Elisabeth Kasper

Cortical thinning and its relation to cognition in amyotrophic lateral sclerosis

Clinical, genetic, and pathological findings suggest a close relationship between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We studied the patterns of cortical atrophy across the spectrum between ALS and ALS-FTD. A surface-based morphometry analysis based on an age- and sex-matched sample of 81 ALS patients and 62 healthy control subjects (HC) was conducted. In addition, we used an age-matched subsample of 57 ALS patients and 31 HC to compare cortical thickness between 3 groups of neuropsychologically characterized ALS patients: (1) cognitively unimpaired; (2) cognitively impaired; and (3) ALS-FTD patients. Compared with HC, the entire sample of patients demonstrated cortical thinning in the bilateral precentral gyrus, right precuneus, and right frontal and temporal lobes. ALS-FTD patients showed cortical thinning in regions including the frontal and temporal gyri and the posterior cingulate cortex. Cognitively impaired ALS patients showed cortical thinning in regions largely overlapping with those found in ALS-FTD, but changes were less widespread. In conclusion, the cognitive status of ALS subjects is associated with different patterns of cortical atrophy.

Focal thinning of the motor cortex mirrors clinical features of amyotrophic lateral sclerosis and their phenotypes: a neuroimaging study

AbstractAmyotrophic lateral sclerosis (ALS) is characterised by degeneration of upper (UMN) and lower motor neurons (LMN).We aimed to relate clinical variables to cortical thinning of the primary motor cortex (PMC). The PMC was defined as the region of interest in high-resolution structural MRI scans. We related vertex-wise measures of cortical thinning to UMN involvement, bulbar/limb onset, the total ALS functional rating scale (ALSFRS-R), and its bulbar and upper limb subscore. In total, 93 ALS patients were recruited (60 with classical ALS; 17 with dominant UMN, e.g., primary lateral sclerosis; 16 with pure LMN variant, e.g., progressive muscular atrophy, flail arm or leg syndrome) and compared to 67 age and gender matched healthy controls. The UMN signs in the bulbar regions were associated with bilateral thinning within the bulbar segment on the motor cortex, and UMN signs in spinal regions were associated with thinning in the limb segment of the motor cortex. The site of disease onset (bulbar/lower limb) exhibited the most pronounced thinning in the corresponding part of the motor cortex. According to our analysis, dominant UMN patients demonstrated the most distinct thinning followed by classical ALS patients. Pure LMN variants did not differ from healthy controls. The bulbar subscore of the ALSFRS-R correlated with thinning of the left inferior PMC. Focal morphological changes within the PMC correspond to clinically measured impairments and depend on disease phenotype. Measuring cortical thickness may potentially offer an objective in vivo marker to quantify disease pathology.

Memory deficits in amyotrophic lateral sclerosis are not exclusively caused by executive dysfunction: a comparative neuropsychological study of amnestic mild cognitive impairment.

BackgroundRecent work suggests that ALS and frontotemporal dementia can occur together and share at least in part the same underlying pathophysiology. However, it is unclear at present whether memory deficits in ALS stem from a temporal lobe dysfunction, or are rather driven by frontal executive dysfunction. In this study we sought to investigate the nature of memory deficits by analyzing the neuropsychological performance of 40 ALS patients in comparison to 39 amnestic mild cognitive impairment (aMCI) patients and 40 healthy controls (HC). The neuropsychological battery tested for impairment in executive functions, as well as memory and visuo-spatial skills, the results of which were compared across study groups. In addition, we calculated composite scores for memory (learning, recall, recognition) and executive functions (verbal fluency, cognitive flexibility, working memory). We hypothesized that the nature of memory impairment in ALS will be different from those exhibited by aMCI patients.ResultsPatient groups exhibited significant differences in their type of memory deficit, with the ALS group showing impairment only in recognition, whereas aMCI patients showed short and delayed recall performance deficits as well as reduced short-term capacity. Regression analysis revealed a significant impact of executive function on memory performance exclusively for the ALS group, accounting for one fifth of their memory performance. Interestingly, merging all sub scores into a single memory and an executive function score obscured these differences.ConclusionThe presented results indicate that the interpretation of neuropsychological scores needs to take the distinct cognitive profiles in ALS and aMCI into consideration. Importantly, the observed memory deficits in ALS were distinctly different from those observed in aMCI and can be explained only to some extent in the context of comorbid (coexisting) executive dysfunction. These findings highlight the qualitative differences in temporal lobe dysfunction between ALS and aMCI patients, and support temporal lobe dysfunction as a mechanism underlying the distinct cognitive impairments observed in ALS.

Basal Forebrain and Hippocampus as Predictors of Conversion to Alzheimer's Disease in Patients with Mild Cognitive Impairment - A Multicenter DTI and Volumetry Study

BACKGROUND Hippocampal grey matter (GM) atrophy predicts conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD). Pilot data suggests that mean diffusivity (MD) in the hippocampus, as measured with diffusion tensor imaging (DTI), may be a more accurate predictor of conversion than hippocampus volume. In addition, previous studies suggest that volume of the cholinergic basal forebrain may reach a diagnostic accuracy superior to hippocampal volume in MCI. OBJECTIVE The present study investigated whether increased MD and decreased volume of the hippocampus, the basal forebrain and other AD-typical regions predicted time to conversion from MCI to AD dementia. METHODS 79 MCI patients with DTI and T1-weighted magnetic resonance imaging (MRI) were retrospectively included from the European DTI Study in Dementia (EDSD) dataset. Of these participants, 35 converted to AD dementia after 6-46 months (mean: 21 months). We used Cox regression to estimate the relative conversion risk predicted by MD values and GM volumes, controlling for age, gender, education and center. RESULTS Decreased GM volume in all investigated regions predicted an increased risk for conversion. Additionally, increased MD in the right basal forebrain predicted increased conversion risk. Reduced volume of the right hippocampus was the only significant predictor in a stepwise model combining all predictor variables. CONCLUSION Volume reduction of the hippocampus, the basal forebrain and other AD-related regions was predictive of increased risk for conversion from MCI to AD. In this study, volume was superior to MD in predicting conversion.

Microstructural White Matter Changes Underlying Cognitive and Behavioural Impairment in ALS – An In Vivo Study Using DTI

Background A relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients. Methods We assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures. Results Patients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts. Conclusion In non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients.

The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer's disease.

In this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimers disease (AD) using diffusion tensor imaging (DTI).

TDP-43 pathology and cognition in ALS: A prospective clinicopathologic correlation study

Objective: Although a systematic spread of pathologic TDP-43 expression throughout the CNS in amyotrophic lateral sclerosis (ALS) has been proposed, the relationship between cognition and the extent and neuroanatomic distribution of TDP-43 pathology has not received considerable attention. Methods: We investigated the association between cognitive functioning and the extent of TDP-43 pathology in postmortem CNS tissue from 18 patients with ALS stratified into 3 groups based on detailed prospective neuropsychological testing (cognitively not impaired, n = 6; cognitively impaired, n = 6; ALS– frontotemporal dementia [FTD], n = 6) and analyzed these cases for clinicopathologic correlations. Results: Our findings demonstrate a close relationship between cognition and the extent of TDP-43 pathology in non–primary motor areas with a striking difference between ALS-FTD and the 2 other cognitive groups. The specificity of our results was underscored by 2 key findings: first, the absence of an Alzheimer pathology effect, a common confounder in older patients; second, the lack of correlations between the primary motor regions with the highest TDP-43 intensity and cognitive status. Conclusions: Our data suggest a distinct dynamic of TDP-43 progression and distribution in ALS-FTD in contrast to ALS without FTD.

Minor cognitive disturbances in X-linked spinal and bulbar muscular atrophy, Kennedy's disease

Abstract Spinal and bulbar muscular atrophy (SBMA), Kennedys disease, is an adult-onset hereditary neurodegenerative disorder, associated predominantly with a lower motor neuron syndrome and eventually endocrine and sensory disturbances. In contrast to other motor neuron diseases such as amyotrophic lateral sclerosis (ALS), the impairment of cognition in SBMA is not well documented. We conducted a systematic cross-sectional neuropsychological study in order to investigate cognition in SBMA patients more thoroughly. We investigated 20 genetically proven SBMA patients compared to 20 age- and education-matched control subjects using a comprehensive neuropsychological test battery, measuring executive functioning, attention, memory and visuospatial abilities. The SBMA patients performed significantly worse than healthy controls in three sub-tests in the executive and attention domains. This low performance was in the working memory (digit span backward task), verbal fluency category (single letter fluency task) and memory storage capacity (digit span forward task). No disturbances were detected in other cognitive domains. The impairments were subclinical and not relevant to the patients’ everyday functioning. In addition, no correlations were found between cognitive scores and the CAG repeat length. In conclusion, we found minor cognitive disturbances in patients with SBMA, which could indicate subtle frontal lobe dysfunction. These findings extend our neurobiological understanding of SBMA.

Does Functional Connectivity Provide a Marker for Cognitive Rehabilitation Effects in Alzheimer’s Disease? An Interventional Study

Background: Cognitive rehabilitation (CR) is a cognitive intervention for patients with Alzheimer’s disease (AD) that aims to maintain everyday competences. The analysis of functional connectivity (FC) in resting-state functional MRI has been used to investigate the effects of cognitive interventions. Objectives: We evaluated the effect of CR on the default mode network FC in a group of patients with mild AD, compared to an active control group. Methods: We performed a three-month interventional study including 16 patients with a diagnosis of AD. The intervention group (IG) consisted of eight patients, performing twelve sessions of CR. The active control group (CG) performed a standardized cognitive training. We used a seed region placed in the posterior cingulate cortex (PCC) for FC analysis, comparing scans acquired before and after the intervention. Effects were thresholded at a significance of p < 0.001 (uncorrected) and a minimal cluster size of 50 voxels. Results: The interaction of group by time showed a higher increase of PCC connectivity in IG compared to CG in the bilateral cerebellar cortex. CG revealed widespread, smaller clusters of higher FC increase compared with IG. Across all participants, an increase in quality of life was associated with connectivity increase over time in the bilateral precuneus. Conclusions: CR showed an effect on the FC of the DMN in the IG. These effects need further study in larger samples to confirm if FC analysis may suit as a surrogate marker for the effect of cognitive interventions in AD.

The Primacy Effect in Amnestic Mild Cognitive Impairment: Associations with Hippocampal Functional Connectivity

Background: The “primacy effect,” i.e., increased memory recall for the first items of a series compared to the following items, is reduced in amnestic mild cognitive impairment (aMCI). Memory task-fMRI studies demonstrated that primacy recall is associated with higher activation of the hippocampus and temporo-parietal and frontal cortical regions in healthy subjects. Functional magnetic resonance imaging (fMRI) at resting state revealed that hippocampus functional connectivity (FC) with neocortical brain areas, including regions of the default mode network (DMN), is altered in aMCI. The present study aimed to investigate whether resting state fMRI FC between the hippocampus and cortical brain regions, especially the DMN, is associated with primacy recall performance in aMCI. Methods: A number of 87 aMCI patients underwent resting state fMRI and verbal episodic memory assessment. FC between the left or right hippocampus, respectively, and all other voxels in gray matter was mapped voxel-wise and used in whole-brain regression analyses, testing whether FC values predicted delayed primacy recall score. The delayed primacy score was defined as the number of the first four words recalled on the California Verbal Learning Test. Additionally, a partial least squares (PLS) analysis was performed, using DMN regions as seeds to identify the association of their functional interactions with delayed primacy recall. Results: Voxel-based analyses indicated that delayed primacy recall was mainly (positively) associated with higher FC between the left and right hippocampus. Additionally, significant associations were found for higher FC between the left hippocampus and bilateral temporal cortex, frontal cortical regions, and for higher FC between the right hippocampus and right temporal cortex, right frontal cortical regions, left medial frontal cortex and right amygdala (p < 0.01, uncorr.). PLS analysis revealed positive associations of delayed primacy recall with FC between regions of the DMN, including the left and right hippocampus, as well as middle cingulate cortex and thalamus (p < 0.04). In conclusion, in the light of decreased hippocampus function in aMCI, inter-hemispheric hippocampus FC and hippocampal FC with brain regions predominantly included in the DMN may contribute to residual primacy recall in aMCI.