Nikki H. Stricker

Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer's disease supports retrogenesis.

The retrogenesis model of Alzheimers disease (AD) posits that white matter (WM) degeneration follows a pattern that is the reverse of myelogenesis. Using diffusion tensor imaging (DTI) to test this model, we predicted greater loss of microstructural integrity in late-myelinating WM fiber pathways in AD patients than in healthy older adults, whereas differences in early-myelinating WM fiber pathways were not expected. We compared 16 AD patients and 14 demographically-matched healthy older adults with a whole-brain approach via tract-based spatial statistics (TBSS), and a region of interest (ROI) approach targeting early-myelinating (posterior limb of internal capsule, cerebral peduncles) and late-myelinating (inferior longitudinal fasciculus [ILF], superior longitudinal fasciculus [SLF]) fiber pathways. Permutation-based voxelwise analysis supported the retrogenesis model. There was significantly lower fractional anisotropy (FA) in AD patients compared to healthy older adults in late-myelinating but not early-myelinating pathways. These group differences appeared to be driven by loss of myelin integrity based on our finding of greater radial diffusion in AD than in healthy elderly. ROI analyses were generally in agreement with whole-brain findings, with significantly lower FA and increased radial diffusion in the ILF in the AD group. Consistent with the retrogenesis model, AD patients showed demonstrable changes in late-myelinating WM fiber pathways. Given greater change in the ILF than the SLF, wallerian degeneration secondary to cortical atrophy may also be a contributing mechanism. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups.

Posterior Cingulum White Matter Disruption and Its Associations with Verbal Memory and Stroke Risk in Mild Cognitive Impairment

Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimers disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk.

Beta amyloid, tau, neuroimaging, and cognition: sequence modeling of biomarkers for Alzheimer's Disease.

Alzheimer’s disease (AD) is associated with a cascade of pathological events involving formation of amyloid-based neuritic plaques and tau-based neurofibrillary tangles, changes in brain structure and function, and eventually, cognitive impairment and functional disability. The precise sequence of when each of these disease markers becomes abnormal is not yet clearly understood. The present study systematically tested the relationship between classes of biomarkers according to a proposed model of temporal sequence by Jack et al. (Lancet Neurology 9:119–128, 2010). We examined temporal relations among four classes of biomarkers: CSF Aβ, CSF tau, neuroimaging variables (hippocampal volume, ventricular volume, FDG PET), and cognitive variables (memory and executive function). Random effects modeling of longitudinal data obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to test hypotheses that putative earlier markers of AD predicted change in later markers, and that intervening markers reduced effects of earlier on later markers. Specifically, we hypothesized that CSF tau would explain CSF Aβ’s relation to neuroimaging and cognitive variables, and neuroimaging variables would explain tau’s relation to cognitive variables. Consistent with hypotheses, results indicated that CSF Aβ effects on cognition change were substantially attenuated by CSF tau and measures of brain structure and function, and CSF tau effects on cognitive change were attenuated by neuroimaging variables. Contrary to hypotheses, CSF Aβ and CSF tau were observed to have independent effects on neuroimaging and CSF tau had a direct effect on baseline cognition independent of brain structure and function. These results have implications for clarifying the temporal sequence of AD changes and corresponding biomarkers.

Increased functional brain response during word retrieval in cognitively intact older adults at genetic risk for Alzheimer's disease.

Recent language studies in aging and dementia provide two complementary lines of evidence that: (1) measures of semantic knowledge and word-finding ability show declines comparable to those of episodic memory, and greater impairment than executive function measures, during the prodromal period of Alzheimers disease and (2) cognitively intact older adult carriers of the apolipoprotein E (APOE) epsilon4 allele also demonstrate poorer object naming than their low-risk peers. Given that possible changes in the neural substrates of word retrieval (e.g., Brocas area and fusiform gyrus) in at-risk adults may signal impending cognitive decline and serve as a prodromal marker of AD, we examined whether APOE epsilon4 carriers exhibit changes in brain response in regions subserving word retrieval and semantic knowledge. Eleven cognitively intact APOE epsilon4 older adults and 11 age, education, and family history of AD-matched APOE epsilon3 adults named aloud photographs of animals, tools, and vehicles during event-related fMRI. Results showed that, in the face of equivalent naming accuracy, APOE epsilon4 adults demonstrated more widespread brain response with greater signal change in the left fusiform gyrus, bilateral medial prefrontal cortex, and right perisylvian cortex. Findings are discussed in the context of possible compensatory mechanisms invoked to maintain performance in those at genetic risk for AD.

CSF biomarker associations with change in hippocampal volume and precuneus thickness: implications for the Alzheimer’s pathological cascade

Neurofibrillary tangles (NFT) and amyloid plaques are hallmark neuropathological features of Alzheimer’s disease (AD). There is some debate as to which neuropathological feature comes first in the disease process, with early autopsy studies suggesting that NFT develop first, and more recent neuroimaging studies supporting the early role of amyloid beta (Aβ) deposition. Cerebrospinal fluid (CSF) biomarkers of Aβ42 and hyperphosphorylated tau (p-tau) have been shown to serve as in vivo proxy measures of amyloid plaques and NFT, respectively. The aim of this study was to examine the association between CSF biomarkers and rate of atrophy in the precuneus and hippocampus. These regions were selected because the precuneus appears to be affected early and severely by Aβ deposition, and the hippocampus similarly by NFT pathology. We predicted (1) baseline Aβ42 would be related to accelerated rate of cortical thinning in the precuneus and volume loss in the hippocampus, with the latter relationship expected to be weaker, (2) baseline p-tau181p would be related to accelerated rate of hippocampal atrophy and cortical thinning in the precuneus, with the latter relationship expected to be weaker. Using all ADNI cohorts, we fitted separate linear mixed-effects models for changes in hippocampus and precuneus longitudinal outcome measures with baseline CSF biomarkers modeled as predictors. Results partially supported our hypotheses: Both baseline p-tau181p and Aβ42 were associated with hippocampal atrophy over time. Neither p-tau181p nor Aβ42 were significantly related to cortical thinning in the precuneus over time. However, follow-up analyses demonstrated that having abnormal levels of both Aβ42 and p-tau181p was associated with an accelerated rate of atrophy in both the hippocampus and precuneus. Results support early effects of Aβ in the Alzheimer’s disease process, which are less apparent than and perhaps dependent on p-tau effects as the disease progresses. However, amyloid deposition alone may be insufficient for emergence of significant morphometric changes and clinical symptoms.

APOE interacts with age to modify rate of decline in cognitive and brain changes in Alzheimer's disease

To determine (1) whether age‐standardized cognitive declines and brain morphometric change differ between Young‐Old patients with Alzheimers disease (YOAD) and Very‐Old patients with Alzheimers disease (VOAD), and (2) whether the apolipoprotein E (APOE) genotype modifies these neuropsychological and morphometric changes.

Distinct profiles of brain and cognitive changes in the very old with Alzheimer disease

Objective: To determine whether age-standardized brain morphometric and cognitive profiles differ in young-old (aged 60–75 years) and very-old (aged 80–91 years) patients with Alzheimer disease (AD). Methods: Using a case-control retrospective design, we compared hippocampal volume and cortical gray matter thickness in areas known to be affected by AD in 105 patients with AD and 125 healthy control (HC) participants divided into young-old and very-old subgroups. Brain morphometric and cognitive scores of the AD groups were standardized to their respective age-appropriate HC subgroup and then compared. Results: Several cognitive domains (executive function, immediate memory, and attention/processing speed) were less abnormal in the very old with AD than in the young old with AD. Similarly, the very old with AD showed less severe cortical thinning than the young old with AD in the left posterior cingulate cortex, right lateral temporal cortex, and bilateral parietal cortex and in overall cortical thickness. This effect is partially explained by an age-related decrease in cortical thickness in these brain regions in the HC participants. Conclusions: The typical pattern of AD-related cognitive and morphometric changes seen in the young old appear to be less salient in the very old. Thus, mild cases of AD in the very old may go undetected if one expects to see the prototypical pattern and severity of cognitive or brain changes that occur in the young old with AD. These results underscore the importance of interpreting neuropsychological test performance and morphometric brain measures in reference to the individuals age. Neurology® 2011;77:713–721

Altered brain response for semantic knowledge in Alzheimer's disease

Word retrieval deficits are common in Alzheimers disease (AD) and are thought to reflect a degradation of semantic memory. Yet, the nature of semantic deterioration in AD and the underlying neural correlates of these semantic memory changes remain largely unknown. We examined the semantic memory impairment in AD by investigating the neural correlates of category knowledge (e.g., living vs. nonliving) and featural processing (global vs. local visual information). During event-related fMRI, 10 adults diagnosed with mild AD and 22 cognitively normal (CN) older adults named aloud items from three categories for which processing of specific visual features has previously been dissociated from categorical features. Results showed widespread group differences in the categorical representation of semantic knowledge in several language-related brain areas. For example, the right inferior frontal gyrus showed selective brain response for nonliving items in the CN group but living items in the AD group. Additionally, the AD group showed increased brain response for word retrieval irrespective of category in Brocas homologue in the right hemisphere and rostral cingulate cortex bilaterally, which suggests greater recruitment of frontally mediated neural compensatory mechanisms in the face of semantic alteration.

Performance-Based Everyday Functioning after Stroke: Relationship with IADL Questionnaire and Neurocognitive Performance

Neuropsychologists frequently are asked to comment on everyday functioning, but the research relies mostly on questionnaire-based assessment of daily functioning. While performance-based assessment of everyday functioning has many advantages over commonly used questionnaires, there are few empirically validated comprehensive performance-based measures. We present data here on a performance-based battery of daily living skills, the Functional Impact Assessment (FIA) in 47 unilateral stroke patients and 37 matched healthy controls. The FIA was validated by comparing it to performance on the self- and informant-report version of the Functional Activities Questionnaire (FAQ). We also examined the relationship between the FIA and cognitive functioning using the Neuropsychological Assessment Battery (NAB). The stroke groups performance on the FIA, FAQ (self and informant), and NAB (total and domain scores) was significantly (ds ≥ .80) lower than the control group. The NAB total score and all domain scores were highly correlated with the FIA in the stroke group (rs > .7), and only one NAB domain score (visuospatial) was a unique predictor. This may be due to the fact that most of the NAB domains have a statistical problem of multicollinearity, which may explain why only the spatial domain was a unique predictor. While the informant FAQ was significantly correlated with FIA total score (r = .48, p < .01), the NAB total score was a significantly better predictor (r = .83, p < .001) than the informant FAQ. NAB total scaled score of less than 86 predicted impairment on the FIA with 92% sensitivity and 84% specificity. Our findings argue that the FIA is sensitive to deficits associated with stroke and is highly associated with all neuropsychological domains (attention, executive functions, language and spatial skills, and memory).

Decreased white matter integrity in neuropsychologically defined mild cognitive impairment is independent of cortical thinning.

Improved understanding of the pattern of white matter changes in early and prodromal Alzheimer’s disease (AD) states such as mild cognitive impairment (MCI) is necessary to support earlier preclinical detection of AD, and debate remains whether white matter changes in MCI are secondary to gray matter changes. We applied neuropsychologically based MCI criteria to a sample of normally aging older adults; 32 participants met criteria for MCI and 81 participants were classified as normal control (NC) subjects. Whole-head high resolution T1 and diffusion tensor imaging scans were completed. Tract-Based Spatial Statistics was applied and a priori selected regions of interest were extracted. Hippocampal volume and cortical thickness averaged across regions with known vulnerability to AD were derived. Controlling for corticalthic kness, the MCI group showed decreased average fractional anisotropy (FA) and decreased FA in parietal white matter and in white matter underlying the entorhinal and posterior cingulate cortices relative to the NC group. Statistically controlling for cortical thickness, medial temporal FA was related to memory and parietal FA was related to executive functioning. These results provide further support for the potential role of white matter integrity as an early biomarker for individuals at risk for AD and highlight that changes in white matter may be independent of gray matter changes.