Validation of ELISA assays for the calculation of FLC indices for the diagnosis of intrathecal immunoglobulin synthesis.

OBJECTIVES: Define the cutoff thresholds of the Kappa (K) and Lambda (L) free light chains (FLC) indices for the detection of intrathecal immunoglobulin synthesis (IIS) using the new K and L FLC ELISA from SEBIA. The reference technique, which is not readily standardized between laboratories, is based on the demonstration of oligoclonal banding (OCB) in cerebrospinal fluid (CSF) which is absent in serum. For the past 6 years, we have also routinely calculated the K FLC index using The Binding Site (TBS) reagents on an Optilite instrument, an approach increasingly used as an alternative and/or a complement to electrophoretic analysis. METHODS: We analyzed 391 serum/CSF pairs divided into three groups. The first group were cases without OCB and with normal albumin CSF/serum ratio (n=174). The second group were cases with specific OCB (n=73). The last group included patients with increased albumin CSF/sera ratio without OCB (n=142). RESULTS: Analysis of the first group determined that the cutoffs for detection of IIS are respectively 2.55 and 1.02 for the K FLC and L FLC indices. Of the 73 cases with IIS, only 2 had a K FLC index below this threshold (sensitivity of 97.26%), while 16 out of 73 cases (78.08%) and 13 out of 72 cases (81.94%) had an IgG and L FLC index below the cutoffs, respectively. Additionally, we illustrate equivalent performances for prediction of the presence of OCB between SEBIA and TBS methods. CONCLUSIONS: Sebia K FLC and L FLC assays are adequate alternative methods for the diagnosis of IIS.

Prevalence of amyloid-ß pathology in distinct variants of primary progressive aphasia.

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

Functional connectivity changes differ in early and late-onset Alzheimer's disease.

At a similar stage, patients with early onset Alzheimer's disease (EOAD) have greater neocortical but less medial temporal lobe dysfunction and atrophy than the late-onset form of the disease (LOAD). Whether the organization of neural networks also differs has never been investigated. This study aims at characterizing basal functional connectivity (FC) patterns of EOAD and LOAD in two groups of 14 patients matched for disease duration and severity, relative to age-matched controls. All subjects underwent an extensive neuropsychological assessment. Magnetic resonance imaging was used to quantify atrophy and resting-state FC focusing on : the default mode network (DMN), found impaired in earlier studies on AD, and the anterior temporal network (ATN) and dorso-lateral prefrontal network (DLPFN), respectively involved in declarative memory and executive functions. Patterns of atrophy and cognitive impairment in EOAD and LOAD were in accordance with previous reports. FC within the DMN was similarly decreased in both EOAD and LOAD relative to controls. However, a double-dissociated pattern of FC changes in ATN and DLPFN was found. EOAD exhibited decreased FC in the DLPFN and increased FC in the ATN relative to controls, while the reverse pattern was found in LOAD. In addition, ATN and DLPFN connectivity correlated respectively with memory and executive performances, suggesting that increased FC is here likely to reflect compensatory mechanisms. Thus, large-scale neural network changes in EOAD and LOAD endorse both common features and differences, probably related to a distinct distribution of pathological changes.

Cued recall measure predicts the progression of gray matter atrophy in patients with amnesic mild cognitive impairment.

Amnesic mild cognitive impairment (aMCI) is a heterogeneous syndrome that could be subdivided into distinct neuropsychological variants. To investigate relationships between the neuropsychological profile of memory impairment at baseline and the neuroimaging pattern of grey matter (GM) loss over 18 months, we performed a prospective volumetric brain study on 31 aMCI patients and 29 matched controls. All subjects were tested at baseline using a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for the assessment of verbal declarative memory. Over 18 months, patients with impaired free recall but normal total recall (high index of cueing) on the FCSRT developed subcortical and frontal GM loss, while patients with impaired free and total recall (low index of cueing) developed GM atrophy within the left anterior and lateral temporal lobe. In summary, cued recall deficits are associated with a progression of atrophy that closely parallels the spatiotemporal distribution of neurofibrillary degeneration in early Alzheimer's disease (AD), indicating possible AD pathological changes.

How cognitive performance-induced stress can influence right VLPFC activation: an fMRI study in healthy subjects and in patients with social phobia.

The neural bases of interactions between anxiety and cognitive control are not fully understood. We conducted an fMRI study in healthy participants and in patients with an anxiety disorder (social phobia) to determine the impact of stress on the brain network involved in cognitive control. Participants performed two working memory tasks that differed in their level of performance-induced stress. In both groups, the cognitive tasks activated a frontoparietal network, involved in working memory tasks. A supplementary activation was observed in the right ventrolateral prefrontal cortex (VLPFC) in patients during the more stressful cognitive task. Region of interest analyses showed that activation in the right VLPFC decreased in the more stressful condition as compared to the less stressful one in healthy subjects and remain at a similar level in the two cognitive tasks in patients. This pattern was specific to the right when compared to the left VLPFC activation. Anxiety was positively correlated with right VLPFC activation across groups. Finally, left dorsolateral prefrontal cortex (DLPFC) activation was higher in healthy subjects than in patients in the more stressful task. These findings demonstrate that in healthy subjects, stress induces an increased activation in left DLPFC, a critical region for cognitive control, and a decreased activation in the right VLPFC, an area associated with anxiety. In patients, the differential modulation between these dorsal and ventral PFC regions disappears. This absence of modulation may limit anxious patients' ability to adapt to demanding cognitive control tasks.

Could clinical profile influence CSF biomarkers in early-onset Alzheimer disease?

In common forms of Alzheimer disease (AD), anterograde memory impairment is the first deficit to occur. However, the disease, especially in its presenile forms, may also manifest itself through initial deficits that are predominantly of a nonmemory type. These distinct clinical profiles, which reflect the distinct topography of the underlying pathologic processes, may also differ in terms of their cerebrospinal fluid (CSF) markers. The aim of this study was to assess the levels of total tau, phosphorylated tau, and amyloid-beta 42 peptide in the CSF of "atypical" (nonmemory) early-onset AD patients. CSF biomarkers were evaluated in 22 atypical patients, and compared with those from a group of 13 "typical" patients, with a memory onset form of the disease. Our results show that independently of age, disease duration, education level, and clinical severity indices, patients with an atypical onset have significantly higher levels of total tau in the CSF (P=0.023). These findings indicate that an assessment of CSF biomarkers may be of particular use in the clinical diagnosis of "atypical-onset" forms of early-onset AD in which the initial symptoms involve language and visuospatial abilities rather than memory. In addition, they highlight the heterogeneity of pathologic processes in AD, suggesting more intense degeneration in the forms of the disease that primarily involve neocortical structures.

Clinical Phenotypes in Corticobasal Syndrome with or without Amyloidosis Biomarkers.

Corticobasal syndrome (CBS) is a neuropathologically heterogeneous entity. The use of cerebrospinal fluid and amyloid biomarkers enables detection of underlying Alzheimer's disease (AD) pathology. We thus compared clinical, eye movement, and 18FDG-PET imaging characteristics in CBS in two groups of patients divided according to their amyloid biomarkers profile. Fourteen patients presenting with CBS and amyloidosis (CBS-A+) were compared with 16 CBS patients without amyloidosis (CBS-A-). The two groups showed similar motor abnormalities (parkinsonism, dystonia) and global cognitive functions. Unlike CBS-A+ patients who displayed more posterior cortical abnormalities, CBS-A- patients demonstrated more anterior cortical and brain stem dysfunctions on the basis of neuropsychological testing, study of saccade velocities and brain hypometabolism areas on 18FDG-PET. Interestingly, Dopamine Transporter SPECT imaging showed similar levels of dopaminergic degeneration in both groups. These findings confirm common and distinct brain abnormalities between the different neurodegenerative diseases that result in CBS. We demonstrate the importance of a multidisciplinary approach to improve diagnosis in vivo in particular on oculomotor examination.

[Corticobasal degeneration: clinical and neuropsychological profile]. / La dégénérescence corticobasale : aspects cliniques et neuropsychologiques.

Corticobasal degeneration (CBD) is a rare neurodegenerative disorder, primarily defined on clinical and pathological grounds. CBD may present with a large set of cognitive and motor symptoms in relation with asymmetrically distributed lesions in the fronto-parietal cortex and basal ganglia. CBD has long been considered as a motor system disease, with a prominent alteration of movements and gestures. In recent years, however, cognitive and behavioral disturbances have increasingly been recognized. In some instances, they are the prevalent manifestations of the disorder, leading to diagnostic misclassifications and uncertainties. This article reviews the evolution of the nosological concept of CBD across the past decade, along with describing the main disturbances involving cognition, behavior, body and gesture representations that may occur throughout the course of this illness.

A Spatial Decision Eye-Tracking Task in Patients with Prodromal and Mild Alzheimer's Disease.

BACKGROUND/OBJECTIVE: Performances on spatial decision eye-tracking tasks are known to be impaired in patients with moderate Alzheimer's disease (AD), but the clinical relevance of this deficit during earlier stages of AD remains unclear. METHODS: This study recruited patients with amnestic mild cognitive impairment (aMCI, prodromal AD), patients with mild AD, and age-matched controls from three French memory clinics. Participants' ability to make spatial judgments and decisions was assessed with an eye-tracking system, and cognitive performance on conventional neuropsychological tests was evaluated. RESULTS: We enrolled 26 controls, 25 aMCI patients (median Mini-Mental State Exam [MMSE] 26), and 23 mild-AD patients (median MMSE 23). Patients with mild AD had higher error rates on the spatial decision task than aMCI patients and controls (32.4% versus 23.5%; p < 0.01 and 32.4% versus 22.2%; p < 0.05, respectively), but there were no differences among the groups in anticipation rate or the percentage of express saccades. Additionally, error rates on the spatial decision task were inversely correlated with performance on visual memory tests (immediate and delayed recall on the DMS- 48: r =-0.44, p = 0.0019 and r =-0.43, p = 0.0020, respectively), semantic fluency (r =-0.44, p = 0.0016), and global cognition (MMSE: r =-0.44, p = 0.0019). Performance on the spatial decision task was not correlated with anti-saccades, processing speed, or attentional performance. CONCLUSIONS: Patients with mild AD made more errors on a spatial decision task than aMCI patients and controls. We hypothesize that impaired visuospatial judgment may explain these results and distinguish aMCI patients from mild AD patients.

Imaging Biomarkers of Neurodegeneration in Alzheimer's Disease: Distinct Contributions of Cortical MRI Atrophy and FDG-PET Hypometabolism.

BACKGROUND: Neurodegeneration biomarkers are routinely used in the diagnosis of Alzheimer's disease (AD). OBJECTIVE: To evaluate the respective contributions of two neuroimaging biomarkers, structural MRI and 18FDG-PET, in the assessment of neurodegeneration in AD dementia. METHODS: Patients with mild AD dementia diagnosed based on clinical and cerebrospinal fluid criteria and cognitively healthy subjects, from the Marseille cohort ADAge with cognitive, structural MRI and 18FDG-PET assessments, were included. Extent of atrophy on MRI and of hypometabolism on 18FDG-PET were individually evaluated in each patient using a voxel-based analysis on whole-brain approach and compared to healthy subjects. Patients were divided in distinct groups according to their atrophy extent on the one hand and to their hypometabolism extent on the other, then, to their imaging profile combining the extent of the two biomarkers. RESULTS: Fifty-two patients were included. The MMSE score was significantly lower in the "Extensive hypometabolism" group than in the "Limited hypometabolism" group (respectively 19.5/30 versus 23/30). A lower Innotest Amyloid Tau Index was associated with an extensive hypometabolism (p = 0.04). There were more patients with low educational level in the "Extensive atrophy" group, while a higher educational level was more found in the "Limited atrophy" group (p = 0.005). CONCLUSION: 18FDG-PET hypometabolism extent is associated with the pathological processes and clinical severity of AD, while MRI atrophy seems to be influenced by the cognitive reserve. In the context of mild AD dementia, these two biomarkers of neurodegeneration are thus not interchangeable and require to be considered in combination rather than in isolation.

Prodromal Alzheimer's Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task.

Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

Difference in imaging biomarkers of neurodegeneration between early and late-onset amnestic Alzheimer's disease.

Neuroimaging biomarkers differ between patients with early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Whether these changes reflect cognitive heterogeneity or differences in disease severity is still unknown. This study aimed at investigating changes in neuroimaging biomarkers, according to the age of onset of the disease, in mild amnestic Alzheimer's disease patients with positive amyloid biomarkers in cerebrospinal fluid. Both patient groups were impaired on tasks assessing verbal and visual recognition memory. EOAD patients showed greater executive and linguistic deficits, while LOAD patients showed greater semantic memory impairment. In EOAD and LOAD, hypometabolism involved the bilateral temporoparietal junction and the posterior cingulate cortex. In EOAD, atrophy was widespread, including frontotemporoparietal areas, whereas it was limited to temporal regions in LOAD. Atrophic volumes were greater in EOAD than in LOAD. Hypometabolic volumes were similar in the 2 groups. Greater extent of atrophy in EOAD, despite similar extent of hypometabolism, could reflect different underlying pathophysiological processes, different glucose-based compensatory mechanisms or distinct level of premorbid atrophic lesions.

Early-onset and late-onset Alzheimer's disease are associated with distinct patterns of memory impairment.

The goal of this study was to investigate the specific patterns of memory breakdown in patients suffering from early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Twenty EOAD patients, twenty LOAD patients, twenty matched younger controls, and twenty matched older controls participated in this study. All participants underwent a detailed neuropsychological assessment, an MRI scan, an FDG-PET scan, and AD patients had biomarkers as supporting evidence of both amyloïdopathy and neuronal injury. Results of the neuropsychological assessment showed that both EOAD and LOAD groups were impaired in the domains of memory, executive functions, language, praxis, and visuoconstructional abilities, when compared to their respective control groups. EOAD and LOAD groups, however, showed distinct patterns of memory impairment. Even though both groups were similarly affected on measures of episodic, short term and working memory, in contrast semantic memory was significantly more impaired in LOAD than in EOAD patients. The EOAD group was not more affected than the LOAD group in any memory domain. EOAD patients, however, showed significantly poorer performance in other cognitive domains including executive functions and visuoconstructional abilities. A more detailed analysis of the pattern of semantic memory performance among patient groups revealed that the LOAD was more profoundly impaired, in tasks of both spontaneous recall and semantic recognition. Voxel-Based Morphometry (VBM) analyses showed that impaired semantic performance in patients was associated with reduced gray matter volume in the anterior temporal lobe (ATL) region, while PET-FDG analyses revealed that poorer semantic performance was associated with greater hypometabolism in the left temporoparietal region, both areas reflecting key regions of the semantic network. Results of this study indicate that EOAD and LOAD patients present with distinct patterns of memory impairment, and that a genuine semantic impairment may represent one of the clinical hallmarks of LOAD.

Alteration of autobiographical memory in amnestic mild cognitive impairment.

The concept of amnestic mild cognitive impairment (aMCI) concerns a population of older individuals at high risk of developing probable Alzheimer's disease. Although anterograde memory deficits have been largely documented in patients with aMCI, little is known about the integrity of their autobiographical memory (AuM). This study aimed at evaluating AuM in aMCI individuals and at investigating whether their ability to retrieve AuMs varied as a function of whether the tests used required recognition or effortful retrieval processes. Fourteen aMCI patients and 14 matched controls underwent a standard neuropsychological evaluation and an extensive autobiographical assessment. AuM was explored using verbal material, the Autobiographical Memory Interview, and a visual task of personal photographs. Together, these tests tapped the semantic and episodic components of AuM and different cognitive processes involved in retrieval (recall and recognition). Results indicate that AuM is altered in aMCI patients. This impairment affects both episodic and semantic components of AuM, and is characterized by a general difficulty in recollecting personal episodes covering the entire lifespan, along with a loss of recognition of recently experienced episodes. Furthermore, recollection of personal episodes was correlated with scores on tests requiring retrieval abilities, while recognition of familiar photographs was correlated with scores on tests assessing encoding/storage of new information. Results suggest that the AuM deficit in aMCI patients may result from the combination of two mechanisms, an anterograde memory impairment impeding the storage of newly experienced events, and a global alteration of recollection affecting the recall of AuM covering all periods of life. Alteration of these processes may possibly be related to the progression and distribution of the neuropathological lesions in medial temporal and frontal lobe structures found in Alzheimer's disease.

Striatal hypermetabolism in limbic encephalitis.

Striatal hypermetabolism on 18FDG-PET scan is a neuroradiological finding that has been described in association with autoimmune disorders such as Sydenham chorea, lupus or antiphospholipid syndrome. Here, we report three patients with non-paraneoplastic limbic encephalitis characterized by 18FDG-PET hypermetabolism of both striata, in contrast with diffuse hypometabolism in the rest of the brain. All patients developed subacute dementia, and antibodies to voltage-gated potassium channels were found in all cases. Brain metabolism and neurological status improved within a few months of immunosuppressive therapy. The finding of striatal hypermetabolism on 18FDG-PET images could thus be highly indicative of limbic encephalitis associated with anti-neuropil antibodies. It could be of significant help in the diagnosis of this rare and treatable condition, and may also provide a useful marker of disease outcome.

Extent and neural basis of semantic memory impairment in mild cognitive impairment.

An increasing number of studies indicate that semantic memory is impaired in mild cognitive impairment (MCI). However, the extent and the neural basis of this impairment remain unknown. The aim of the present study was: 1) to evaluate whether all or only a subset of semantic domains are impaired in MCI patients; and 2) to assess the neural substrate of the semantic impairment in MCI patients using voxel-based analysis of MR grey matter density and SPECT perfusion. 29 predominantly amnestic MCI patients and 29 matched control subjects participated in this study. All subjects underwent a full neuropsychological assessment, along with a battery of five tests evaluating different domains of semantic memory. A semantic memory composite Z-score was established on the basis of this battery and was correlated with MRI grey matter density and SPECT perfusion measures. MCI patients were found to have significantly impaired performance across all semantic tasks, in addition to their anterograde memory deficit. Moreover, no temporal gradient was found for famous faces or famous public events and knowledge for the most remote decades was also impaired. Neuroimaging analyses revealed correlations between semantic knowledge and perirhinal/entorhinal areas as well as the anterior hippocampus. Therefore, the deficits in the realm of semantic memory in patients with MCI is more widespread than previously thought and related to dysfunction of brain areas beyond the limbic-diencephalic system involved in episodic memory. The severity of the semantic impairment may indicate a decline of semantic memory that began many years before the patients first consulted.