[Show abstract][Hide abstract] ABSTRACT: Healthy older adults typically perform worse than younger adults at rule-based category learning, but better than patients with Alzheimer’s or Parkinson’s disease. To further investigate aging’s effect on rule-based category learning, we monitorfed event-related potentials (ERPs) while younger and neuropsychologically typical older adults performed a visual category-learning task with a rule-based category structure and trial-by-trial feedback. Using these procedures, we previously identified ERPs sensitive to categorization strategy and accuracy in young participants. In addition, previous studies have demonstrated the importance of neural processing in prefrontal cortex and the medial temporal lobe for this task. In this study, older adults showed lower accuracy and longer response times than younger adults, but there were two distinct subgroups. One subgroup showed near-chance performance throughout the procedure, never categorizing accurately. The other subgroup reached asymptotic accuracy that was equivalent to that in younger adults, although they categorized more slowly. These two subgroups were further distinguished via ERPs. Consistent with the compensation theory of cognitive aging, older adults who successfully learned showed larger frontal ERPs when compared with younger adults. Recruitment of prefrontal resources may have improved performance while slowing response times. Additionally, correlations of feedback-locked P300 amplitudes with category-learning accuracy differentiated successful younger and older adults. Overall, the results suggest that the ability to adapt one’s behavior in response to feedback during learning varies across older individuals, and that the failure of some to adapt their behavior may reflect inadequate engagement of prefrontal cortex.
Aging Neuropsychology and Cognition 09/2015; DOI:10.1080/13825585.2015.1091438 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Basal forebrain cholinergic neurons (BFCN) are selectively vulnerable in Alzheimer's disease (AD). We have shown that most of the BFCN in the human brain contain the calcium-binding protein calbindin-D28K (CB), a large proportion lose their CB in the course of normal aging, and the BFCN which degenerate in AD lack CB. Here, we investigated the relationship between CB in the BFCN and the process of tangle formation in AD using antibodies to tau epitopes that appear early, intermediate or late in the process of tangle formation. Very small percentages (0%-3.7%) of CB-positive BFCN contained pretangles and/or tangles, and very small percentages (0%-5%) of the total BFCN pretangles and/or tangles were in CB-immunoreactive neurons. The number of CB-positive BFCN which contained tau immunoreactivity was highest for the early epitope and lower for intermediate epitopes. A late appearing epitope was absent from CB-positive BFCN. Age-related loss of CB appears to coincide with tangle formation in the BFCN and is associated with the full range of tau pathology, including late appearing epitopes.
Neurobiology of aging 09/2015; DOI:10.1016/j.neurobiolaging.2015.09.001 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eye movement trajectories during a verbally cued object search task were used as probes of lexico-semantic associations in an anomic patient with primary progressive aphasia. Visual search was normal on trials where the target object could be named but became lengthy and inefficient on trials where the object failed to be named. The abnormality was most profound if the noun denoting the object could not be recognized. Even trials where the name of the target object was recognized but not retrieved triggered abnormal eye movements, demonstrating that retrieval failures can have underlying associative components despite intact comprehension of the corresponding noun.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer neuropathology (AD) is found in almost half of patients with non-semantic primary progressive aphasia (PPA). This study examined hippocampal abnormalities in PPA to determine similarities to those described in amnestic AD.
In 37 PPA patients and 32 healthy controls, we generated hippocampal subfield surface maps from structural MRIs and administered a face memory test. We analyzed group and hemisphere differences for surface shape measures and their relationship with test scores and ApoE genotype.
The hippocampus in PPA showed inward deformity (CA1 and subiculum subfields) and outward deformity (CA2-4+DG subfield) and smaller left than right volumes. Memory performance was related to hippocampal shape abnormalities in PPA patients, but not controls, even in the absence of memory impairments.
Hippocampal deformity in PPA is related to memory test scores. This may reflect a combination of intrinsic degenerative phenomena with transsynaptic or Wallerian effects of neocortical neuronal loss.
[Show abstract][Hide abstract] ABSTRACT: Combined pathologies are common, particularly in the very elderly with AD as the primary pathologic diagnosis. In such patients, AD plus vascular disease (VaD) or Lewy body disease (LBD), or both, with or without limbic TDP-43 inclusions, are the most frequent combined pathologies. In contrast, combined pathologies are rare in cases with a primary diagnosis of frontotemporal lobar degeneration (FTLD). Autopsy remains the gold standard for specific pathologic / molecular diagnoses. We present the case of an 80 year old woman with an 11 year history of a mixed behavioral and aphasic phenotype who subsequently displayed gait abnormality, tremor, and falls. Evaluation of microscopic H & E sections and histochemical and immunohistochemical stains revealed three major pathologic diagnoses: AD, FTLD-TDP, and FTLD-tau-PSP. The FTLD-TDP pathology (type A) was prominent in frontal and temporal cortex; the AD tangle density was greatest in the parietal lobe; and the PSP pathology was predominantly in basal ganglia and brainstem. We felt that the FTLD-TDP and AD pathologies were most likely to have contributed to the language and behavior abnormalities while the PSP pathology was most likely to have contributed to the movement disorder. This patient shows that in old age, cognitive impairments are likely to reflect complex interactions of multiple etiologic factors, each of which may have a differential contribution to the overall clinical picture. The results emphasize the importance of following recommended guidelines for evaluating all pathologies present in brains from those with dementia of any type, and for careful clinicopathologic correlation.
American Association of Neuropathologists, 2015., Denver, Colorado; 01/2015
[Show abstract][Hide abstract] ABSTRACT: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden.
Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources.
Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies).
The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673.
The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.
[Show abstract][Hide abstract] ABSTRACT: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
[Show abstract][Hide abstract] ABSTRACT: Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.
[Show abstract][Hide abstract] ABSTRACT: Objective:
The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials.
Changes in cortical thickness and volume loss as well as neuropsychological performance were assessed at baseline and 2-year follow-up in 26 patients who fulfilled criteria for logopenic (8 patients), agrammatic (10 patients), and semantic (8 patients) PPA subtypes. Whole-brain vertex-wise and ROI imaging analysis were conducted using the FreeSurfer longitudinal pipeline.
Clinical deficits and cortical atrophy patterns showed distinct patterns of change among the subtypes over 2 years. Results confirmed that progression for each of the 3 subtypes showed left greater than right hemisphere asymmetry. An ROI analysis also revealed that progression was greater within, rather than outside, the language network.
Preferential neurodegeneration of the left hemisphere language network is a common denominator for all 3 PPA subtypes, even as the disease progresses. Using a focal cortical language network ROI as an outcome measure of disease progression appears to be more sensitive than whole-brain or ventricular volume measures of change and may be helpful for designing future clinical trials in PPA.
[Show abstract][Hide abstract] ABSTRACT: New strategies are needed to help people cope with the repercussions of neurodegenerative disorders such as Alzheimer's disease. Patients and caregivers face different challenges, but here we investigated an intervention tailored for this combined population. The program focused on training skills such as attending to the present moment nonjudgmentally, which may help reduce maladaptive emotional responses. Patients participated together with caregivers in weekly group sessions over 8 weeks. An assessment battery was individually administered before and after the program. Pre-post analyses revealed several benefits, including increased quality-of-life ratings, fewer depressive symptoms, and better subjective sleep quality. In addition, participants indicated that they were grateful for the opportunity to learn to apply mindfulness skills and that they would recommend the program to others. In conclusion, mindfulness training can be beneficial for patients and their caregivers, it can be delivered at low cost to combined groups, and it is worthy of further investigation.
American Journal of Alzheimer s Disease and Other Dementias 08/2014; 30(3). DOI:10.1177/1533317514545377 · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Language facilitates communication and efficient encoding of thought and experience. Because of its essential role in early childhood development, in educational achievement and in subsequent life adaptation, language was included as one of the subdomains in the NIH Toolbox for the Assessment of Neurological and Behavioral Function Cognition Battery (NIHTB-CB). There are many different components of language functioning, including syntactic processing (i.e., morphology and grammar) and lexical semantics. For purposes of the NIHTB-CB, two tests of language-a picture vocabulary test and a reading recognition test-were selected by consensus based on literature reviews, iterative expert input, and a desire to assess in English and Spanish. NIHTB-CB's picture vocabulary and reading recognition tests are administered using computer adaptive testing and scored using item response theory. Data are presented from the validation of the English versions in a sample of adults ages 20-85 years (Spanish results will be presented in a future publication). Both tests demonstrated high test-retest reliability and good construct validity compared to corresponding gold-standard measures. Scores on the NIH Toolbox measures were consistent with age-related expectations, namely, growth in language during early development, with relative stabilization into late adulthood. (JINS, 2014, 20, 1-10).
Journal of the International Neuropsychological Society 06/2014; 20(6):1-10. DOI:10.1017/S1355617714000411 · 2.96 Impact Factor