Lejla Koric

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

At a similar stage, patients with early onset Alzheimers 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. Hum Brain Mapp 35:2978–2994, 2014.

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.

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-β 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.

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 Alzheimers 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 Alzheimers disease.

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 Alzheimers disease (AD), indicating possible AD pathological changes.

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

Neuroimaging biomarkers differ between patients with early-onset Alzheimers disease (EOAD) and late-onset Alzheimers 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 Alzheimers 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.

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.

N - 11 Un trouble isolé de la mémoire autobiographique

Introduction La memoire autobiographique (MAu) fait reference a la memoire des experiences personnellement vecues, episodiques ou semantiques. Les troubles isoles de la MAu constituent un rare motif de plainte en neurologie. Observation Nous rapportons l’observation du sujet (n 06-2432), sans antecedent notable, venu consulter pour des plaintes vivaces de sa MAu. L’evaluation neuropsychologique standardisee, et en particulier mnesique, s’avera strictement normale. En revanche, l’etude specifique de sa MAu montra l’existence d’une lacune episodique retrograde portant sur les 5 dernieres annees de vie, epargnant cependant les souvenirs recents. De plus, en comparaison avec un groupe de sujets controles, le rappel a « tres long terme » (6 semaines) d’informations acquises lors du bilan initial mit en evidence l’existence d’une dissociation entre : d’une part, un rappel deficitaire sur le rappel d’informations structurees (histoires logiques, memoire spatiale) ; d’autre part, des performances intactes sur les epreuves de reconnaissance d’information isolees. Son EEG de veille etait normal, mais l’EEG de sommeil revela la presence d’anomalies rythmiques fronto-temporales droites. L’etude neuroradiologique (IRM, TEP) mit en evidence un aspect de sclerose hippocampique droite, ainsi que des anomalies metaboliques au niveau de cette meme region. Discussion Ce patient presente des troubles isoles de la MAu, dans sa composante « episodique ». La normalite des performances lors du bilan standardise et l’alteration de celles-ci lors du rappel tres differe suggerent l’existence d’un trouble de la consolidation de ce type de materiel. Cette hypothese est compatible avec l’atteinte structurale, metabolique et electrophysiologique observee au niveau de la formation hippocampique. Conclusion Cette observation encourage a rechercher des anomalies electrophysiologiques en presence de ce profil singulier de plainte mnesique. Elle illustre egalement le role des hippocampes dans les processus de consolidation mnesique.

Progressive supranuclear palsy and corticobasal degeneration: Diagnostic challenges and clinicopathological considerations

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are two atypical parkinsonian syndromes first described half a century ago. The spectrum of these conditions as well as, more generally, the concept of tauopathy have dramatically changed over the past decade and especially in recent years. In particular, clinicopathological correlations have led to the description of several subtypes of these diseases and the features they share with other neurodegenerative diseases. The present paper is a review of how the concepts of PSP and CBD have evolved over time. In particular, it focuses on the different presentations of the disease and the overlapping syndromes that can complicate the differential diagnoses. Also discussed are some of the tools that may prove useful in making a diagnosis. Indeed, differential diagnosis issues are of particular importance in light of the likely emergence of pathology-specific disease-modifying therapies in the near future.

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

Saccade alterations are potential early signs of Alzheimers 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 Alzheimers disease (n = 29), as compared to both aged-matched mild Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.