Prolonged cholinergic enrichment influences regional cortical activation in early Alzheimer's disease

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) indicate that the short and long term actions of ChEIs are dissimilar. fMRI studies of the ChEI rivastigmine have focused on its short term action. In this exploratory study the effect of prolonged (20 weeks) rivastigmine treatment on regional brain activity was measured with fMRI in patients with mild AD. Eleven patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. There was an increase in task-related brain activity after treatment with activations more like those of normal healthy elderly. Behaviorally, however, there were no significant differences between baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Variable patient response and drug dynamic/kinetic factors in small patient groups will inevitably bias (either way) the effect size of any relevant drug related changes in activation. Future studies should take drug response into account to provide more insight into the benefits of ChEI drugs at the individual level

Charting the decline in spontaneous writing in Alzheimer's disease: a longitudinal study.

Objective: This study aims to document the nature and progression of the spontaneous writing impairment observed in patients with Alzheimer's disease (AD) over a 12-month period using both a cross-sectional and prospective longitudinal design. Methods: Thirty-one minimal-moderate AD patients and 30 controls matched for age and socio-cultural background completed a simple and complex written description task at baseline. The AD patients then had follow-up assessments at 6 and 12 months. Results: Cross-sectional comparisons indicated that minimal-moderate AD patients produced more semantic paraphasias, phonological paraphasias, and empty and indefinite phrases, whilst producing fewer pictorial themes, repairing fewer errors, and producing shorter and less complex sentences than controls. The two groups could not be distinguished on visual paraphasias. Longitudinal follow-up, however, suggested that visual processing deteriorates over time, where the prevalence of visual errors increased over 12 months. Discussion: The findings suggest that the deterioration of writing skills observed in the spontaneous writings of AD patients shows a pattern of impairment dominated by semantic errors with a secondary impairment in phonological processing, which is later joined by a disruption of visuospatial and graphomotor processing

Item-Level Scores on the Boston Naming Test as an Independent Predictor of Perirhinal Volume in Individuals with Mild Cognitive Impairment

We explored the methodological value of an item-level scoring procedure applied to the Boston Naming Test (BNT), and the extent to which this scoring approach predicts grey matter (GM) variability in regions that sustain semantic memory. Twenty-seven BNT items administered as part of the Alzheimer’s Disease Neuroimaging Initiative were scored according to their “sensorimotor interaction” (SMI) value. Quantitative scores (i.e., the count of correctly named items) and qualitative scores (i.e., the average of SMI scores for correctly named items) were used as independent predictors of neuroanatomical GM maps in two sub-cohorts of 197 healthy adults and 350 mild cognitive impairment (MCI) participants. Quantitative scores predicted clusters of temporal and mediotemporal GM in both sub-cohorts. After accounting for quantitative scores, the qualitative scores predicted mediotemporal GM clusters in the MCI sub-cohort; clusters extended to the anterior parahippocampal gyrus and encompassed the perirhinal cortex. This was confirmed by a significant yet modest association between qualitative scores and region-of-interest-informed perirhinal volumes extracted post hoc. Item-level scoring of BNT performance provides complementary information to standard quantitative scores. The concurrent use of quantitative and qualitative scores may help profile lexical–semantic access more precisely, and might help detect changes in semantic memory that are typical of early-stage Alzheimer’s disease

Serial Recall Order and Semantic Features of Category Fluency Words to Study Semantic Memory in Normal Ageing

Copyright © 2021 De Marco, Blackburn and Venneri. Background: Category Fluency Test (CFT) is a common measure of semantic memory (SM). Test performance, however, is also influenced by other cognitive functions. We here propose a scoring procedure that quantifies the correlation between the serial recall order (SRO) of words retrieved during the CFT and a number of linguistic features, to obtain purer SM measures. To put this methodology to the test, we addressed a proof-of-concept hypothesis whereby, in alignment with the literature, older adults would show better SM. Methods: Ninety participants (45 aged 18–21 years; 45 aged 70–81 years) with normal neurological and cognitive functioning completed a 1-min CFT. SRO was scored as an ordinal variable incrementing by one unit for each valid entry. Each word was also scored for 16 additional linguistic features. Participant-specific normalised correlation coefficients were calculated between SRO and each feature and were analysed with group comparisons and graph theory. Results: Younger adults showed more negative correlations between SRO and “valence” (a feature of words pleasantness). This was driven by the first five words generated. When analysed with graph theory, SRO had significantly higher degree and lower betweenness centrality among older adults. Conclusion: In older adults, SM relies significantly less on pleasantness of entries typically retrieved without semantic control. Moreover, graph-theory metrics indicated better optimised links between SRO and linguistic features in this group. These findings are aligned with the principle whereby SM processes tend to solidify with ageing. Although additional work is needed in support of an SRO-based item-level scoring procedure of CFT performance, these initial findings suggest that this methodology could be of help in characterising SM in a purer form.Neurocare (United Kingdom), Grant agreement No. 181924 to MDM and AV; Alzheimer’s Research United Kingdom, Pump Priming Grant scheme to MDM

Sex differences in olfactory cortex neuronal loss in aging

IntroductionAging plays a major role in neurodegenerative disorders such as Alzheimer’s disease, and impacts neuronal loss. Olfactory dysfunction can be an early alteration heralding the presence of a neurodegenerative disorder in aging. Studying alterations in olfaction-related brain regions might help detection of neurodegenerative diseases at an earlier stage as well as protect individuals from any danger caused by loss of sense of smell.ObjectiveTo assess the effect of age and sex on olfactory cortex volume in cognitively healthy participants.MethodNeurologically healthy participants were divided in three groups based on their age: young (20–35 years; n = 53), middle-aged (36–65 years; n = 66) and older (66–85 years; n = 95). T1-weighted MRI scans acquired at 1.5 T were processed using SPM12. Smoothed images were used to extract the volume of olfactory cortex regions.ResultsANCOVA analyses showed significant differences in volume between age groups in the olfactory cortex (p ≤ 0.0001). In women, neuronal loss started earlier than in men (in the 4th decade of life), while in men more substantial neuronal loss in olfactory cortex regions was detected only later in life.ConclusionData indicate that age-related reduction in the volume of the olfactory cortex starts earlier in women than in men. The findings suggest that volume changes in olfaction-related brain regions in the aging population deserve further attention as potential proxies of increased risk of neurodegenerative diseases

The effect of physical activity on white matter integrity in aging and prodromal to mild Alzheimer’s disease with vascular comorbidity

BackgroundPhysical activity is a modifiable lifestyle factor that has been previously associated with reduced vascular burden and reduced risk of dementia.ObjectivesThis study tested whether physical activity (i.e., being inactive vs. active) contributed to preservation of white matter microstructure in healthy aging controls and patients in prodromal to mild Alzheimer’s disease with low/high vascular burden.MaterialsA total of 213 participants were recruited from memory clinics. They were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Diffusion-weighted images were acquired for all participants and pre-processed based on a standard protocol.MethodsA factorial design using voxel-wise tract-based spatial statistics (TBSS) was adopted, with 5,000 permutations and threshold-free cluster enhancement (TFCE), to identify significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD), and radial diffusivity (RD).ResultsClusters of higher FA and lower AxD, MD, and RD values were found for physically active compared with inactive participants that were widespread covering mainly association and projection tracts but also some commissural tracts. A three-way Group × Physical Activity × Vascular Burden interaction effect was found for FA mostly in a variety of projection tracts with a right predominance, and some commissural and association tracts. Post hoc analyses revealed higher FA in patients with high vascular burden who were physically active compared with those patients with high vascular burden who were inactive mainly in projection and association/limbic tracts with a right predominance. Additionally, higher FA was observed in physically active patients with high vascular burden as compared with physically inactive controls with high vascular burden, mainly in bilateral projection fibers and cerebellar regions.ConclusionVoxel-wise TBSS analysis revealed better preservation of white matter microstructure that was prominent in the high-risk group such as the patients with high vascular burden, specifically those who were physically active. The beneficial effects of physical activity on white matter microstructure were not observed in the controls

Task- and response related dissociations between neglect in near and far space: A morphometric case study

Introduction: Patients with unilateral neglect may show line bisection errors selectively in either near (within hand reaching) or far (beyond hand reaching) space which suggests that these two spatial areas are coded differently by the brain. This exploratory study investigated, whether any difference in performance between these spatial domains might be task-independent or modulated by the requirement for a motor response. Methods: A 31-year-old right brain damaged patient (MF) and a group of age matched healthy controls were assessed with two serial visual search tasks and a Landmark paradigm. Both types of task required either a directional (pointing) or non-directional (button press) motor response. Participants were assessed with both task types and response modes in near (57 cm) and far space (114 cm). Results: MF showed left neglect during visual search only in far space for the perceptual condition and in near space for the motor condition. MF showed no neglect in both versions of the Landmark task irrespective of spatial distance. A voxel-based morphometric assessment of MF's brain lesion showed marked damage in the right ventro-temporal cortex, superior temporal gyrus, insula, inferior frontal gyrus, angular gyrus and bilaterally in the posterior cingulate cortex. Conclusions: Our preliminary findings suggest that processing of far space during visual search is associated with ventral stream damage but only when space is coded through visual information. Neglect involving directional motor activity in near space seems to be associated with damage of structures sharing close connections with the dorsal stream

The neural signatures of psychoses in Alzheimer’s disease: a neuroimaging genetics approach

Psychoses in Alzheimer’s disease (AD) are associated with worse prognosis. Genetic vulnerability for schizophrenia (SCZ) may drive AD-related psychoses, yet its impact on brain constituents is still unknown. This study aimed to investigate the association between polygenic risk scores (PRSs) for SCZ and psychotic experiences (PE) and grey matter (GM) volume in patients with AD with (AD-PS) and without (AD-NP) psychosis. Clinical, genetic and T1-weighted MRI data for 800 participants were extracted from the ADNI database: 203 healthy controls, 121 AD-PS and 476 AD-NP. PRSs were calculated using a Bayesian approach and analysed at ten p-value thresholds. Standard voxel-based morphometry was used to process MRI data. Logistic regression models including both PRSs for SCZ and PE, and an AD-PRS were used to predict psychosis in AD. Associations between PRSs and GM volume were investigated in the whole sample and the three groups independently. Only the AD-PRS predicted psychosis in AD. Inconsistent associations between the SCZ-PRS and PE-PRS and GM volumes were found across groups. The SCZ-PRS was negatively associated with medio-temporal/subcortical volumes and positively with medial/orbitofrontal volumes in the AD-PS group. Only medio-temporal areas were more atrophic in the AD-PS group, while there was no significant correlation between psychosis severity and GM volume. Although not associated with psychoses, the SCZ-PRS was correlated with smaller medio-temporal and larger orbitofrontal volumes in AD-PS. Similar alterations have also been observed in SCZ patients. This finding suggest a possible disconnection between these regions associated with psychoses in more advanced AD

Recovery from Transient Global Amnesia Following Restoration of Hippocampal and Fronto–Cingulate Perfusion

A patient who suffered a transient global amnesia (TGA) attack underwent regional cerebral blood flow (rCBF) SPECT imaging and neuropsychological testing in the acute phase, after one month and after one year. Neuropsychological testing in the acute phase showed a pattern of anterograde and retrograde amnesia, whereas memory was within age normal limits at follow up. SPECT data were analysed with a within subject comparison and also compared with those of a group of healthy controls. Within subject comparison between the one month follow up and the acute phase detected increases in rCBF in the hippocampus bilaterally; further rCBF increases in the right hippocampus were detected after one year. Compared to controls, significant hypoperfusion was found in the right precentral, cingulate and medial frontal gyri in the acute phase; after one month significant hypoperfusion was detected in the right precentral and cingulate gyri and the left postcentral gyrus; after one year no significant hypoperfusion appeared. The restoration of memory was paralleled by rCBF increases in the hippocampus and fronto-limbic-parietal cortex; after one year neither significant rCBF differences nor cognitive deficits were detectable. In conclusion, these data indicate that TGA had no long lasting cognitive and neural alterations in this patient