Brain plasticity after cognitive intervention in patients with mild cognitive impairment (MCI) evaluated by multimodal MR imaging in a randomized, controlled trial.

Postponed access: the file will be accessible after 2023-12-16Hjerneplasitisitet undersøkt hos individer med mild kognitiv svikt etter PC-administrert arbeidsminnetrening, evaluert med multimodal MRI teknikk, en randomisert kontroll studie. Formål: Hovedmålet med studien var å undersøke effekten av pc-administrert arbeidsminne trening, hos personer med mild kognitive svikt(MCI), samt få kjennskap til grad av nevrokognitive funksjonstap og nevrodegenerative forandringer synlig ved MR avbildning av hjernen. Man ønsket videre å korrelere om det var en sammenheng mellom utfall i kognitive områder og visuelle scoring systemer på MR. Vi forsøkte å avklare om individer med MCI har bevart plastisitet med undersøkelser av hjernebarkens tykkelse (strukturell MR teknikk) og endringer i hvit substans (tensor basert MR teknikk). Videre ønsket vi å avklare om bærerskap av spesifikke APOE og LMX1a gener påvirket treningseffekt. Bakgrunn: MCI er en tilstand med redusert hukommelse som ikke påvirker dagliglivets funksjoner. Tilstanden ses på som et forstadie til demens, og om lag 10-15 % av denne gruppen glir over i en demenstilstand hvert år. En teori ved MCI-tilstander er at hjernens kompensatoriske mekanismer er ikke tilstrekkelige til å håndtere bakenforliggende hjernesykdom. MCI gruppen kan deles inn i to grupper; amnestisk MCI med redusert hukommelse og ikke-amnestisk MCI hvor funksjonstapet er i ikke-hukommelses relaterte kognitive domener. Felles for begge gruppene er ofte redusert arbeidsminne. Det finnes i dag ingen behandling for denne tilstanden. Av den grunn ønsket vi å undersøke om pc-administrert arbeidsminne trening kunne bedre pasientens arbeidsminne. Arbeidsminnetrening er basert på teorier om nevroplastisitet og kognitiv motstandsdyktighet. Nevroplastisitet er hjernens evne til å tilpasse seg ytre påvirkninger ved å øke tettheten av nerveender og volumet på hjerneceller. Repetert stimulering over tid er vist å kunne igangsette nevroplastisitet og dermed kunne bidra til økte kognitive reserver. Disse mikrostrukturelle forandringene kan påvises ved endringer i hjernebarkens tykkelse eller hvit substans på MR bilder. I studier hos friske personer med normal hukommelse har arbeidsminnetrening en påvisbar effekt ved nevrokognitive tester som også gjenfinnes på MR bilder, men effekten hos eldre med kognitiv svikt er ikke undersøkt i samme grad. Det foreligger noen preliminære rapporter om positiv treningseffekt på arbeidsminne hos personer med MCI, men studiene har hatt lav statistisk styrke, og varierende resultater. Det er mange bakenforliggende sykdommer som kan føre til en MCI tilstand. Dette gir utslag i varierende grad av påvisbare endringer i hjernen. Design: Individer med MCI ble rekruttert fra fire hukommelsesklinikker i Helse-Sør Øst. Deltagerne gjennomgikk nevrokognitive tester og MR undersøkelser ved baseline, 4 uker og 4 mnd etter trening. Ved inklusjon ble deltagerne randomisert inn i to grupper, adaptiv og aktiv kontroll. Vi brukte et PC-administrert arbeidsminnetreningsprogram med en adaptiv og en placebo arm. Gruppen med adaptiv trening fikk vanskelighetsgraden på oppgavene automatisk regulert slik at de trente dynamisk på egen maksimal vanskelighetsgrad. Den aktive kontrollgruppen brukte samme treningsprogram, men med fast lav vanskelighetsgrad uten individuell tilpasning. Videre undersøkte vi en sammenlignbar gruppe individer uten kognitiv svikt med MR undersøkelser og kognitive tester tilsvarende treningsgruppene ved baseline. Denne gruppen ble rekruttert vi media og Sørlandet sykehus sin hjemmeside. For å måle lokalisert atrofi eller hvitsubstans forandringer i hjernen, ofte er assosiert med spesifikke nevrodegenerative sykdommer eller skade på hvit substans mikrostruktur, brukte vi 4 aldersjusterte kliniske visuelle skalaer. Resultater: Det ble rekruttert 84 deltagere i studien, hvor 62 individer hadde minst to MR undersøkelser. Genetisk profil tilgjengelig for 54 personer. Den amnestiske MCI gruppen hadde økt andel av MRI identifiserte hjerneforandringer sammenlignet med ikke-amnestisk gruppe og de kognitivt friske. Scheltens skala for å måle medial temporal lapps atrofi, viste seg å være den beste til å skille mellom MCI og kontrollgruppen. Amnestisk-MCI gruppen hadde høyere grad av hjernesvinn i tinninglappen enn både ikke-amnestisk MCI og kontroll gruppen. Hjernebarkens tykkelse endret seg ikke signifikant hos gruppen MCI pasientene etter arbeidsminnetrening. LMX1a-AA viste seg å ha en mulig modulerende treningseffekt uttrykt ved økning av tykkelse i hjernebarken hos pasienter med MCI. APOE genet hadde ingen signifikant modulerende effekt på hjernebarken etter arbeidsminne trening. Endringer i hvit substans etter trening ble undersøkt ved «mean diffusivity». Denne undersøkelse gir et bilde på synaptisk tetthet, dvs antall nerveender i et område. I denne studien fant vi en økning i «mean diffusivity» i venstre sagital stratum hos den adaptive gruppen, men ikke hos non-adaptiv gruppe ved kontrollen fire måneder etter trening. Dette området rommer flere store hjernebaner og endringen er et tegn på treningseffekt bare hos den gruppen som trener på høy vanskelighetsgrad. VI fant ingen tegn til at lett trening ga økt antall nerveender. Gruppen med ikke amnestisk MCI hadde fremdeles etter fire måneder høyere andel nerveender i to områder assosiert med hukommelse og arbeidsminne sammenlignet med de som hadde amnestisk MCI. Bærerskap av undergrupper av APOE-genet og LMX1aa hadde ingen innvirkning på treningseffekten målt i hvit substans. Konklusjon: Individer med MCI som fikk adaptiv trening hadde treningseffekt målt med MR. Dette tyder på at adaptiv arbeidsminnetrening kan bidra til å forbedre forbindelse mellom nerveceller også ved begynnende hukommelsessvikt. Videre fant vi at det var en sammenheng mellom nedsatt funksjon i forskjellige nevropsykologiske domener og funn på MR bilder. Bærere av LMX1a-AA fikk en positiv utvikling av hjernebarktykkelsen etter trening, som vedvarte etter fire måneder sammenlignet med bærere av LMX1a-GG/GA. Vi finner ingen påvirkning av bærerskap av forskjellige APOE gener på treningseffekt.Aim: The main aim of this study was to investigate the effects of computer-based working memory training, measured by MRI in individuals with Mild cognitive impairment (MCI), and to investigate a possible correlation between the structural loss detectable with the radiological visual scoring systems and domain-specific function loss. Furthermore, we wanted to investigate if the neuroplasticity in MCI patients was workload-dependent or if the effect of the training was modulated by the genotypes LMX1a or APOE. Background: Individuals with MCI have a cognitive decline above expected for normal aging, but the decline does not affect activities of daily living. A high annual transition rate from MCI to dementia of 10-15% targets this population as suitable for any delaying interventions. Currently, no treatments are available for MCI. . Depending on whether the impairment primarily affects memory, MCI is subdivided into amnestic and non-amnestic(aMCI/naMCI) groups. A common feature in both MCI groups is often the decline in working memory function. The concept behind the effect of working memory training(WMT) is based on neuroplasticity; repeated stimuli trigger a neuroplastic response in the brain resulting in increased glial volume or increased synaptic density, leading to increased connectivity. Investigating the neuroplastic process in response to WMT can be done objectively with structural or diffusion-weighted MRI imaging techniques. This is previously reported in cognitively healthy adults, but few studies with divergent results have investigated if WMT can induce brain changes detectable on MRI in MCI patients. A knowledge gap exists regarding the ability of the MCI brain to utilize neuroplasticity after stimuli. Design: A total of 84 individuals diagnosed with MCI from four hospitals in the South-East Health Care region were included in the study. Of these, 63 had at least two MRI images harvested, and genetic results were available for 54 individuals. The participants were randomized to either adaptive working memory training or active control at inclusion. The participants participated in a computer-based WMT program for 25 sessions over five weeks and underwent cognitive testing and MRI imaging at baseline, four weeks, and four months after training . To investigate the computerized working memory training (CMWT)effect, we utilized longitudinal multimodal MRI techniques. A group of 51 healthy controls was recruited through media and Sorlandet hospital’s web page. This group underwent testing and MRI similar to baseline. Results: The MCI group had a greater degree of brain pathology than the non-amnestic and healthy control groups, as previously reported. Age-adjusted Schelten’s medial temporal atrophy (MTA) was superior to the other three visual scoring systems for measuring localized atrophy or white matter structural damage. The decline was diverse, ranging from single domain MCI to multiple domains MCI. This is in accordance with previous studies both radiologically and neurocognitively. No significant cortical thickness changes longitudinally after CWMT were found, nor any significant differences after adaptive or non-adaptive CMWT training measured by cortical thickness. Carriers of the LMX1a-AA had a significantly greater cortical thickness trajectory than the LMX1a-GG/GA group in the right superior frontal gyrus, indicating a possible modulating effect. These findings are considered promising for further studies. Diffusion-weighted MRI found significantly decreased mean diffusivity in the left sagittal stratum in the adaptive training group at four months compared to the non-adaptive. The sagittal stratum is a junction region for several large tracts associated with working memory. The finding indicates that some white matter changes are workload-dependent. Four months after training, significant changes were observed favoring the naMCI group compared to the aMCI group in the left posterior thalamic radiation and left hippocampal cingulum. We did not detect any modulating training effect on the white matter from APOE and LMX1a.Doktorgradsavhandlin

Cortical thickness changes after computerized working memory training in patients with mild cognitive impairment

Background: Adaptive computerized working memory (WM) training has shown favorable effects on cerebral cortical thickness as compared to non-adaptive training in healthy individuals. However, knowledge of WM training-related morphological changes in mild cognitive impairment (MCI) is limited. Objective: The primary objective of this double-blind randomized study was to investigate differences in longitudinal cortical thickness trajectories after adaptive and non-adaptive WM training in patients with MCI. We also investigated the genotype effects on cortical thickness trajectories after WM training combining these two training groups using longitudinal structural magnetic resonance imaging (MRI) analysis in Freesurfer. Method: Magnetic resonance imaging acquisition at 1.5 T were performed at baseline, and after four- and 16-weeks post training. A total of 81 individuals with MCI accepted invitations to undergo 25 training sessions over 5 weeks. Longitudinal Linear Mixed effect models investigated the effect of adaptive vs. non-adaptive WM training. The LME model was fitted for each location (vertex). On all statistical analyzes, a threshold was applied to yield an expected false discovery rate (FDR) of 5%. A secondary LME model investigated the effects of LMX1A and APOE-ε4 on cortical thickness trajectories after WM training. Results: A total of 62 participants/patients completed the 25 training sessions. Structural MRI showed no group difference between the two training regimes in our MCI patients, contrary to previous reports in cognitively healthy adults. No significant structural cortical changes were found after training, regardless of training type, across all participants. However, LMX1A-AA carriers displayed increased cortical thickness trajectories or lack of decrease in two regions post-training compared to those with LMX1A-GG/GA. No training or training type effects were found in relation to the APOE-ε4 gene variants. Conclusion: The MCI patients in our study, did not have improved cortical thickness after WM training with either adaptive or non-adaptive training. These results were derived from a heterogeneous population of MCI participants. The lack of changes in the cortical thickness trajectory after WM training may also suggest the lack of atrophy during this follow-up period. Our promising results of increased cortical thickness trajectory, suggesting greater neuroplasticity, in those with LMX1A-AA genotype need to be validated in future trials.publishedVersio

Working Memory Training in Amnestic and Non-amnestic Patients With Mild Cognitive Impairment: Preliminary Findings From Genotype Variants on Training Effects

Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations in APOE-epsilon (APOE-ε) and LMX1A genotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped for APOE-ε and LMX1A completed 4 weeks/20–25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups (p < 0.0001), but at 16 weeks the effects only remained in the naMCI group. Better performance was found after training for the naMCI patients with LMX1A-AA genotype and for the APOE-ε4 carriers. Only the naMCI-APOE-ε4 group showed improved Executive Function at 16 weeks. WMT improved working memory and some non-trained cognitive functions in individuals with MCI. The naMCI group had greater training gain than aMCI group, especially in those with LMX1A-AA genotype and among APOE-ε4-carriers. Further research with larger sample sizes for the subgroups and longer follow-up evaluations is warranted.publishedVersio

Cortical thickness changes after computerized working memory training in patients with mild cognitive impairment

Background: Adaptive computerized working memory (WM) training has shown favorable effects on cerebral cortical thickness as compared to non-adaptive training in healthy individuals. However, knowledge of WM training-related morphological changes in mild cognitive impairment (MCI) is limited. Objective: The primary objective of this double-blind randomized study was to investigate differences in longitudinal cortical thickness trajectories after adaptive and non-adaptive WM training in patients with MCI. We also investigated the genotype effects on cortical thickness trajectories after WM training combining these two training groups using longitudinal structural magnetic resonance imaging (MRI) analysis in Freesurfer. Method: Magnetic resonance imaging acquisition at 1.5 T were performed at baseline, and after four- and 16-weeks post training. A total of 81 individuals with MCI accepted invitations to undergo 25 training sessions over 5 weeks. Longitudinal Linear Mixed effect models investigated the effect of adaptive vs. non-adaptive WM training. The LME model was fitted for each location (vertex). On all statistical analyzes, a threshold was applied to yield an expected false discovery rate (FDR) of 5%. A secondary LME model investigated the effects of LMX1A and APOE-ε4 on cortical thickness trajectories after WM training. Results: A total of 62 participants/patients completed the 25 training sessions. Structural MRI showed no group difference between the two training regimes in our MCI patients, contrary to previous reports in cognitively healthy adults. No significant structural cortical changes were found after training, regardless of training type, across all participants. However, LMX1A-AA carriers displayed increased cortical thickness trajectories or lack of decrease in two regions post-training compared to those with LMX1A-GG/GA. No training or training type effects were found in relation to the APOE-ε4 gene variants. Conclusion: The MCI patients in our study, did not have improved cortical thickness after WM training with either adaptive or non-adaptive training. These results were derived from a heterogeneous population of MCI participants. The lack of changes in the cortical thickness trajectory after WM training may also suggest the lack of atrophy during this follow-up period. Our promising results of increased cortical thickness trajectory, suggesting greater neuroplasticity, in those with LMX1A-AA genotype need to be validated in future trials

Working Memory Training in Amnestic and Non-amnestic Patients With Mild Cognitive Impairment: Preliminary Findings From Genotype Variants on Training Effects

Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations in APOE-epsilon (APOE-ε) and LMX1A genotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped for APOE-ε and LMX1A completed 4 weeks/20–25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups (p < 0.0001), but at 16 weeks the effects only remained in the naMCI group. Better performance was found after training for the naMCI patients with LMX1A-AA genotype and for the APOE-ε4 carriers. Only the naMCI-APOE-ε4 group showed improved Executive Function at 16 weeks. WMT improved working memory and some non-trained cognitive functions in individuals with MCI. The naMCI group had greater training gain than aMCI group, especially in those with LMX1A-AA genotype and among APOE-ε4-carriers. Further research with larger sample sizes for the subgroups and longer follow-up evaluations is warranted

Adaptive computerized working memory training in patients with mild cognitive impairment. A randomized double-blind active controlled trial

Objective: We investigated if a 5-week computerized adaptive working memory training program (Cogmed®) of 20 to 25 sessions would be effective in improving the working memory capacity and other neuropsychological functions compared to a non-adaptive working memory training program (active-controlled) in adult patients with mild cognitive impairment (MCI). Methods: This randomized double-blinded active control trial included 68 individuals aged 43 to 88 years, 45 men and 23 women, who were diagnosed with MCI at four Memory clinics. The study sample was randomized by block randomization to either adaptive or non-adaptive computerized working memory training. All participants completed the training, and were assessed with a comprehensive neuropsychological test battery before the intervention, and at 1 and 4 months after training. Results: Compared to the non-adaptive training group, the adaptive training group did not show significantly greater improvement on the main outcome of working memory performance at 1 and 4 months after training. Conclusion: No difference were found between the two types of training on the primary outcome of working memory, or on secondary outcomes of cognitive function domains, in this sample of MCI patients. Hence, the hypothesis that the adaptive training program would lead to greater improvements compared to the non-adaptive training program was not supported. Within group analyses was not performed due to the stringent RCT design

Working Memory Training in Amnestic and Non-amnestic Patients With Mild Cognitive Impairment: Preliminary Findings From Genotype Variants on Training Effects

Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations in APOE-epsilon (APOE-ε) and LMX1A genotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped for APOE-ε and LMX1A completed 4 weeks/20-25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups (

Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients With Mild Cognitive Impairment

In this cross-sectional study, we sought to describe cognitive and neuroimaging profiles of Memory clinic patients with Mild Cognitive Impairment (MCI). 51 MCI patients and 51 controls, matched on age, sex, and socio-economic status (SES), were assessed with an extensive neuropsychological test battery that included a measure of intelligence (General Ability Index, “GAI,” from WAIS-IV), and structural magnetic resonance imaging (MRI). MCI subtypes were determined after inclusion, and z-scores normalized to our control group were generated for each cognitive domain in each MCI participant. MR-images were scored by visual rating scales. MCI patients performed significantly worse than controls on 23 of 31 cognitive measures (Bonferroni corrected p = 0.001), and on 8 of 31 measures after covarying for intelligence (GAI). Compared to nonamnestic MCI patients, amnestic MCI patients had lower test results in 13 of 31 measures, and 5 of 31 measures after co-varying for GAI. Compared to controls, the MCI patients had greater atrophy on Schelten's Medial temporal lobe atrophy score (MTA), especially in those with amnestic MCI. The only structure-function correlation that remained significant after correction for multiple comparisons was the MTA—long delay recall domain. Intelligence operationalized as GAI appears to be an important moderator of the neuropsychological outcomes. Atrophy of the medial temporal lobe, based on MTA scores, may be a sensitive biomarker for the functional episodic memory deficits associated with MCI

Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients With Mild Cognitive Impairment

In this cross-sectional study, we sought to describe cognitive and neuroimaging profiles of Memory clinic patients with Mild Cognitive Impairment (MCI). 51 MCI patients and 51 controls, matched on age, sex, and socio-economic status (SES), were assessed with an extensive neuropsychological test battery that included a measure of intelligence (General Ability Index, “GAI,” from WAIS-IV), and structural magnetic resonance imaging (MRI). MCI subtypes were determined after inclusion, and z-scores normalized to our control group were generated for each cognitive domain in each MCI participant. MR-images were scored by visual rating scales. MCI patients performed significantly worse than controls on 23 of 31 cognitive measures (Bonferroni corrected p = 0.001), and on 8 of 31 measures after covarying for intelligence (GAI). Compared to nonamnestic MCI patients, amnestic MCI patients had lower test results in 13 of 31 measures, and 5 of 31 measures after co-varying for GAI. Compared to controls, the MCI patients had greater atrophy on Schelten's Medial temporal lobe atrophy score (MTA), especially in those with amnestic MCI. The only structure-function correlation that remained significant after correction for multiple comparisons was the MTA—long delay recall domain. Intelligence operationalized as GAI appears to be an important moderator of the neuropsychological outcomes. Atrophy of the medial temporal lobe, based on MTA scores, may be a sensitive biomarker for the functional episodic memory deficits associated with MCI