No Change in Executive Performance in ALS Patients: A Longitudinal Neuropsychological Study.

BACKGROUND/AIMS: A substantial proportion of amyotrophic lateral sclerosis (ALS) patients develop cognitive impairments. Longitudinal investigations of cognition in ALS have shown mixed results. While some authors report that cognitive performance remains stable as the disease progresses, others have found evidence for deterioration in various domains. Our objective was to investigate cognitive performance in ALS longitudinally, using the example of executive functions. METHODS: 93 ALS patients and 73 age-, sex- and education-matched healthy controls underwent up to four neuropsychological evaluations, separated by 3- to 6-month intervals. We examined whether performance declined longitudinally on seven tests assessing various sub-components of executive functioning. Furthermore, we assigned an executive-performance-based 'cognitive status' to each participant for every evaluation, examining whether cognitive deterioration (if present) was modulated by their baseline cognitive status and whether cognitive status changed over time. RESULTS: Regardless of their cognitive status at baseline, ALS patients showed no significant decline in the sub-components of executive functioning. CONCLUSION: Our findings imply that the executive deficits which develop in some ALS patients emerge before motor symptoms and remain stable after an initial decline. The discrepancy between this trajectory and the progressive decline in motor functions may result from a differential vulnerability of motor and non-motor prefrontal neurons to the pathomechanism of ALS.

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

BACKGROUND: Recent 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. RESULTS: Patient 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. CONCLUSION: The 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.

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

BACKGROUND: In this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). METHODS: We analyzed fractional anisotropy (FA) and mean diffusivity (MD) as indices of WM integrity in 70 AD patients (35 APOE ε4 carriers, 35 noncarriers) and 56 healthy control (HC) subjects (28 APOE ε4 carriers, 28 noncarriers). APOE ε4 carriers and noncarriers were matched for age and gender within each diagnostic group. RESULTS: We found significant effects of diagnosis (Pcorrected < .05 [FWE]; i.e., smaller FA values and larger MD values in AD patients compared with HCs) and significant effects (P < .001) of APOE ε4 carrier status on MD in HCs but not in AD subjects. CONCLUSIONS: The results indicate that APOE ε4 has a moderate effect on WM integrity in HCs, but no effect on WM integrity in manifest AD.

Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.

OBJECTIVE: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results. METHODS: We analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans. RESULTS: ALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC. INTERPRETATION: Our study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.

Verbal expressive language minimally affected in non-demented people living with amyotrophic lateral sclerosis.

Objective: Language dysfunction is one of the most common cognitive impairments in amyotrophic lateral sclerosis (ALS). Although discourse capacities are essential for daily functioning, verbal expressive language has not been widely investigated in ALS. The existing research available suggests that discourse impairments are prevalent. This study investigates verbal expressive language in people living with ALS (plwALS) in contrast to healthy controls (HC).Methods: 64 plwALS and 49 age, gender and education-matched healthy controls were ask to describe the Cookie Theft Picture Task. The recordings were analyzed for discourse productivity, discourse content, syntactic complexity, speech fluency and verb processing. We applied the Bayesian hypothesis-testing framework, incorporating the effects of dysarthria, cognitive impairment status (CIS), and premorbid crystalline verbal IQ.Results: Compared to HC, plwALS only showed a single impairment: speech dysfluency. Discourse productivity, discourse content, syntactic complexity and verb processing were not impaired. Cognition and dysarthria exceeded the influence of verbal IQ for total words spoken and content density. Cognition alone seemed to explain dysfluency. Body-agent verbs were produced at even higher rates than other verb types. For the remaining outcomes, verbal IQ was the most decisive factor.Conclusions: In contrast to existing research, our data demonstrates no discernible impairment in verbal expressive language in ALS. What our findings show to be decisive is accounting for the influence of dysarthria, cognitive impairment status, and verbal IQ as variables on spontaneous verbal expressive language. Minor impairments in verbal expressive language appear to be influenced to a greater degree by executive dysfunctioning and dysarthria than by language impairment.

PROSA-a multicenter prospective observational study to develop low-burden digital speech biomarkers in ALS and FTD.

Objective: There is a need for novel biomarkers that can indicate disease state, project disease progression, or assess response to treatment for amyotrophic lateral sclerosis (ALS) and associated neurodegenerative diseases such as frontotemporal dementia (FTD). Digital biomarkers are especially promising as they can be collected non-invasively and at low burden for patients. Speech biomarkers have the potential to objectively measure cognitive, motor as well as respiratory symptoms at low-cost and in a remote fashion using widely available technology such as telephone calls. Methods: The PROSA study aims to develop and evaluate low-burden frequent prognostic digital speech biomarkers. The main goal is to create a single, easy-to-perform battery that serves as a valid and reliable proxy for cognitive, respiratory, and motor domains in ALS and FTD. The study will be a multicenter 12-months observational study aiming to include 75 ALS and 75 FTD patients as well as 50 healthy controls and build on three established longitudinal cohorts: DANCER, DESCRIBE-ALS and DESCRIBE-FTD. In addition to the extensive clinical phenotyping in DESCRIBE, PROSA collects a comprehensive speech protocol in fully remote and automated fashion over the telephone at four time points. This longitudinal speech data, together with gold standard measures, will allow advanced speech analysis using artificial intelligence for the development of speech-based phenotypes of ALS and FTD patients measuring cognitive, motor and respiratory symptoms. Conclusion: Speech-based phenotypes can be used to develop diagnostic and prognostic models predicting clinical change. Results are expected to have implications for future clinical trial stratification as well as supporting innovative trial designs in ALS and FTD.

Cognitive reserve protects ALS-typical cognitive domains: A longitudinal study.

BACKGROUND AND OBJECTIVES: To determine whether cognitive reserve (CR) as measured by verbal intelligence quotient, educational length, and achievement protects amyotrophic lateral sclerosis (ALS) patients' verbal fluency, executive functioning, and memory against brain volume loss over a period of 12 months. METHODS: This cohort study was completed between 2013 and 2016 with a follow-up duration of 12 months. ALS patients were recruited from two specialist out-patient clinics in Rostock and Magdeburg in Germany. Participants underwent cognitive testing and magnetic resonance imaging both at baseline and again after 12 months. The cognitive domains assessed included verbal memory in addition to executive functions such as verbal fluency, working memory, shifting and selective attention. RESULTS: Thirty-eight ALS patients took part; 25 patients had no cognitive impairment (ALSni), and 13 were cognitively impaired (ALSci). On average, patients lost 294 mm3 in their superior frontal gyri, 225 mm3 in their orbitofrontal gyri, and 15.97 mm3 in their hippocampi over 12 months. There was strong evidence that CR protected letter fluency from further decline (Bayes factor [BF] >10) and moderate evidence that it supported learning effects in letter flexibility (BF >3). However, there is a lack of evidence supporting the notion that working memory, shifting, selective attention or verbal memory (BF = 1) are protected. DISCUSSION: As CR is easily determined and protects ALS-specific cognitive domains over time, it should be regarded as a valuable predictive marker.

Loss of "insight" into behavioral changes in ALS: Differences across cognitive profiles.

OBJECTIVE: Behavioral impairment occurs in amyotrophic lateral sclerosis (ALS) and ALS-fronto-temporal dementia (ALS-FTD). It has been proposed that ALS patients without FTD retain an awareness of their behavioral impairment while ALS-FTD patients lose this awareness (referred to as retention vs. loss of "insight"). Loss of insight has not yet been studied across the entire ALS-FTD spectrum; our study addresses this gap by including patients with all the ALS cognitive-behavioral profiles. METHODS: Eighty-three ALS patients (and their informants) took part in this bicentric study involving two German recruitment sites. Patients and informants completed the Frontal Systems Behavior Scale covering the domains of apathy, disinhibition, and executive dysfunctioning. Patients were classified into five groups according to the Strong and Rascovsky criteria: cognitively unimpaired (ALSni), cognitively impaired without dementia (ALSci), behaviorally impaired (ALSbi), a combination of behaviorally and cognitively impaired (ALScbi), and ALS-FTD. We applied Bayesian two-way ANOVA to test whether there were subgroup differences regarding insight into their behavioral decline. RESULTS: All patient subgroups experienced behavioral decline (Bayes factor > 3). Only ALS-FTD patients lost insight into disinhibition and executive dysfunctioning. ALSbi patients exhibited worse insight than ALSni and ALSci patients (Bayes factor > 10). Evidence regarding the ALScbi patients was inconclusive. Higher IQ was associated with worse insight (Bayes factor > 3). CONCLUSIONS: Our findings provide solid support for the notion that ALS patients without dementia experience behavioral decline regardless of their cognitive-behavioral profile and retain different levels of insight into this decline. The inverse association of premorbid verbal intelligence with insight was unexpected, leaving room for further investigation.

Cognitive and behavioural but not motor impairment increases brain age in amyotrophic lateral sclerosis.

Age is the most important single risk factor of sporadic amyotrophic lateral sclerosis. Neuroimaging together with machine-learning algorithms allows estimating individuals' brain age. Deviations from normal brain-ageing trajectories (so called predicted brain age difference) were reported for a number of neuropsychiatric disorders. While all of them showed increased predicted brain-age difference, there is surprisingly few data yet on it in motor neurodegenerative diseases. In this observational study, we made use of previously trained algorithms of 3377 healthy individuals and derived predicted brain age differences from volumetric MRI scans of 112 amyotrophic lateral sclerosis patients and 70 healthy controls. We correlated predicted brain age difference scores with voxel-based morphometry data and multiple different motoric disease characteristics as well as cognitive/behavioural changes categorized according to Strong and Rascovsky. Against our primary hypothesis, there was no higher predicted brain-age difference in the amyotrophic lateral sclerosis patients as a group. None of the motoric phenotypes/characteristics influenced predicted brain-age difference. However, cognitive/behavioural impairment led to significantly increased predicted brain-age difference, while slowly progressive as well as cognitive/behavioural normal amyotrophic lateral sclerosis patients had even younger brain ages than healthy controls. Of note, the cognitive/behavioural normal amyotrophic lateral sclerosis patients were identified to have increased cerebellar brain volume as potential resilience factor. Younger brain age was associated with longer survival. Our results raise the question whether younger brain age in amyotrophic lateral sclerosis with only motor impairment provides a cerebral reserve against cognitive and/or behavioural impairment and faster disease progression. This new conclusion needs to be tested in subsequent samples. In addition, it will be interesting to test whether a potential effect of cerebral reserve is specific for amyotrophic lateral sclerosis or can also be found in other neurodegenerative diseases with primary motor impairment.

Case Report: Cognitive Conversion in a Non-brazilian VAPB Mutation Carrier (ALS8).

Amyotrophic lateral sclerosis 8 (ALS8) is a predominantly lower motor neuron syndrome originally described in a Portuguese-Brazilian family, which originated from a common founder. ALS8 is caused by a VAPB mutation and extremely rare in Central Europe. We present a 51-year-old German man with ALS8 who had the P56S VAPB mutation independently of the founder effect. In the final 4 years of his life (disease duration 10 years), the patient had five MRI scans and four in-depth neuropsychological assessments. This paper addresses the course of the patient's cognitive status and relates cognitive performance to structural brain changes in order to determine whether this ALS8 case showed a different pattern of cognitive decline compared with sporadic ALS. The executive functions, verbal fluency, and memory of the patient and 17 age-, sex-, and education-matched controls were assessed on four different occasions. His cognitive performance and decline were investigated for abnormality using cross-sectional and longitudinal matched case-control analysis. We obtained five T1-weighted MRI, which we analyzed using voxel-wise non-parametric analysis with statistical non-parametric mapping in Matlab. Moreover, we conducted a single-subject correlation between cognitive performance and brain atrophy. The cognitive profile of the index patient featured executive dysfunction. Notably, his working memory and shifting ability declined from a healthy baseline to an impaired performance, leading to a transition from cognitively non-impaired (ALSni) to cognitively impaired (ALSci). The correlations we observed between cerebellar atrophy and verbal fluency in addition to fusiform gyrus atrophy and shifting are novel findings. We found that the conversion from ALSni to ALSci was associated with widespread cerebral atrophy, which extended beyond the primary motor and premotor cortex and affected, among others, the cerebellum and left fusiform gyrus. The index patients' cognitive profile resembles that of other ALS phenotypes, but the extensive atrophy beyond extra-motor areas has not yet been described.

Longitudinal clinical and neuroanatomical correlates of memory impairment in motor neuron disease.

Memory impairment in motor neuron disease (MND) is still an underrecognized feature and has traditionally been attributed to executive dysfunction. Here, we investigate the rate of memory impairment in a longitudinal cohort of MND patients, its relationship to other cognitive functions and the underlying neuroanatomical correlates. 142 patients with MND and 99 healthy controls (HC) underwent comprehensive neuropsychological testing and structural MRI at 3T up to four times over a period of 18 months. Linear-mixed effects models were fitted to identify changes at baseline and over time in episodic memory function (learning, immediate and delayed recall, recognition), composed cognitive scores (memory, verbal fluency, executive function), and memory-related structural brain regions (hippocampus, entorhinal cortex, parahippocampal gyrus). Associations between episodic memory performance and volumetric or cortical thickness changes of these regions were computed using Pearson's r. Learning, immediate and delayed recall, as well as recognition performance were significantly reduced in MND when compared to controls at baseline. Performances in these subtests improved over time although MND showed less improvement than controls. This relationship did not change when only "classical" ALS patients were considered. Patients with MND showed thinning of the right parahippocampal gyrus (PhG) in comparison to controls that was progressing over time. Bilateral hippocampal atrophy was observed in MND patients with memory impairment after splitting the group according to their overall episodic memory performance, with the right hippocampus shrinking over time. In MND patients, the bilateral hippocampal atrophy was associated with impairment in learning, recall, and recognition at baseline. In contrast, left PhG thinning was associated with a poorer learning performance. These results show that episodic memory impairment in MND is a frequent cognitive dysfunction. Since deficits are not clearly declining with disease course, an early involvement of this cognitive domain in the disease seems probable. The memory performance-dependent atrophy of the hippocampus and PhG provide evidence for a widespread involvement of these non-motor cortical areas in disease pathology.

Cognitive Profiles of Amyotrophic Lateral Sclerosis Differ in Resting-State Functional Connectivity: An fMRI Study.

BACKGROUND: Half of all amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) patients are classified as cognitively impaired, of which 10% have frontotemporal dementia (FTD), and an additional 40% suffer from a frontotemporal syndrome not severe enough to be described as dementia (cognitively impaired/ALSci). As changes in cerebral function measured by resting-state magnet resonance imaging (rs-fMRI) are known in ALS, we investigated whether group differences in resting-state functional connectivity (RSFC) networks could be observed between ALS patients with different cognitive profiles against healthy controls (HC). Furthermore, we correlated cognition and motor functioning with network connectivity. METHODS: Healthy controls, 69, and 97 ALS patients underwent functional MRI scanning and cognitive assessment. The ALS patients were categorized as non-impaired (ALSni; n = 68), cognitively impaired (ALSci; n = 21), and ALS-FTD (n = 8). Group differences in connectivity of the default mode network (DMN), motor network (MN), and ventral attention network (VAN) were investigated using a full-factorial model; correlations between global cognitive performance, shifting, and motor symptom severity were established using Pearson's correlation. RESULTS: At a liberal alpha level of uncorrected p < 0.005 and a cluster size exceeding 20 voxels, we found widespread decreases in functional connectivity in all three networks when comparing ALS patients to HC. Similar patterns of hypoconnectivity in the bilateral motor cortices and frontotemporal emerged when comparing the ALSci and ALS-FTD patients to those not cognitively impaired. Hyperconnectivity in the DMN temporal gyrus correlated with worse global cognition; moreover, hyperconnectivity in the VAN thalamus, insula, and putamen correlated with worse shifting ability. Better-preserved motor function correlated with higher MN connectivity. Only the motor-related effects prevailed at a more conservative significance level of p FDR < 0.001. CONCLUSION: Resting-state functional connectivity differs between cognitive profiles of ALS and is directly associated with clinical presentation, specifically with motor function, and cognitive shifting.

Cognitive reserve and regional brain volume in amyotrophic lateral sclerosis.

OBJECTIVE: We investigated whether cognitive reserve measured by education and premorbid IQ allows amyotrophic lateral sclerosis patients to compensate for regional brain volume loss. METHODS: This was a cross-sectional study. We recruited sixty patients with amyotrophic lateral sclerosis from two specialist out-patient clinics. All participants underwent neuropsychological assessment; the outcomes were standardized z-scores reflecting verbal fluency, executive functions (shifting, planning, working memory), verbal memory and visuo-constructive ability. The predictor was regional brain volume. The moderating proxies of cognitive reserve were premorbid IQ (estimated by vocabulary) and educational years. We hypothesized that higher cognitive reserve would correlate with better performance on a cognitive test battery, and tested this hypothesis with Bayesian analysis of covariance. RESULTS: The analyses provided moderate to very strong evidence in favor of our hypothesis with regard to verbal fluency functions, working memory, verbal learning and recognition, and visuo-constructive ability (all BF01 > 3): higher cognitive reserve was associated with a mild increase in performance. For shifting and planning ability, the evidence was anecdotal. CONCLUSIONS: These results indicate that cognitive reserve moderates the effect of brain morphology on cognition in ALS. Patients draw small but meaningful benefits from higher reserve, preserving fluency, memory and visuo-constructive functions. Executive functions presented a dissociation: verbally assessed functions benefitted from cognitive reserve, non-verbally assessed functions did not. This motivates future research into cognitive reserve in ALS and practical implications, such as strengthening reserve to delay decline.

Motor speech disorders in the nonfluent, semantic and logopenic variants of primary progressive aphasia.

OBJECTIVE: Motor speech disorders (MSDs) are characteristic for nonfluent primary progressive aphasia (nfvPPA). In primary progressive aphasia (PPA) of the semantic (svPPA) and of the logopenic type (lvPPA), speech motor function is considered typically intact. However, knowledge on the prevalence of MSDs in svPPA and lvPPA is mainly based on studies with a priori knowledge of PPA syndrome diagnosis. This fully blinded retrospective study aims to provide data on the prevalence of all types of MSDs in a large sample of German-speaking patients with different subtypes of PPA. METHOD: Two raters, blinded for PPA subtype, independently evaluated connected speech samples for MSD syndrome and severity from 161 patients diagnosed with nfvPPA, svPPA or lvPPA in the database of the German Consortium of Frontotemporal Lobar Degeneration (FTLDc). In case of disagreement, a third experienced rater re-evaluated the speech samples, followed by a consensus procedure. Consensus was reached for 160 patients (74 nfvPPA, 49 svPPA, 37 lvPPA). MAIN RESULTS: Across all PPA syndromes, 43.8% of the patients showed MSDs. Patients with nfvPPA demonstrated the highest proportion of MSDs (62.2%), but MSDs were also identified in svPPA (26.5%) and lvPPA (29.7%), respectively. Overall, dysarthria was the most common class of MSDs, followed by apraxia of speech. In addition, we identified speech abnormalities presenting as "syllabic speech", "dysfluent speech", and "adynamic speech". DISCUSSION: Our study confirmed MSDs as frequently occurring in PPA. The study also confirmed MSDs to be most common in patients with nfvPPA. However, MSDs were also found in substantial proportions of patients with svPPA and lvPPA. Furthermore, our study identified speech motor deficits that have not received attention in previous studies on PPA. The results are discussed against the background of the existing literature on MSDs in PPA, including theoretical considerations of the neuroanatomical conditions described for each of the different subtypes of PPA.

Mirror Movements in Amyotrophic Lateral Sclerosis: A Combined Study Using Diffusion Tensor Imaging and Transcranial Magnetic Stimulation.

Objective: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder predominantly affecting the motor system. In a number of patients, mirror movements (MMs) suggest involvement of transcallosal fiber tracts in conjunction with upper motor neuron involvement. The aim of the study was to elucidate functional and structural alterations of callosal integrity in ALS patients with MMs. Methods: Nineteen patients with ALS displaying MMs and 20 controls underwent clinical assessment, transcranial magnetic stimulation (TMS), and diffusion tensor imaging (DTI). TBSS (tract based spatial statistics) was performed. We investigated ipsilateral silent period (iSP) as a measure of transcallosal inhibition, and diffusion changes in the corpus callosum and corticospinal tract (CST) as measure of structural integrity. Results: In ALS patients TMS revealed a longer mean iSP latency than controls. Twelve ALS patients (63.2%) showed loss of iSP, but none of the controls. Using region of interest analysis, fractional anisotropy (FA) values of the CST were significantly lower in ALS patients compared with controls, but diffusion parameters of the corpus callosum did not differ between patients and controls. The lack of diffusion changes in the corpus callosum was confirmed in whole brain tract based statistics, assessing FA as well as mean, radial, and axial diffusivity. There was a significant negative correlation between resting motor threshold and FA values of the CST, but not between iSP and FA of the corpus callosum. Conclusion: In conclusion the study failed to show microstructural changes in the corpus callosum in conjunction with MMs. One possible reason may be that functional disturbance of transcallosal pathways precede microstructural changes in the corpus callosum.

Sleep Disturbances and Sleep Disordered Breathing Impair Cognitive Performance in Parkinson's Disease.

BACKGROUND: Sleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson's disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance. OBJECTIVE: This post hoc analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD. METHODS: Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients' subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated. RESULTS: We did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, P = 0.020, unpaired two-sided t-test). CONCLUSION: Sleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.

Music, language and meaning: brain signatures of semantic processing.

Semantics is a key feature of language, but whether or not music can activate brain mechanisms related to the processing of semantic meaning is not known. We compared processing of semantic meaning in language and music, investigating the semantic priming effect as indexed by behavioral measures and by the N400 component of the event-related brain potential (ERP) measured by electroencephalography (EEG). Human subjects were presented visually with target words after hearing either a spoken sentence or a musical excerpt. Target words that were semantically unrelated to prime sentences elicited a larger N400 than did target words that were preceded by semantically related sentences. In addition, target words that were preceded by semantically unrelated musical primes showed a similar N400 effect, as compared to target words preceded by related musical primes. The N400 priming effect did not differ between language and music with respect to time course, strength or neural generators. Our results indicate that both music and language can prime the meaning of a word, and that music can, as language, determine physiological indices of semantic processing.

Prefrontal cortical thickness in motor neuron disease.

Objective: To examine whether the distribution of prefrontal cortical thickness in patients with motor neuron disease is normal or bimodal and how it compares to the normal population. Methods: 158 patients with motor neuron disease (MND) and 86 healthy controls (HC) were enrolled in a prospective, two-center study with a common structural MRI protocol. Cortical thickness measures were extracted for the prefrontal cortex, premotor cortex, motor cortex, and occipital cortex using FreeSurfer, adjusted for age and sex, and tested for normality of distribution. Results: Cortical thickness measures of the bilateral prefrontal, premotor, motor, and occipital cortex were normally distributed in patients and healthy controls. MND-related cortical thinning was observed in the right motor cortex (p = 0.002), reflected in a significantly higher proportion of MND cases being worse than -1 standard deviation of the healthy control mean: 29.1% in the right motor cortex (p = 0.002). Cortical thinning of the left motor cortex was a function of clinical phenotype and physical disability. Left prefrontal cortical thickness was reduced in patients with additional cognitive and/or behavioural deficits compared to MND patients without cognitive deficits. Prefrontal, premotor, motor, and occipital cortical thickness was related to patients' general cognitive abilities. Conclusion: The study shows that prefrontal cortical thickness in MND is normally distributed but shifted towards thinner cortex in MND patients with cognitive and/or behavioural impairment. The distribution of thickness values did not indicate the assumption of a bimodal distribution although patients with comorbid cognitive deficits are more likely to suffer from prefrontal cortical thinning.

Cognitive Rehabilitation in Alzheimer's Disease: A Controlled Intervention Trial.

BACKGROUND: Cognitive Rehabilitation for Alzheimer's disease (AD) is an integrative multimodal intervention. It aims to maintain autonomy and quality of life by enhancing the patients' abilities to compensate for decreased cognitive functioning. OBJECTIVE: We evaluated the feasibility of a group-based Cognitive Rehabilitation approach in mild AD dementia and assessed its effect on activities of daily living (ADL). METHODS: We included 16 patients with AD dementia in a controlled partial-randomized design. We adapted the manual-guided Cognitive Rehabilitation program (CORDIAL) to a group setting. Over the course of three months, one group received the Cognitive Rehabilitation intervention (n = 8), while the other group received a standardized Cognitive Training as an active control condition (n = 8). ADL-competence was measured as primary outcome. The secondary outcome parameters included cognitive abilities related to daily living, functional cognitive state, and non-cognitive domains, e.g., quality of life. For each scale, we assessed the interaction effect 'intervention by time', i.e., from pre-to post-intervention. RESULTS: We found no significant interaction effect of intervention by time on the primary outcome ADL-competence. The interaction effect was significant for quality of life (Cohen's d: -1.43), showing an increase in the intervention group compared with the control group. CONCLUSIONS: Our study demonstrates the feasibility of a group-based Cognitive Rehabilitation program for patients with mild AD dementia. The Cognitive Rehabilitation showed no significant effect on ADL, possibly reflecting a lack of transfer between the therapy setting and real life. However, the group setting enhanced communication skills and coping mechanisms. Effects on ADL may not have reached statistical significance due to a limited sample size. Furthermore, future studies might use an extended duration of the intervention and integrate caregivers to a greater extent to increase transfer to activities of daily living.

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.