Aaron Bonner-Jackson

Cognitive reserve and brain reserve in prodromal Huntington's disease

Huntington disease (HD) is associated with decline in cognition and progressive morphological changes in brain structures. Cognitive reserve may represent a mechanism by which disease-related decline may be delayed or slowed. The current study examined the relationship between cognitive reserve and longitudinal change in cognitive functioning and brain volumes among prodromal (gene expansion-positive) HD individuals. Participants were genetically confirmed individuals with prodromal HD enrolled in the PREDICT-HD study. Cognitive reserve was computed as the composite of performance on a lexical task estimating premorbid intellectual level, occupational status, and years of education. Linear mixed effects regression (LMER) was used to examine longitudinal changes on four cognitive measures and three brain volumes over approximately 6 years. Higher cognitive reserve was significantly associated with a slower rate of change on one cognitive measure (Trail Making Test, Part B) and slower rate of volume loss in two brain structures (caudate, putamen) for those estimated to be closest to motor disease onset. This relationship was not observed among those estimated to be further from motor disease onset. Our findings demonstrate a relationship between cognitive reserve and both a measure of executive functioning and integrity of certain brain structures in prodromal HD individuals.

Verbal and non-verbal memory and hippocampal volumes in a memory clinic population

IntroductionBetter characterization of the relationship between episodic memory and hippocampal volumes is crucial in early detection of neurodegenerative disease. We examined these relationships in a memory clinic population.MethodsParticipants (n = 226) underwent structural magnetic resonance imaging and tests of verbal (Hopkins Verbal Learning Test-Revised, HVLT-R) and non-verbal (Brief Visuospatial Memory Test-Revised, BVMT-R) memory. Correlational analyses were performed, and analyses on clinical subgroups (i.e., amnestic Mild Cognitive Impairment, non-amnestic Mild Cognitive Impairment, probable Alzheimer’s disease, intact memory) were conducted.ResultsPositive associations were identified between bilateral hippocampal volumes and both memory measures, and BVMT-R learning slope was more strongly positively associated with hippocampal volumes than HVLT-R learning slope. Amnestic Mild Cognitive Impairment (aMCI) participants showed specific positive associations between BVMT-R performance and hippocampal volumes bilaterally. Additionally, analyses of the aMCI group showed trend-level evidence of material-specific lateralization, such that retention of verbal information was positively associated with left hippocampal volume, whereas learning curve and retention of non-verbal information was positively associated with right hippocampal volume.ConclusionsFindings support the link between episodic memory and hippocampal volumes in a memory clinic population. Non-verbal memory measures also may have higher diagnostic value, particularly in individuals at elevated risk for Alzheimer’s disease.

Genetic risk for Alzheimer's disease alters the five-year trajectory of semantic memory activation in cognitively intact elders.

Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimers disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65-85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy.

Retinal Nerve Fiber Layer Thinning in Alzheimer’s Disease A Case–Control Study in Comparison to Normal Aging, Parkinson’s Disease, and Non-Alzheimer’s Dementia

Retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL) thickness, and macular volume (MV) utilizing spectral domain optical coherence tomography (SD-OCT) were compared among patients with Alzheimer’s disease (AD) dementia, non-Alzheimer’s disease (non-AD) dementia, amnestic mild cognitive impairment (aMCI), Parkinson’s disease (PD), and age- and sex-matched controls in a cross-sectional cohort study. A total of 116 participants were diagnosed and evaluated (21 AD, 20 aMCI, 20 non-AD, 20 PD, and 34 controls) after comprehensive neurological, neuropsychology, and magnetic resonance imaging (MRI) volumetric evaluations. Retinal nerve fiber layer thickness, GCL thickness, and MV were measured. Analysis of variance models were used to compare groups on MRI volumetric measures, cognitive test results, and SD-OCT measures. Associations between SD-OCT measures and other measures were performed using mixed-effect models. Spectral domain optical coherence tomography analysis of retinal markers, including RNFL thickness, GCL thickness, and MV, did not differ between amnestic MCI, AD dementia, PD, non-AD, dementia, and age- and sex-matched controls in a well-characterized patient cohort.

Higher Working Memory Predicts Slower Functional Decline in Autopsy-Confirmed Alzheimer's Disease

Background: There is heterogeneity in the pattern of early cognitive deficits in Alzheimers disease (AD). However, whether the severity of initial cognitive deficits relates to different clinical trajectories of AD progression is unclear. Objective: To determine if deficits in specific cognitive domains at the initial visit relate to the rate of progression in clinical trajectories of AD dementia. Methods: 68 subjects from the National Alzheimers Coordinating Center database who had autopsy-confirmed AD as the primary diagnosis and at least 3 serial assessments a year apart, with a Mini-Mental State Examination (MMSE) score >15 and a Clinical Dementia Rating Scale-Global (CDR-G) score ≤1 at the initial visit were included. A mixed regression model was used to examine the association between initial neuropsychological performance and rate of change on the MMSE and CDR Sum of Boxes. Results: Preservation of working memory, but not episodic memory, in the mild cognitive impairment and early dementia stages of AD relates to slower rate of functional decline. Discussion: These findings are relevant for estimating the rate of decline in AD clinical trials and in counseling patients and families. Improving working memory performance as a possible avenue to decrease the rate of functional decline in AD dementia warrants closer investigation.

Cross-sectional and longitudinal multimodal structural imaging in prodromal Huntington's disease

Diffusivity in white‐matter tracts is abnormal throughout the brain in cross‐sectional studies of prodromal Huntingtons disease. To date, longitudinal changes have not been observed. The present study investigated cross‐sectional and longitudinal changes in white‐matter diffusivity in relationship to the phase of prodromal Huntingtons progression, and compared them with changes in brain volumes and clinical variables that track disease progression.

Impact of Alzheimer's Disease, Lewy Body and Vascular Co-Pathologies on Clinical Transition to Dementia in a National Autopsy Cohort.

Aims: We examined the effect of vascular or Lewy body co-pathologies in subjects with autopsy-confirmed Alzheimers disease (AD) on the rate of cognitive and functional decline and transition to dementia. Methods: In an autopsy sample of prospectively characterized subjects from the National Alzheimers Coordinating Center database, neuropathology diagnosis was used to define the groups of pure AD (pAD, n = 84), mixed vascular and AD (ADV, n = 54), and mixed Lewy body disease and AD (ADLBD, n = 31). Subjects had an initial Clinical Dementia Rating-Global (CDR-G) score <1, Mini-Mental State Examination ≥15, a final visit CDR-G >1, ≥3 evaluations, and Braak tangle stage ≥III. We compared the rate of cognitive and functional decline between the groups. Results: The rate of functional and cognitive decline was lower for ADV, and ADV patients had less severe deficits on CDR-G and the CDR-Sum of Boxes scores at the last visit than pAD and ADLBD patients. No significant differences were noted between ADLBD and pAD patients. After controlling for age at death, the odds of reaching CDR ≥1 at the last visit were lower in the ADV subjects compared to the pAD subjects. Conclusions: The mean rate of functional and cognitive decline among ADV subjects was slower than among either pAD or ADLBD patients. Vascular pathology did not increase the odds of attaining CDR ≥1 when occurring with AD in this national cohort.

Review of Information and Communication Technology Devices for Monitoring Functional and Cognitive Decline in Alzheimer's Disease Clinical Trials

Detecting and monitoring early cognitive impairment in Alzheimers disease (AD) is a significant need in the field of AD therapeutics. Successful AD clinical trial designs have to overcome challenges related to the subtle nature of early cognitive changes. Continuous unobtrusive assessments using Information and Communication Technology (ICT) devices to capture markers of intra-individual change over time to assess cognitive and functional disability therefore offers significant benefits. We review the literature and provide an overview on randomized clinical trials in AD that use intelligent systems to monitor functional decline, as well as strengths, weaknesses, and future directions for the use of ICTs in a new generation of AD clinical trials.

Lack of Accurate Self-appraisal is Equally Likely in MCI from Parkinson's Disease and Alzheimer's Disease: Self-Appraisal Deficits in MCI from PD

How accurate are mild cognitive impairment (MCI) patients in assessing their cognitive and functional deficit is often unclear to the clinician. The accuracy of patient self‐appraisal in Parkinsons disease‐MCI (PD‐MCI) has received less attention than amnestic MCI (a‐MCI) often associated with Alzheimers disease. We evaluated if PD‐MCI patients demonstrate accurate self‐appraisal of their cognitive deficits compared to patients with amnestic a‐MCI or non‐amnestic MCI (na‐MCI).

Outer retinal assessment using spectral-domain optical coherence tomography in patients with Alzheimer’s and Parkinson’s disease

Purpose To investigate outer retinal parameters among patients with various chronic neurodegenerative disorders by using spectral-domain coherence tomography (OCT) in a prospective cross-sectional cohort study. Methods A total of 132 participants were enrolled following a comprehensive diagnostic evaluation with neurologic, neuropsychology, and magnetic resonance imaging volumetric evaluations. Participants were 50 years or older, either diagnosed with Alzheimers disease (AD) dementia, amnestic mild cognitive impairment (MCI), non-AD dementia, Parkinsons disease (PD), or age- and sex-matched controls. All participants underwent a macular cube scan for both eyes by using the Cirrus 4000 HD-OCT (Zeiss, Oberkochen, Germany). The OCT image with the best quality was selected for further analysis. Outer retinal parameters including ellipsoid zone mapping and outer nuclear layer metrics were evaluated with a novel software platform. Results One hundred twenty-four eyes of 124 participants with AD dementia (24 eyes), amnestic MCI (22 eyes), non-AD dementia (20 eyes), PD (22 eyes), and age- and sex-matched controls (36 eyes) were included in the analysis. Eight eyes were excluded either due to the presence of macular disease or poor quality of the OCT image. The mean ages of participants were 65.9 ± 8.9 years. The outer retinal thickness measures did not show any statistical significance between the groups. However, ellipsoid zone to retinal pigment epithelium volume correlated with cognitive testing scores in all study participants. Conclusions There were no identifiable differences in the outer retinal metrics across neurodegenerative disease groups and controls. The relationship between the degree of cognitive impairment and ellipsoid zone to retinal pigment epithelium volume warrants further study.