic seizures (FBTCS). All demonstrated a mild phenotype, with no recurrence of seizures on single antiseizure treatment at prolonged follow-up. Brain MRI scans were normal in 12 patients (52.3%) and showed nonspecific gliosis or mild atrophy in ten (43.5%); hippocampal sclerosis (HS) was observed in one. In 17/23 (73.9%), the EEG showed slow and/or epileptiform activity of the temporal areas. Brain FDG-PET revealed temporal lobe hypometabolism, mostly ipsilateral to EEG abnormal activity, or multifocal temporal and extra-temporal (cortical, subcortical and subtentorial) clusters of hypometabolism. The neuropsychological analysis demonstrated three different profiles: normal (43.5%), with focal deficits (39.1%) or mild multidomain impairment (17.4%). SIGNIFICANCE: Late-Onset Epilepsy of Unknown origin can present as FOS or FBTCS, both with good prognosis. The application of metabolic imaging and neurophysiology techniques in these patients points to the dysfunction of the temporal structures, whose role in the pathogenetic process of the disease remains to be clarified.

Insights into the Pathophysiology of Psychiatric Symptoms in Central Nervous System Disorders: Implications for Early and Differential Diagnosis.

Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer's disease, fronto-temporal dementia, Parkinson's disease, Huntington's disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.

The Italian version of Cognitive Function Instrument (CFI) for tracking changes in healthy elderly: results at 1-year follow-up.

Cognitive Function Instrument (CFI) is a questionnaire aimed at detecting very early changes in cognitive and functional abilities and useful for monitoring cognitive decline in individuals without clinical impairment. The Italian version has been recently validated. The aim of the present study was to investigate the utility of the Italian version of CFI in tracking early cognitive changes in a cohort of healthy elderly subjects. A consecutive series of 257 cognitively healthy and functionally independent subjects, recruited either among relatives of patients attending our Memory Clinic or as volunteers after advertisement, underwent a baseline neuropsychological assessment. Of them, 157 subjects performed a 1-year follow-up assessment. All subjects completed the CFI, a short questionnaire composed of 14 items administered to both the subject and the referent (study-partner). Cognitive performance was assessed by Mini-Mental State Examination (MMSE) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). At 1-year follow-up, Cronbach's α was 0.79 (95% CI, 0.74-0.84) in self-report and 0.83 (95% CI, 0.79-0.87) for partner-report. CFI self-report correlated with MMSE (rS = - 0.22, p = 0.006) and RBANS (rS = - 0.23, p = 0.004). CFI partner-report showed negative correlation with MMSE (rS = - 0.17, p = 0.037) and RBANS (rS = - 0.20, p = 0.014). CFI 1-year follow-up score correlated with baseline both in self-report (rS = 0.56, p < 0.001) and partner-report (rS = 0.66, p < 0.001). Baseline CFI partner-report (p = 0.014) and CFI self+partner report (p = 0.023) were associated with RBANS total score less than 85 at 1-year follow-up, while only a trend was found considering baseline CFI self-report. Our results support the suitability of the Italian version of CFI for tracking cognitive changes along aging.

The Italian version of cognitive function instrument (CFI): reliability and validity in a cohort of healthy elderly.

The Alzheimer's disease Cooperative Study (ADCS)-Cognitive Function Instrument (CFI) is a 14-item questionnaire administered to the subject and the referent, aimed at detecting early changes in cognitive and functional abilities in individuals without clinical impairment. It is used for monitoring annual variations in cognitive functioning in prevention trials. The aim of the present study was to validate the Italian version of the CFI. A consecutive series of 257 functionally independent subjects was recruited among relatives of patients or as volunteers. They were administered CFI and global cognition measurements: Mini-Mental Status Examination (MMSE) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The reliability and criterion validity were comparable to the original in both self- and partner-report. Similarly to what reported in the original version, we found a corrected item-total correlation ranging between 0.38 and 0.54 in self-report and between 0.33 and 0.64 in partner-report. Cronbach's α was 0.77 (95% CI 0.72-0.83) in self-report and 0.78 (95% CI 0.73-0.84) in partner-report. Total partner- and self-report scores were significantly correlated (rS = 0.31, p < 0.001). CFI self-report and CFI total-score (partner + self-report) were negatively correlated with MMSE (rS = - 0.15, p = 0.022; rS = - 0.17, p = 0.008) and RBANS (rS = - 0.22, p < 0.001; rS = - 0.25, p < 0.001). Analogous trends were found in the partner score, with a correlation with RBANS (rS = - 0.17, p = 0.014) and MMSE (rS = - 0.11, p = 0.071). Our results support the reliability and validity of the Italian version of CFI. In order to definitely propose the use of CFI for tracking longitudinal changes of cognitive and functional abilities in subjects without clinical impairment, data from the follow-up of this cohort are needed.

Predictive value for cerebrospinal fluid Alzheimer's disease profile of different measures of verbal episodic memory in patients with MCI.

Neuropsychological evidence of memory impairment represents the main feature of the clinical onset of typical Alzheimer's disease (AD). Rey's Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) are two tests both assessing verbal episodic memory, widely used in clinical practice. Our aim was to investigate the added value of their combined use in predicting cerebrospinal fluid (CSF) AD biomarkers positivity in a retrospective consecutive series of patients with mild cognitive impairment (MCI). 169 MCI patients were included. For all of them neuropsychological assessment and CSF analysis were available. According to CSF A/T/(N) profile, 109 were defined as MCI due to AD (A+T+), and 60 were non-AD MCI (A-T-). Logistic regression model and receiver-operating characteristic (ROC) curves were analyzed to evaluate the discriminatory power of single and combined sub-measures between AD and non-AD patients. The combination of RAVLT-del with LM could acceptably discriminate the two groups (AUC: 0.69, CI 95% 0.617-0.761, sens: 0.75, spec. 0.58, p < 0.001), while the single tests did not show sufficient discriminative performance. Our study shows that the combination of RAVLT delayed recall with LM better predicts the biological AD diagnosis (A+T+), showing a good discriminative power between MCI-AD from non-AD MCI. Since RAVLT and LM assess different components of verbal episodic memory, they should be considered as complementary, rather than interchangeable, tests.

Repeatable Battery for the Assessment of Neuropsychological Status: Italian Normative Data for Older Adults.

OBJECTIVE: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), widely used for detecting cognitive impairment in different neuropsychiatric conditions, is increasingly applied for measuring cognitive functioning in older individuals. Available normative data for RBANS Italian version suffer from under-representation of the older ages (>60 years) and are not corrected for education. Moreover, normative data are provided only for Indexes and Total scores. We thus administered RBANS Italian version in a larger sample of older adults, taking into account the effect of age, education and gender on all scores. METHOD: We used a regression-based model to assess the effect of age, education, and gender on RBANS Subtests, Indexes and Total scores in a consecutive series of healthy cognitively normal volunteers aged 60-79 years (N = 158). The obtained norms were compared with the Italian original normative data by means of Wilcoxon rank-sum test. RESULTS: Multiple linear regression analyses showed that age and educational level significantly influence performances on most RBANS scores. A free-to-use Excel to calculate subject's percentiles for any single score was developed. When compared with original normative values, our percentiles distribution of Indexes and Total scores did not reveal significant differences (p > .05). CONCLUSION: The obtained normative data show good concordance with previous norms. The instrument seems not significantly affected by educational level. The possibility to correct for any single score could make RBANS a more precise measure for capturing subtle cognitive deficits in prevention studies.

Clinical correlates of state and trait anxiety in multiple sclerosis.

BACKGROUND: Anxiety represents one of the most prevalent psychiatric symptoms in multiple sclerosis (MS), impacting the overall disease burden and quality of life. This psychopathological feature can be expressed as state (S-ANX) and trait (T-ANX) anxiety, but few studies specifically evaluated these two components in MS. The present study was aimed at investigating the prevalence and specific correlates of S-ANX and T-ANX in a cohort of people with MS (PwMS). METHODS: 88 in- and out-patients with MS were consecutively recruited. S-ANX and T-ANX were evaluated with the two subscales of the State and Trait Anxiety Inventory. Bivariate analyses were performed to compare PwMS who displayed clinically significant S-ANX and T-ANX and those who did not. Two logistic regression models were run in order to identify variables significantly associated with S-ANX and T-ANX. RESULTS: S-ANX and T-ANX presented a prevalence of 42% and 45.5%, respectively. S-ANX was more frequent in subjects hospitalized due to recent MS onset. PwMS and S-ANX more frequently had a recent relapse, as well as evidence of disease activity on brain magnetic resonance imaging. Subjects with T-ANX were more often females and displayed higher severity of fatigue. Depressive features at the Beck Depression Inventory were more severe in both S-ANX and T-ANX subjects. PwMS with S-ANX reported a higher prevalence of T-ANX and vice versa. At the logistic regressions, depression severity displayed a significant association with S-ANX and T-ANX. We also detected positive associations between S-ANX and inpatient status, as well as between T-ANX and female sex. CONCLUSION: Both S-ANX and T-ANX are highly prevalent features in PwMS. These two components of anxiety should be adequately identified and discriminated in the clinical practice. The higher severity of depression in PwMS with clinically significant anxiety should not be neglected.

Potential diagnostic value of CSF metabolism-related proteins across the Alzheimer's disease continuum.

BACKGROUND: Alzheimer's disease (AD) cerebrospinal fluid (CSF) core biomarkers (Aß42/40 ratio, p-tau, and t-tau) provide high diagnostic accuracy, even at the earliest stage of disease. However, these markers do not fully reflect the complex AD pathophysiology. Recent large scale CSF proteomic studies revealed several new AD candidate biomarkers related to metabolic pathways. In this study we measured the CSF levels of four metabolism-related proteins not directly linked to amyloid- and tau-pathways (i.e., pyruvate kinase, PKM; aldolase, ALDO; ubiquitin C-terminal hydrolase L1, UCHL1, and fatty acid-binding protein 3, FABP3) across the AD continuum. We aimed at validating the potential value of these proteins as new CSF biomarkers for AD and their possible involvement in AD pathogenesis, with specific interest on the preclinical phase of the disease. METHODS: CSF PKM and ALDO activities were measured with specific enzyme assays while UCHL1 and FABP3 levels were measured with immunoassays in a cohort of patients composed as follows: preclinical AD (pre-AD, n = 19, cognitively unimpaired), mild cognitive impairment due to AD (MCI-AD, n = 50), dementia due to AD (ADdem, n = 45), and patients with frontotemporal dementia (FTD, n = 37). Individuals with MCI not due to AD (MCI, n = 30) and subjective cognitive decline (SCD, n = 52) with negative CSF AD-profile, were enrolled as control groups. RESULTS: CSF UCHL1 and FABP3 levels, and PKM activity were significantly increased in AD patients, already at the pre-clinical stage. CSF PKM activity was also increased in FTD patients compared with control groups, being similar between AD and FTD patients. No difference was found in ALDO activity among the groups. UCHL1 showed good performance in discriminating early AD patients (pre-AD and MCI-AD) from controls (AUC ~ 0.83), as assessed by ROC analysis. Similar results were obtained for FABP3. Conversely, PKM provided the best performance when comparing FTD vs. MCI (AUC = 0.80). Combination of PKM, FABP3, and UCHL1 improved the diagnostic accuracy for the detection of patients within the AD continuum when compared with single biomarkers. CONCLUSIONS: Our study confirmed the potential role of UCHL1 and FABP3 as neurodegenerative biomarkers for AD. Furthermore, our results validated the increase of PKM activity in CSF of AD patients, already at the preclinical phase of the disease. Increased PKM activity was observed also in FTD patients, possibly underlining similar alterations in energy metabolism in AD and FTD.

CSF neurochemical profile and cognitive changes in Parkinson's disease with mild cognitive impairment.

Pathophysiological substrate(s) and progression of Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) are still matter of debate. Baseline cerebrospinal fluid (CSF) neurochemical profile and cognitive changes after 2 years were investigated in a retrospective series of PD-MCI (n = 48), cognitively normal PD (PD-CN, n = 40), prodromal Alzheimer's disease (MCI-AD, n = 25) and cognitively healthy individuals with other neurological diseases (OND, n = 44). CSF biomarkers reflecting amyloidosis (Aß42/40 ratio, sAPPα, sAPPß), tauopathy (p-tau), neurodegeneration (t-tau, NfL, p-NfH), synaptic damage (α-syn, neurogranin) and glial activation (sTREM2, YKL-40) were measured. The great majority (88%) of PD-MCI patients was A-/T-/N-. Among all biomarkers considered, only NfL/p-NfH ratio was significantly higher in PD-MCI vs. PD-CN (p = 0.02). After 2 years, one-third of PD-MCI patients worsened; such worsening was associated with higher baseline levels of NfL, p-tau, and sTREM2. PD-MCI is a heterogeneous entity requiring further investigations on larger, longitudinal cohorts with neuropathological verification.

Clinical and Instrumental Characterization of Patients With Late-Onset Epilepsy.

Epilepsy is classically considered a childhood disease. However, it represents the third most frequent neurological condition in the elderly, following stroke, and dementia. With the progressive aging of the general population, the number of patients with Late-Onset Epilepsy (LOE) is constantly growing, with important economic and social consequences, in particular for the more developed countries where the percentage of elderly people is higher. The most common causes of LOE are structural, mainly secondary to cerebrovascular or infectious diseases, brain tumors, trauma, and metabolic or toxic conditions. Moreover, there is a growing body of evidence linking LOE with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, despite a thorough characterization, the causes of LOE remain unknown in a considerable portion of patients, thus termed as Late-Onset Epilepsy of Unknown origin (LOEU). In order to identify the possible causes of the disease, with an important impact in terms of treatment and prognosis, LOE patients should always undergo an exhaustive phenotypic characterization. In this work, we provide a detailed review of the main clinical and instrumental techniques for the adequate characterization of LOE patients in the clinical practice. This work aims to provide an easy and effective tool that supports routine activity of the clinicians facing LOE.

Educational interventions to improve detection and management of cognitive decline in primary care-An Italian multicenter pragmatic study.

Introduction: Timely detection of cognitive decline in primary care is essential to promote an appropriate care pathway and enhance the benefits of interventions. We present the results of a study aimed to evaluate the effectiveness of an educational intervention addressed to Italian family physicians (FPs) to improve timely detection and management of cognitive decline. Materials and methods: We conducted a pre-post study in six Italian health authorities (HAs) involving 254 FPs and 3,736 patients. We measured process and outcome indicators before the intervention (1 January 2014 to 31 December 2016) and after the intervention (1 January 2018 to 31 December 2019). One interactive face-to-face session workshop was delivered by local cognitive disorders and dementia specialists and FP advisors at each HA, in the period September 2017-December 2017. The session focused on key messages of the local Diagnostic and Therapeutic Care Pathway (DTCP) or regional guidelines: (a) the role of the FP for a timely suspicion of cognitive decline is fundamental; (b) when cognitive decline is suspected, the role of the FP is active in the diagnostic work-up; (c) FP's knowledge on pharmacological and non-pharmacological interventions is essential to improve the management of patients with cognitive decline. Results: An overall improvement in diagnostic procedures and management of patients with cognitive decline by FPs after the intervention was observed. The number of visits per year performed by FPs increased, and the time interval between the first FP consultation and the diagnosis was optimized. Neuroleptic use significantly decreased, whereas the use of benzodiazepines remained steadily high. Non-pharmacological interventions, or use of support services, were underrepresented even in the post-intervention. Differences among the participating HAs were identified and discussed. Discussion: Results from this study suggest the success of the educational intervention addressed to FPs in improving early detection and management of cognitive decline, highlighting the importance to continue medical education in this field. At the same time, further initiatives of care pathway dissemination and implementation should promote strategies to enhance interactions between primary and secondary care optimizing the collaboration between FPs and specialists.

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.

IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers.

Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.

Automatic multispectral MRI segmentation of human hippocampal subfields: an evaluation of multicentric test-retest reproducibility.

Accurate and reproducible automated segmentation of human hippocampal subfields is of interest to study their roles in cognitive functions and disease processes. Multispectral structural MRI methods have been proposed to improve automated hippocampal subfield segmentation accuracy, but the reproducibility in a multicentric setting is, to date, not well characterized. Here, we assessed test-retest reproducibility of FreeSurfer 6.0 hippocampal subfield segmentations using multispectral MRI analysis pipelines (22 healthy subjects scanned twice, a week apart, at four 3T MRI sites). The harmonized MRI protocol included two 3D-T1, a 3D-FLAIR, and a high-resolution 2D-T2. After within-session T1 averaging, subfield volumes were segmented using three pipelines with different multispectral data: two longitudinal ("long_T1s" and "long_T1s_FLAIR") and one cross-sectional ("long_T1s_FLAIR_crossT2"). Volume reproducibility was quantified in magnitude (reproducibility error-RE) and space (DICE coefficient). RE was lower in all hippocampal subfields, except for hippocampal fissure, using the longitudinal pipelines compared to long_T1s_FLAIR_crossT2 (average RE reduction of 0.4-3.6%). Similarly, the longitudinal pipelines showed a higher spatial reproducibility (1.1-7.8% of DICE improvement) in all hippocampal structures compared to long_T1s_FLAIR_crossT2. Moreover, long_T1s_FLAIR provided a small but significant RE improvement in comparison to long_T1s (p = 0.015), whereas no significant DICE differences were found. In addition, structures with volumes larger than 200 mm3 had better RE (1-2%) and DICE (0.7-0.95) than smaller structures. In summary, our study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and 3D-FLAIR. Adapting a longitudinal pipeline to include high-resolution 2D-T2 may lead to further improvements.

A/T/(N) Profile in Cerebrospinal Fluid of Parkinson's Disease with/without Cognitive Impairment and Dementia with Lewy Bodies.

Neuropathological investigations report that in synucleinopathies with dementia, namely Parkinson's disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB), the histopathological hallmarks of Alzheimer's Disease (AD), in particular amyloid plaques, are frequently observed. In this study, we investigated the cerebrospinal fluid (CSF) AD biomarkers in different clinical phenotypes of synucleinopathies. CSF Aß42/Aß40 ratio, phosphorylated tau and total tau were measured as markers of amyloidosis (A), tauopathy (T) and neurodegeneration (N) respectively, in 98 PD (48 with mild cognitive impairment, PD-MCI; 50 cognitively unimpaired, PD-nMCI), 14 PDD and 15 DLB patients, and 48 neurological controls (CTRL). In our study, CSF AD biomarkers did not significantly differ between CTRL, PD-MCI and PD-nMCI patients. In PD-nMCI and PD-MCI groups, A-/T-/N- profile was the most represented. Prevalence of A+ was similar in PD-nMCI and PD-MCI (10% and 13%, respectively), being higher in PDD (64%) and in DLB (73%). DLB showed the lowest values of Aß42/Aß40 ratio. Higher total tau at baseline predicted a worse neuropsychological outcome after one year in PD-MCI. A+/T+, i.e., AD-like CSF profile, was most frequent in the DLB group (40% vs. 29% in PDD).

Biomarker-Based Signature of Alzheimer's Disease in Pre-MCI Individuals.

Alzheimer's disease (AD) pathology begins decades before the onset of clinical symptoms. It is recognized as a clinicobiological entity, being detectable in vivo independently of the clinical stage by means of pathophysiological biomarkers. Accordingly, neuropathological studies that were carried out on healthy elderly subjects, with or without subjective experience of cognitive decline, reported evidence of AD pathology in a high proportion of cases. At present, mild cognitive impairment (MCI) represents the only clinically diagnosed pre-dementia stage. Several attempts have been carried out to detect AD as early as possible, when subtle cognitive alterations, still not fulfilling MCI criteria, appear. Importantly, pre-MCI individuals showing the positivity of pathophysiological AD biomarkers show a risk of progression similar to MCI patients. In view of successful treatment with disease modifying agents, in a clinical setting, a timely diagnosis is mandatory. In clinical routine, biomarkers assessment should be taken into consideration whenever a subject with subtle cognitive deficits (pre-MCI), who is aware of his/her decline, requests to know the cause of such disturbances. In this review, we report the available neuropsychological and biomarkers data that characterize the pre-MCI patients, thus proposing pre-MCI as the first clinical manifestation of AD.

Prevalence and risk of progression of preclinical Alzheimer's disease stages: a systematic review and meta-analysis.

BACKGROUND: Alzheimer's disease (AD) pathology begins several years before the clinical onset. The long preclinical phase is composed of three stages according to the 2011National Institute on Aging and Alzheimer's Association (NIA-AA) criteria, followed by mild cognitive impairment (MCI), a featured clinical entity defined as "due to AD", or "prodromal AD", when pathophysiological biomarkers (i.e., cerebrospinal fluid or positron emission tomography with amyloid tracer) are positive. In the clinical setting, there is a clear need to detect the earliest symptoms not yet fulfilling MCI criteria, in order to proceed to biomarker assessment for diagnostic definition, thus offering treatment with disease-modifying drugs to patients as early as possible. According to the available evidence, we thus estimated the prevalence and risk of progression at each preclinical AD stage, with special interest in Stage 3. METHODS: Cross-sectional and longitudinal studies published from April 2008 to May 2018 were obtained through MEDLINE-PubMed, screened, and systematically reviewed by four independent reviewers. Data from included studies were meta-analyzed using random-effects models. Heterogeneity was assessed by I2 statistics. RESULTS: Estimated overall prevalence of preclinical AD was 22% (95% CI = 18-26%). Rate of biomarker positivity overlapped in cognitively normal individuals and people with subjective cognitive decline. The risk of progression increases across preclinical AD stages, with individuals classified as NIA-AA Stage 3 showing the highest risk (73%, 95% CI = 40-92%) compared to those in Stage 2 (38%, 95% CI = 21-59%) and Stage 1 (20%, 95% CI = 10-34%). CONCLUSION: Available data consistently show that risk of progression increases across the preclinical AD stages, where Stage 3 shows a risk of progression comparable to MCI due to AD. Accordingly, an effort should be made to also operationalize the diagnostic work-up in subjects with subtle cognitive deficits not yet fulfilling MCI criteria. The possibility to define, in the clinical routine, a patient as "pre-MCI due to AD" could offer these subjects the opportunity to use disease-modifying drugs at best.