Effects of White Matter Hyperintensities on Verbal Fluency in Healthy Older Adults and MCI/AD.

BACKGROUND: White matter hyperintensities (WMHs) are markers for cerebrovascular pathology, which are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Verbal fluency is often impaired especially in AD, but little research has been conducted concerning the specific effects of WMH on verbal fluency in MCI and AD. OBJECTIVE: Our aim was to examine the relationship between WMH and verbal fluency in healthy old age and pathological aging (MCI/AD) using quantified MRI data. METHODS: Measures for semantic and phonemic fluency as well as quantified MRI imaging data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86) were utilized. Analyses were performed both using the total sample that contained seven left-handed/ambidextrous participants, as well with a sample containing only right-handed participants (n = 79) in order to guard against possible confounding effects regarding language lateralization. RESULTS: After controlling for age and education and adjusting for multiple correction, WMH in the bilateral frontal and parieto-occipital areas as well as the right temporal area were associated with semantic fluency in cognitively healthy and MCI/AD patients but only in the models containing solely right-handed participants. CONCLUSION: The results indicate that white matter pathology in both frontal and parieto-occipital cerebral areas may have associations with impaired semantic fluency in right-handed older adults. However, elevated levels of WMH do not seem to be associated with cumulative effects on verbal fluency impairment in patients with MCI or AD. Further studies on the subject are needed.

Domain-specific cognitive effects of white matter pathology in old age, mild cognitive impairment and Alzheimer's disease.

Concomitant white matter (WM) brain pathology is often present in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Cognitive effects of WM pathology on cognition in normal and pathological aging have been studied, but very little is known about possible group-specific effects in old age, MCI and AD. The purpose of the current study was to examine the relationship between WM pathology and cognitive functioning in four cognitive domains in old age, MCI and AD. The study utilized multi-domain neuropsychological data and visually rated MRI imaging data from a sample of 56 healthy older adults, 40 patients with MCI and 52 patients with AD (n = 148). After controlling for age and education, main effects of frontal WM pathology (especially in the left hemisphere) were found for cognitive performances in two domains, whereas a main effect of parieto-occipital WM pathology was only found for processing speed. In addition, with regard to processing speed, an interaction between group and WM changes was found: Patients with AD that had moderate or severe left frontal WM pathology were considerably slower than patients with AD that had milder cerebrovascular pathology. Frontal WM pathology, especially in the left hemisphere, seems to affect cognitive functions in many domains in all three groups. The results of the study increase our knowledge of cognitive repercussions stemming from frontal and/or parieto-occipital WM pathology in AD. Clinicians should be aware that patients with AD with prominent frontal cerebrovascular pathology can have considerably slowed cognitive processing.

Tau Protein is Associated with Longitudinal Memory Decline in Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels.

BACKGROUND: We investigated a sample of cognitively healthy subjects with normal Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes. OBJECTIVE: Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline. METHODS: Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau↓ (tau < 228.64 pg/ml; n = 16) and CBN-Tau↑ (tau > 228.64 pg/ml; n = 16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance. RESULTS: Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B = -0.17, p < 0.05; r = -0.414; p < 0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31) = 8.37; p < 0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes. CONCLUSIONS: The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects.

White Matter Hyperintensities and Cognitive Impairment in Healthy and Pathological Aging: A Quantified Brain MRI Study.

BACKGROUND: Brain changes involving the white matter (WM), often an indication of cerebrovascular pathology, are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Few studies have examined possible cognitive domain- or group-specific cognitive effects of WM pathology in old age, MCI, and AD. OBJECTIVE: Our purpose was to examine the relationship between WM hyperintensities (WMH), a typical marker for WM pathology, and cognitive functioning in healthy old age and pathological aging using quantified MRI data. METHODS: We utilized multidomain neuropsychological data and quantified MRI data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86). RESULTS: After controlling for age and education, WMH in the temporal and parieto-occipital lobes was associated with impairments in processing speed and parieto-occipital pathology with verbal memory impairment in the whole sample. Additionally, temporal WMH was associated with impaired processing speed in the patient group specifically. CONCLUSIONS: WM pathology is strongly associated with impaired processing speed, and our results indicate that these impairments arise from WMH in the temporal and parieto-occipital regions. In MCI and AD patients with temporal WMH, processing speed impairments are especially prominent. The results of this study increase our knowledge of cognitive repercussions stemming from temporal and/or parieto-occipital WM pathology in healthy and pathological aging.

Cognitive Effects of White Matter Pathology in Normal and Pathological Aging.

We examined whether cerebrovascular white matter pathology is related to cognition as measured by the compound score of CERAD neuropsychological battery in cognitively normal older adults, patients with mild cognitive impairment, and patients with Alzheimer's disease (total n = 149), controlling for age and education. Trend-level effects of white matter pathology on cognition were only observed in patients with Alzheimer's disease (p = 0.062, η2  = 0.052), patients with severe frontal white matter pathology performed notably worse than those with milder pathology. This indicates that frontal cerebrovascular pathology may have an additive negative effect on cognition in Alzheimer's disease.

Pattern of Near Transfer Effects Following Working Memory Training With a Dual N-Back Task.

In a randomized controlled trial, we investigated the pattern of near transfer effects of working memory (WM) training with an adaptive auditory-visuospatial dual n-back training task in healthy young adults. The results revealed significant task-specific transfer to an untrained single n-back task, and more general near transfer to a WM updating composite score plus a nearly significant effect on a composite score measuring interference control in WM. No transfer effects were seen on Active or Passive WM composites. The results are discussed in the light of cognitive versus strategy-related overlap between training and transfer tasks.

Early Detection of Learning Difficulties when Confronted with Novel Information in Preclinical Alzheimer's Disease Stage 1.

We employed a highly demanding experimental associative learning test (the AFE-T) to explore memory functioning in Preclinical Alzheimer's Disease stage 1 (PreAD-1) and stage 2 (PreAD-2). The task consisted in the learning of unknown object/name pairs and our comprehensive setup allowed the analysis of learning curves, immediate recall, long-term forgetting rates at one week, three months, and six months, and relearning curves. Forty-nine cognitively healthy subjects were included and classified according to the presence or absence of abnormal CSF biomarkers (Control, n = 31; PreAD-1, n = 14; PreAD-2, n = 4). Control and PreAD-1 performances on the experimental test were compared by controlling for age and education. These analyses showed clear learning difficulties in PreAD-1 subjects (F = 6.98; p = 0.01). Between-group differences in long-term forgetting rates were less notable, reaching statistical significance only for the three-month cued forgetting rate (F = 4.83; p = 0.03). Similarly, relearning sessions showed only statistical trends between the groups (F = 3.22; p = 0.08). In the whole sample, significant correlations between CSF Aß42/tau ratio and the AFE-T were found, both in the total learning score (r = 0.52; p < 0.001) and in the three-month cued forgetting rate (r = -0.38; p < 0.01). Descriptive subanalyses involving PreAD-2 suggested greater learning and recall difficulties in these subjects when compared with the PreAD-1 group. The present results suggest that explicit learning difficulties when binding information could be one of the earliest signs of the future emergence of episodic memory difficulties on the Alzheimer's disease continuum. Our findings indicate that the AFE-T is a sensitive test, capable of detecting subtle memory difficulties in PreAD-1.

Limited Effects of Set Shifting Training in Healthy Older Adults.

Our ability to flexibly shift between tasks or task sets declines in older age. As this decline may have adverse effects on everyday life of elderly people, it is of interest to study whether set shifting ability can be trained, and if training effects generalize to other cognitive tasks. Here, we report a randomized controlled trial where healthy older adults trained set shifting with three different set shifting tasks. The training group (n = 17) performed adaptive set shifting training for 5 weeks with three training sessions a week (45 min/session), while the active control group (n = 16) played three different computer games for the same period. Both groups underwent extensive pre- and post-testing and a 1-year follow-up. Compared to the controls, the training group showed significant improvements on the trained tasks. Evidence for near transfer in the training group was very limited, as it was seen only on overall accuracy on an untrained computerized set shifting task. No far transfer to other cognitive functions was observed. One year later, the training group was still better on the trained tasks but the single near transfer effect had vanished. The results suggest that computerized set shifting training in the elderly shows long-lasting effects on the trained tasks but very little benefit in terms of generalization.

Learning and forgetting new names and objects in MCI and AD.

We studied how subjects with mild cognitive impairment (MCI), early Alzheimer's disease (AD) and age-matched controls learned and maintained the names of unfamiliar objects that were trained with or without semantic support (object definitions). Naming performance, phonological cueing, incidental learning of the definitions and recognition of the objects were tested during follow-up. We found that word learning was significantly impaired in MCI and AD patients, whereas forgetting patterns were similar across groups. Semantic support showed a beneficial effect on object name retrieval in the MCI group 8 weeks after training, suggesting that the MCI patients' preserved semantic memory can compensate for impaired episodic memory. The MCI group performed equally well as the controls in the tasks measuring incidental learning and recognition memory, whereas the AD group showed impairment in this respect. Both the MCI and the AD group benefited less from phonological cueing than the controls. Our findings indicate that word learning is compromised in both MCI and AD, whereas long-term retention of newly learned words is not affected to the same extent. Incidental learning and recognition memory seem to be well preserved in MCI.

Neurocognitive processing of auditorily and visually presented inflected words and pseudowords: evidence from a morphologically rich language.

The aim of the study was to investigate how the input modality affects the processing of a morphologically complex word. The processing of Finnish inflected vs. monomorphemic words and pseudowords was examined during a lexical decision task, using behavioral responses and event-related potentials. The stimuli were presented in two modalities, visually and auditorily, to two groups of participants. Half of the words and pseudowords carried a case-inflection. At the behavioral level, the inflected words elicited a processing cost with longer decision latencies and higher error rates. At the neural level, pseudowords elicited an N400 effect, which was more pronounced in the visual modality. Inflected words elicited an N400 effect in both modalities, which, however, differed in topography and latency. The N400 effect for inflected words most probably reflects access and possible integration of the stem and suffix. The results suggest that the inflectional processing cost stems from the later, lexical-semantic stage of processing in both modalities. The ERP responses to inflected pseudowords did not differ from the ERP responses to monomorphemic pseudowords in either modality, suggesting that combinatorial case-inflection processing requires a real word stem in order to proceed.