Enhancing Cognitive Performance Prediction through White Matter Hyperintensity Connectivity Assessment: A Multicenter Lesion Network Mapping Analysis of 3,485 Memory Clinic Patients.

Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed this approach to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. Methods & results: We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity across 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. The capacity of total and regional WMH volumes and LNM scores in predicting cognitive function was compared using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention and executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater disruptive effects of WMH on regional connectivity, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Conclusion: Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network effects, particularly in attentionrelated brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts.

INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.

Functional (un-)Coupling: Impairment, Compensation, and Future Progression in Alzheimer's Disease.

Background: Functional (un-)coupling (task-related change of functional connectivity) between different sites of the brain is a mechanism of general importance for cognitive processes. In Alzheimer's disease (AD), prior research identified diminished cortical connectivity as a hallmark of the disease. However, little is known about the relation between the amount of functional (un-)coupling and cognitive performance and decline in AD. Method: Cognitive performance (based on CERAD-Plus scores) and electroencephalogram (EEG)-based functional (un-)coupling measures (connectivity changes from rest to a Face-Name-Encoding task) were assessed in 135 AD patients (age: M = 73.8 years; SD = 9.0). Of these, 68 patients (M = 73.9 years; SD = 8.9) participated in a follow-up assessment of their cognitive performance 1.5 years later. Results: The amounts of functional (un-)coupling in left anterior-posterior and homotopic interhemispheric connections in beta1-band were related to cognitive performance at baseline (ß = .340; p < .001; ß = .274; P = .001, respectively). For both markers, a higher amount of functional coupling was associated with better cognitive performance. Both markers also were significant predictors for cognitive decline. However, while patients with greater functional coupling in left anterior-posterior connections declined less in cognitive performance (ß = .329; P = .035) those with greater functional coupling in interhemispheric connections declined more (ß = -.402; P = .010). Conclusion: These findings suggest an important role of functional coupling mechanisms in left anterior-posterior and interhemispheric connections in AD. Especially the complex relationship with cognitive decline in AD patients might be an interesting aspect for future studies.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients.

BACKGROUND: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. METHODS: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. RESULTS: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). CONCLUSIONS: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.

The amnestic syndrome of posterior cerebral artery infarction.

BACKGROUND AND PURPOSE: Little is known about the character and underlying lesions of ischaemic amnesia. Episodic memory functions and brain lesions were therefore studied in 84 patients with acute ischaemic infarcts in the supply territory of the posterior cerebral artery. The aim was also to learn how the neural memory systems are organized. METHODS: Standard neuropsychological tests were used to assess verbal and figural memory. Patients were split into memory-impaired and memory-intact groups. Lesions were demarcated, normalized and anatomically labelled, using standard mapping procedures. RESULTS: Of the 84 patients more than 80% had an amnestic syndrome, mostly with combined memory impairment, less often with figural or verbal memory impairment. Amnesia in subjects with left hemispheric lesions was more frequent and more severe, with significantly lower scores on the verbal memory test. Normal performance or figural amnesia were prevalent after right hemispheric lesions. However, no amnesia subtype was strictly tied to left- or right-sided brain damage. Hippocampal and thalamic lesions were common, but 30% of lesions were extrahippocampal located in the ventral occipito-temporal cortex and long occipital white matter tracts. Most amnestic patients lacked awareness for their memory impairment. CONCLUSIONS: Memory impairment is a key clinical manifestation of acute posterior cerebral artery stroke. Amnesia is more frequent and more severe after left stroke, suggesting a left hemisphere dominance of the two memory systems. Domain specific memory appears not to be strictly lateralized, since deficits in verbal and figural memory were found after lesions of both sides. Extrahippocampal lesions may also cause memory impairment.

Serum NfL in Alzheimer Dementia: Results of the Prospective Dementia Registry Austria.

Background and Objectives: The neurofilament light chain (NfL) is a biomarker for neuro-axonal injury in various acute and chronic neurological disorders, including Alzheimer's disease (AD). We here investigated the cross-sectional and longitudinal associations between baseline serum NfL (sNfL) levels and cognitive, behavioural as well as MR volumetric findings in the Prospective Dementia Registry Austria (PRODEM-Austria). Materials and Methods: All participants were clinically diagnosed with AD according to NINCDS-ADRDA criteria and underwent a detailed clinical assessment, cognitive testing (including the Mini Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)), the neuropsychiatric inventory (NPI) and laboratory evaluation. A total of 237 patients were included in the study. Follow-up examinations were done at 6 months, 1 year and 2 years with 93.3% of patients undergoing at least one follow-up. We quantified sNfL by a single molecule array (Simoa). In a subgroup of 125 subjects, brain imaging data (1.5 or 3T MRI, with 1 mm isotropic resolution) were available. Brain volumetry was assessed using the FreeSurfer image analysis suite (v6.0). Results: Higher sNfL concentrations were associated with worse performance in cognitive tests at baseline, including CERAD (B = −10.084, SE = 2.999, p < 0.001) and MMSE (B = −3.014, SE = 1.293, p = 0.021). The sNfL levels also correlated with the presence of neuropsychiatric symptoms (NPI total score: r = 0.138, p = 0.041) and with smaller volumes of the temporal lobe (B = −0.012, SE = 0.003, p = 0.001), the hippocampus (B = −0.001, SE = 0.000201, p = 0.013), the entorhinal (B = −0.000308, SE = 0.000124, p = 0.014), and the parahippocampal cortex (B = −0.000316, SE = 0.000113, p = 0.006). The sNfL values predicted more pronounced cognitive decline over the mean follow-up period of 22 months, but there were no significant associations with respect to change in neuropsychiatric symptoms and brain volumetric measures. Conclusions: the sNfL levels relate to cognitive, behavioural, and imaging hallmarks of AD and predicts short term cognitive decline.

Utility of the Repeat and Point Test for Subtyping Patients With Primary Progressive Aphasia.

BACKGROUND: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). OBJECTIVE: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA. METHOD: During the R&P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed. RESULTS: Controls completed both tasks with >90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R&P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA (<60%). CONCLUSION: The R&P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA.

Anatomically Standardized Detection of MRI Atrophy Patterns in Early-Stage Alzheimer's Disease.

MRI studies have consistently identified atrophy patterns in Alzheimer's disease (AD) through a whole-brain voxel-based analysis, but efforts to investigate morphometric profiles using anatomically standardized and automated whole-brain ROI analyses, performed at the individual subject space, are still lacking. In this study we aimed (i) to utilize atlas-derived measurements of cortical thickness and subcortical volumes, including of the hippocampal subfields, to identify atrophy patterns in early-stage AD, and (ii) to compare cognitive profiles at baseline and during a one-year follow-up of those previously identified morphometric AD subtypes to predict disease progression. Through a prospectively recruited multi-center study, conducted at four Austrian sites, 120 patients were included with probable AD, a disease onset beyond 60 years and a clinical dementia rating of ≤1. Morphometric measures of T1-weighted images were obtained using FreeSurfer. A principal component and subsequent cluster analysis identified four morphometric subtypes, including (i) hippocampal predominant (30.8%), (ii) hippocampal-temporo-parietal (29.2%), (iii) parieto-temporal (hippocampal sparing, 20.8%) and (iv) hippocampal-temporal (19.2%) atrophy patterns that were associated with phenotypes differing predominately in the presentation and progression of verbal memory and visuospatial impairments. These morphologically distinct subtypes are based on standardized brain regions, which are anatomically defined and freely accessible so as to validate its diagnostic accuracy and enhance the prediction of disease progression.

Occupation-related effects on motor cortex thickness among older, cognitive healthy individuals.

Both, decline of sensorimotor functions and cortical thickness are known processes in healthy aging. Physical activity has been suggested to enhance the execution of daily routine activities and to extend the time of functional independence in advanced age. We hypothesized that cortical thickness of motor areas in retired individuals could be related to physical demands of the profession carried out during working life. Depending on their former occupations, 69 cognitively healthy individuals (range 70-85 years) were divided into higher and lower physically complex occupations (HPCO n = 27 and LPCO n = 42) according to the international standard classification of occupations (ISCO-08). Participants underwent a high-resolution 3T T1-weighted MRI scan. Surface-based analysis revealed higher cortical thickness in the left precentral (P = 0.001) and postcentral gyrus (P < 0.001) and right postcentral gyrus (P = 0.001) for the HPCO relative to the LPCO group (corrected for multiple comparisons, sex, age and leisure activities in the past 20 years). Physical leisure activities associated with exertion were positively correlated with cortical thickness in the left pre- and postcentral gyrus (P = 0.037) of the LPCO group. Time since retirement was negatively associated with cortical thickness in the left postcentral gyrus (P = 0.004) of the HPCO group. Executing a higher physically complex occupation before retirement was related to relative higher cortical thickness in the primary motor and somatosensory cortex in later life, supporting the hypothesis that physical activity contributes to neural reserve in these regions. However, these benefits appear to vanish when physical activity is reduced due to retirement.

Effects of Cognitive Functioning and Education on Later-Life Health Numeracy.

INTRODUCTION: Previous studies have shown an association between a high health numeracy and good cognitive functioning. OBJECTIVE: To investigate the moderation effect of education on this relationship and which brain structures support health numeracy. METHODS: We examined 70 healthy older persons (66% females; mean ± SD: age, 75.73 ± 4.52 years; education, 12.21 ± 2.94 years). The participants underwent a T1-weighted 3-T MRI and a neuropsychological assessment including a health numeracy task. Statistical parametric mapping was applied to identify focal changes in cortical thickness throughout the entire brain and to correlate image parameters with behavioral measures. RESULTS: Executive functions and mental calculation emerged as predictors of health numeracy (B = 0.22, p < 0.05, and B = 0.38, p < 0.01). An interaction was found between education and executive functions (B = -0.16, p = 0.01) and between education and mental calculation (B = -0.11, p < 0.05). Executive functions and mental calculation had an impact on health numeracy in participants with a low to intermediate edu-cation (≤12 years) but not in those with a higher education (>12 years). Health numeracy scores were associated with cortical thickness in the right dorsomedial prefrontal cortex and the right superior temporal gyrus (p = 0.01). CONCLUSIONS: Older people with a higher education perform better in health numeracy tasks than those with a lower education. They have access to previously acquired knowledge about ratio concepts and do not need to rely on executive functions and computational skills. This is highly relevant when decisions about health care have to be made.

The impact of folate and vitamin B12 status on cognitive function and brain atrophy in healthy elderly and demented Austrians, a retrospective cohort study.

BACKGROUND: Dementia, and in particular Alzheimer's disease (AD), is a debilitating progressive disease with high prevalence in our society. Vitamin B12 and folate deficiency are potential modifiable risk factors. However, previous studies reported inconsistent results. RESULTS: The average concentrations of all biochemical markers were within the respective reference ranges. Cross-sectional and longitudinal analyses did not reveal significant associations between biochemical markers and cognitive function, global or regional brain volume, cortical thickness or cortical surface area, neither in controls nor in AD patients. CONCLUSIONS: Variations of direct and indirect markers of B12 and folate status are not associated with cognitive dysfunction and brain atrophy. METHODS: This retrospective study explored the association between biochemical markers of B12 and folate status, cognitive function and MRI-based brain atrophy in cognitive normal elderly (controls) and AD patients. Folate, total and active vitamin B12 and MMA were measured in blood samples from 378 controls and 217 AD patients. Neuropsychiatric tests capturing memory, executive function and visuopractical skills were performed in all participants. Brain atrophy was assessed by MRI in 155 controls and 217 AD patients. In a subset of participants cognitive testing (n=234) and MRI (n=182) was repeated after an average median between 1.25 and 6.25 years.

Cognitive reserve does not support the retrieval of well-known proper names in older people.

OBJECTIVE: To assess the role of cognitive reserve, age, gender and brain structure in proper name retrieval in advanced age. METHOD: Performance in 2 naming tasks (asking for proper names or common names) and 2 memory tasks was assessed. In separate hierarchical regressions, we evaluated whether retrieval was predicted by gray matter thickness or volume in selected structures (Model 1) and whether the addition of age and gender (Model 2) or of education (Model 3) explained significantly more variance. Participants were healthy persons (ages 70-90 years). Out of 91 individuals, 18 were excluded after inspection of magnetic resonance imaging scans showing relevant white matter changes. The remaining 73 individuals (47 women) showed good cognitive abilities. RESULTS: Age was a significant predictor for the retrieval of well-known proper names, whereas selected gray matter measures and education had no significant effect. In contrast, education was predictive of common names retrieval and performance in the memory tasks. Gray matter measures predicted performance in the 2 memory tasks. CONCLUSIONS: Cognitive reserve has a differential effect on cognitive abilities in advances age. Education did not support the retrieval of well-known proper names but positively affected the retrieval of common names and performance in memory tasks. Cognitive reserve has to be considered in neuropsychological diagnostic procedures. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The anatomy of spatial neglect after posterior cerebral artery stroke.

Spatial neglect is a common consequence of stroke in the territory of the right middle cerebral artery. Damage to a perisylvian fronto-temporo-parietal network has been demonstrated to underlie this disorder. Less common, stroke to the posterior cerebral artery territory may also lead to spatial neglect. This study aimed to uncover the anatomical underpinnings of spatial neglect after posterior cerebral artery infarction. A sample of 50 posterior cerebral artery infarct patients was screened for spatial neglect. Neural correlates of neglect were investigated both with voxel-based lesion behaviour mapping and with region-of-interest analyses. Brain damage neither to the splenium, nor to the parahippocampal gyrus, nor to the thalamus was predictive of spatial neglect. Only damage to the perisylvian fronto-temporo-parietal network of spatial neglect was significantly associated with neglect severity. We conclude that both posterior and middle cerebral artery stroke induce spatial neglect after damage to the same perisylvian brain network. The findings contradict previous theories that postulated neural correlates of spatial neglect specifically supplied by the posterior cerebral artery. In posterior cerebral artery stroke patients, affected parts of this network are located at the border zone between the posterior and middle cerebral artery territories. Inter-individual variability in the localization of the border between both artery territories appears to mediate the occurrence of spatial neglect after posterior cerebral artery stroke.

Specific Neuropsychiatric Symptoms Are Associated with Faster Progression in Alzheimer's Disease: Results of the Prospective Dementia Registry (PRODEM-Austria).

BACKGROUND: Neuropsychiatric symptoms (NPS) occur frequently in the course of Alzheimer's disease (AD) and are suspected to be associated with a faster dementia progression. Numerous reports have defined specific subsyndromes, summarized in clusters of items of the Neuropsychiatric Inventory (NPI). OBJECTIVE: This study investigated the influence of specific NPI subsyndromes and clinical patient characteristics on dementia progression. METHODS: Data of the prospective registry on dementia in Austria (PRODEM) were retrospectively analyzed. Cognitive functioning was determined at baseline and 2 yearly follow-up visits using the Mini-Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's dementia neuropsychological test battery (CERAD). To assess NPS, the NPI was used: NPI items were classified in three subsyndromes (psychotic cluster, behavioral cluster, emotional cluster). RESULTS: Out of the 662 included patients (mean age 76.4±8.4 years), 43% completed follow-up visits for two years. Significant correlation between higher scores in all three subsyndromes and worse cognitive performance were found for MMSE score, naming, and verbal fluency. Results of linear mixed model analysis revealed lower age and higher scores in the psychotic cluster as significant predictors of changes in MMSE with time. CONCLUSION: In this study, we report the influence of psychotic subsyndromes and lower age on faster MMSE decline in early AD. These results emphasize the importance of not only assessing but also differentiating neuropsychiatric symptoms in subsyndromes in the early stages of AD as a possible predictor of disease progression.

Second language learning induces grey matter volume increase in people with multiple sclerosis.

BACKGROUND: Grey matter volume (GMV) decline is a frequent finding in multiple sclerosis (MS), the most common chronic neurological disease in young adults. Increases of GMV were detected in language related brain regions following second language (L2) learning in healthy adults. Effects of L2 learning in people with MS (pwMS) have not been investigated so far. METHODS: This study prospectively evaluated the potential of an eight-week L2 training on grey matter plasticity measured by 3T-MRI, L2 proficiency and health-related quality of life (HRQoL) in people with relapsing-remitting MS (pwMS, n = 11) and healthy, sex- and age-matched controls (HCs; n = 12). RESULTS: Categorical voxel-based analysis revealed significantly less GMV bilaterally of the insula extending to the temporal pole in pwMS at baseline. Following L2 training, significant increases of GMV were evident in the right hippocampus, parahippocampus and putamen of pwMS and in the left insula of HCs. L2 training resulted in significant improvements of listening comprehension, speaking fluency and vocabulary knowledge in both pwMS and HCs. GMV increases of right hippocampus and parahippocampus significantly correlated with vocabulary knowledge gain and L2 learning was associated with a significant increase of HRQoL in pwMS. CONCLUSION: Our findings demonstrate distinct patterns of GMV increases of language related brain regions in pwMS and HCs and indicate disease-related compensatory cortical and subcortical plasticity to acquire L2 proficiency in pwMS.

Is an intact hippocampus necessary for answering 3 × 3? - Evidence from Alzheimer's disease.

Recent evidence has suggested that the hippocampus supports learning and retrieval of arithmetic facts during childhood and adolescence. Whether the hippocampus is also involved in retrieving overlearned arithmetic facts (such as 3 × 5 = 15) during adult age is open for investigation. In this study, we assessed whether patients with hippocampal atrophy due to Alzheimer's disease (AD) are still able to retrieve overlearned arithmetic facts from memory. Sixteen patients (n = 13 with AD, n = 3 with Mild Cognitive Impairment - MCI) were evaluated using standard radiological, neurological, and neuropsychological test procedures. We adopted a multiple single-case analysis in order to acknowledge possible dissociations between hippocampal degeneration and intact arithmetic fact retrieval. All patients performed a neuropsychological screening battery assessing episodic memory as well as arithmetic processing, and underwent a 3-Tesla MRI procedure. A morphometric analysis comprising estimation of both cortical thickness and hippocampal volume, which also included a subfield analysis, was conducted. All patients had marked hippocampal atrophy (bilateral n = 15, unilateral n = 1) in comparison to healthy matched controls and showed deficits in episodic memory (delayed recall). However, 13 out of 16 patients performed in the average range of standardised norms during retrieval of overlearned arithmetic facts (i.e. multiplication tables). Our results suggest that intact retrieval of consolidated arithmetic facts from memory does not depend on the integrity of the hippocampus. This is in line with the view that the hippocampus plays a dynamic and time-limited role in arithmetic processing. While the hippocampus seems to be necessary for learning and consolidating new arithmetic facts in memory, it might not be critically involved in retrieving arithmetic facts when these are well consolidated in memory.

Performance validity measures in clinical patients with aphasia.

INTRODUCTION: Performance validity testing has developed into an indispensible element of neuropsychological assessment, mostly applied in forensic determinations. Its aim is to distinguish genuine patient performance from invalid test profiles. Limits to the applicability of performance validity tests (PVTs) may arise when genuine cognitive symptoms are present. METHOD: We studied the robustness of four commonly used PVTs in a sample of 15 acute patients after cerebrovascular stroke, with first manifestations of aphasia. Severity of aphasia varied from very mild to severe. Subsequent neuroimaging revealed left-hemisphere infarction for all participants. RESULTS: The Test of Memory Malingering was the only measure found to be robust against effects of genuine language impairment (one positive on Trials 1 and 2, none on Trial 3), while unacceptable false-positive rates were found for the Fifteen-Item Test (60%) and two embedded measures, Reliable Spatial Span (40%) and Reliable Digit Span (73.3%). Four patients (26.7%) scored positive on at least three of the four PVTs. CONCLUSIONS: These data add to the ongoing discussion about the risk of false-positive classifications in genuine patient populations. Misdiagnosis with severe consequences for the patient in question may arise if results of PVTs are interpreted without concurrently considering the whole context of clinical evidence.