Judy Pa

Clinical-Neuroimaging Characteristics of Dysexecutive Mild Cognitive Impairment

Subgroups of mild cognitive impairment (MCI) have been proposed, but few studies have investigated the nonamnestic, single‐domain subgroup of MCI. The goal of the study was to compare clinical and neuroimaging characteristics of two single‐domain MCI subgroups: amnestic MCI and dysexecutive MCI.

A parietal–temporal sensory–motor integration area for the human vocal tract: Evidence from an fMRI study of skilled musicians

Several sensory-motor integration regions have been identified in parietal cortex, which appear to be organized around motor-effectors (e.g., eyes, hands). We investigated whether a sensory-motor integration area might exist for the human vocal tract. Speech requires extensive sensory-motor integration, as does other abilities such as vocal musical skills. Recent work found that a posterior superior temporal-parietal region, area Spt, has both sensory (auditory) and motor response properties (for both speech and tonal stimuli). Brain activity of skilled pianists was measured with fMRI while they listened to a novel melody and either covertly hummed the melody (vocal tract effectors) or covertly played the melody on a piano (manual effectors). Activity in area Spt was significantly higher for the covert hum versus covert play condition. A region in the anterior IPS (aIPS) showed the reverse pattern, suggesting its involvement in sensory-manual transformations. This finding suggests that area Spt is a sensory-motor integration area for vocal tract gestures.

Patterns of cerebral hypoperfusion in amnestic and dysexecutive MCI.

Although early studies on mild cognitive impairment (MCI) focused on memory dysfunction; more recent studies suggest that MCI is clinically heterogeneous. The objective of this study is to examine patterns of cerebral perfusion in anmestic (N=12) and nonamnestic (N=12) single-domain MCI patients from 4 a priori regions of interest: middle and superior frontal cortex, posterior cingulate, and precuneus, to compare them relative to healthy controls (N=12), and to correlate perfusion with neuropsychologic measures. Relative to controls, all MCI patients had hypoperfusion in the posterior cingulate, bilaterally. MCI patients with executive dysfunctions also showed hypoperfusion in bilateral middle frontal cortex and the left precuneus relative to controls and in the left middle frontal cortex, left posterior cingulate, and left precuneus relative to amnestic MCI patients. Perfusion in the posterior cingulate correlated positively with memory performance whereas perfusion in all 4 a priori regions of interest, predominately on the left side, correlated with executive function performance. The finding that single-domain MCI patients with prominent deficits in different cognitive domains exhibited different patterns of hypoperfusion relative to controls supports the existence of distinct subgroups of MCI. These data further suggest that cognitive impairment in MCI is related to cerebral hypoperfusion.

Gray matter correlates of set-shifting among neurodegenerative disease, mild cognitive impairment, and healthy older adults

There is increasing recognition that set-shifting, a form of cognitive control, is mediated by different neural structures. However, these regions have not yet been carefully identified as many studies do not account for the influence of component processes (e.g., motor speed). We investigated gray matter correlates of set-shifting while controlling for component processes. Using the Design Fluency (DF), Trail Making Test (TMT), and Color Word Interference (CWI) subtests from the Delis-Kaplan Executive Function System (D-KEFS), we investigated the correlation between set-shifting performance and gray matter volume in 160 subjects with neurodegenerative disease, mild cognitive impairment, and healthy older adults using voxel-based morphometry. All three set-shifting tasks correlated with multiple, widespread gray matter regions. After controlling for the component processes, set-shifting performance correlated with focal regions in prefrontal and posterior parietal cortices. We also identified bilateral prefrontal cortex and the right posterior parietal lobe as common sites for set-shifting across the three tasks. There was a high degree of multicollinearity between the set-shifting conditions and the component processes of TMT and CWI, suggesting DF may better isolate set-shifting regions. Overall, these findings highlight the neuroanatomical correlates of set-shifting and the importance of controlling for component processes when investigating complex cognitive tasks.

Brain imaging of neurovascular dysfunction in Alzheimer’s disease

Neurovascular dysfunction, including blood–brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer’s disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other.

Neural organization of linguistic short-term memory is sensory modality--dependent: Evidence from signed and spoken language

Despite decades of research, there is still disagreement regarding the nature of the information that is maintained in linguistic short-term memory (STM). Some authors argue for abstract phonological codes, whereas others argue for more general sensory traces. We assess these possibilities by investigating linguistic STM in two distinct sensorymotor modalities, spoken and signed language. Hearing bilingual participants (native in English and American Sign Language) performed equivalent STM tasks in both languages during functional magnetic resonance imaging. Distinct, sensory-specific activations were seen during the maintenance phase of the task for spoken versus signed language. These regions have been previously shown to respond to nonlinguistic sensory stimulation, suggesting that linguistic STM tasks recruit sensory-specific networks. However, maintenance-phase activations common to the two languages were also observed, implying some form of common process. We conclude that linguistic STM involves sensory-dependent neural networks, but suggest that sensory-independent neural networks may also exist.

Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis

Importance It is unclear whether female carriers of the apolipoprotein E (APOE) &egr;4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data Sources Twenty-seven independent research studies in the Global Alzheimer’s Association Interactive Network with data on nearly 58 000 participants. Study Selection Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data Extraction and Synthesis Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main Outcomes and Measures Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE &egr;3/&egr;4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE &egr;3/&egr;4 had an increased risk of AD compared with men with APOE &egr;3/&egr;3. The APOE &egr;2/&egr;3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE &egr;3/&egr;4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE &egr;4/&egr;4 showed increased risks vs individuals with &egr;3/&egr;4, but no significant differences between men and women with &egr;4/&egr;4 were seen. Conclusions and Relevance Contrary to long-standing views, men and women with the APOE &egr;3/&egr;4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.

Cholinergic enhancement of functional networks in older adults with mild cognitive impairment

The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group.

Cholinergic enhancement of functional networks in older adults with MCI

The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group.

Baseline Predictors of Clinical Progression among Patients with Dysexecutive Mild Cognitive Impairment

Background/Aims: There are few studies that evaluate the clinical outcomes of individuals with non-amnestic mild cognitive impairment (MCI). The purpose of this study was to evaluate baseline predictors of clinical progression after 2 years for patients with dysexecutive MCI (dMCI), a single-domain non-amnestic MCI subgroup. Methods:We evaluated clinical progression in a sample of 31 older adults with dMCI. Clinical progression was defined as a worsening on the Clinical Dementia Rating sum of boxes at the 2-year visit, whereas patients were classified as stable if the score did not worsen over 2 years. We compared baseline brain MRI, neuropsychological tests, and health risk factors. Results: Twelve individuals with dMCI progressed clinically, and 19 individuals remained stable over 2 years. Compared to the stable dMCI patients, the dMCI patients who progressed showed brain atrophy in the bilateral insula and left lateral temporal lobe on MRI. dMCI patients who progressed were also older, had lower baseline performance on category fluency and a spatial location task, and reported fewer dysexecutive symptoms. Health risk factors, except hypertension, did not differ between groups. Conclusion: The results suggest that dMCI patients who progress relatively quickly over 2 years may have unique clinical and brain MRI features.