Gregory A Jicha

University of Kentucky, Lexington, Kentucky, United States

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Publications (115)882.34 Total impact

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    ABSTRACT: The relationship between primary age-related tauopathy (PART) and Alzheimer’s disease (AD) is currently a matter of discussion. Recently the term PART was referred to cases characterized by mainly allocortical neurofibrillary (NF) pathology (Braak stages 0-IV) with only few or no amyloid (Aβ) deposits (Thal Aβ phases 0-2) [49]. In addition, no elevated soluble Aβ was detected in this disorder [9, 46]. PART cases that lack any Aβ do not meet formal criteria for sporadic AD according to the NIA-AA guidelines [35]. These neurofibrillary tangle (NFT)+/Aβ-brains are commonly observed in extreme old age [9, 15, 19]. When associated with a high density of NFTs in the same distribution and some cognitive deficits, the disorder has been referred to as tangle-predominant senile dementia (TPSD) [27] or “tangle-only dementia” [55].The new neuropathologic criteria recommend subdividing PART cases into “definite” (Braak stage ≤IV, Thal Aβ phase 0) and “possible” (Braak stage ≤IV, Thal Aβ phase 1-2) ...
    Acta Neuropathologica 03/2015; DOI:10.1007/s00401-015-1407-2 · 9.78 Impact Factor
  • Peter T Nelson, Gregory A Jicha
    JAMA Neurology 03/2015; DOI:10.1001/jamaneurol.2015.34 · 7.01 Impact Factor
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    ABSTRACT: Recently, Sugihara proposed an innovative causality concept, which, in contrast to statistical predictability in Granger sense, characterizes underlying deterministic causation of the system. This work exploits Sugihara causality analysis to develop novel EEG biomarkers for discriminating normal aging from mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The hypothesis of this work is that scalp EEG based causality measurements have different distributions for different cognitive groups and hence the causality measurements can be used to distinguish between NC, MCI, and AD participants. The current results are based on 30-channel resting EEG records from 48 age-matched participants (mean age 75.7 years) - 15 normal controls (NCs), 16 MCI, and 17 early-stage AD. First, a reconstruction model is developed for each EEG channel, which predicts the signal in the current channel using data of the other 29 channels. The reconstruction model of the target channel is trained using NC, MCI, or AD records to generate an NC-, MCI-, or AD-specific model, respectively. To avoid over fitting, the training is based on the leave-one-out principle. Sugihara causality between the channels is described by a quality score based on comparison between the reconstructed signal and the original signal. The quality scores are studied for their potential as biomarkers to distinguish between the different cognitive groups. First, the dimension of the quality scores is reduced to two principal components. Then, a three-way classification based on the principal components is conducted. Accuracies of 95.8%, 95.8%, and 97.9% are achieved for resting eyes open, counting eyes closed, and resting eyes closed protocols, respectively. This work presents a novel application of Sugihara causality analysis to capture characteristic changes in EEG activity due to cognitive deficits. The developed method has excellent potential as individualized biomarkers in the detection of pathophysiological changes in early-stage AD.
    01/2015; 7:258-65. DOI:10.1016/j.nicl.2014.12.005
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    ABSTRACT: Mild cognitive impairment (MCI) is a neurological condition related to early stages of dementia including Alzheimer's disease (AD). This study investigates the potential of measures of transfer entropy in scalp EEG for effectively discriminating between normal aging, MCI, and AD participants. Resting EEG records from 48 age-matched participants (mean age 75.7 years)-15 normal controls, 16 MCI, and 17 early AD-are examined. The mean temporal delays corresponding to peaks in inter-regional transfer entropy are computed and used as features to discriminate between the three groups of participants. Three-way classification schemes based on binary support vector machine models demonstrate overall discrimination accuracies of 91.7- 93.8%, depending on the protocol condition. These results demonstrate the potential for EEG transfer entropy measures as biomarkers in identifying early MCI and AD. Moreover, the analyses based on short data segments (two minutes) render the method practical for a primary care setting.
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    ABSTRACT: The Boston Naming Test (BNT) is a commonly used neuropsychological test of confrontation naming that aids in determining the presence and severity of dysnomia. Many short versions of the original 60-item test have been developed and are routinely administered in clinical/research settings. Because of the common need to translate similar measures within and across studies, it is important to evaluate the operating characteristics and agreement of different BNT versions. We analyzed longitudinal data of research volunteers (n = 681) from the University of Kentucky Alzheimer's Disease Center longitudinal cohort. With the notable exception of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) 15-item BNT, short forms were internally consistent and highly correlated with the full version; these measures varied by diagnosis and generally improved from normal to mild cognitive impairment (MCI) to dementia. All short forms retained the ability to discriminate between normal subjects and those with dementia. The ability to discriminate between normal and MCI subjects was less strong for the short forms than the full BNT, but they exhibited similar patterns. These results have important implications for researchers designing longitudinal studies, who must consider that the statistical properties of even closely related test forms may be quite different. © 2015 S. Karger AG, Basel.
    Dementia and Geriatric Cognitive Disorders 01/2015; 39(3-4):215-27. DOI:10.1159/000370108 · 2.81 Impact Factor
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    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.
    JAMA Neurology 12/2014; DOI:10.1001/jamaneurol.2014.2157 · 7.01 Impact Factor
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    ABSTRACT: Introduction The Uniform Data Set (UDS) neuropsychological battery is frequently used in clinical studies. However, practice effects, effectiveness as a measure of global cognitive functioning, and detection of mild cognitive impairment have not been examined. Methods A normative total score for the UDS has been developed. Linear discriminant analysis determined classification accuracy in identifying cognitively normal and impaired groups. Practice effects were examined in cognitively normal and cognitively impaired groups. Results The total score differentiates between cognitively normal participants and those with dementia, but does not accurately identify individuals with mild cognitive impairment (MCI). Mean total scores for test-exposed participants were significantly higher than test-naive participants in both the normal and MCI groups and were higher, but not significantly so, in the dementia group. Conclusion The total score’s classification accuracy discriminates between cognitively normal versus participants who have dementia. The total score appears subject to practice effects.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 11/2014; DOI:10.1016/j.jalz.2013.11.007 · 17.47 Impact Factor
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    ABSTRACT: We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
    Acta Neuropathologica 10/2014; DOI:10.1007/s00401-014-1349-0 · 9.78 Impact Factor
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    Arun Swaminathan, Gregory A Jicha
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    ABSTRACT: A nutritional approach to prevent, slow, or halt the progression of disease is a promising strategy that has been widely investigated. Much epidemiologic data suggests that nutritional intake may influence the development and progression of Alzheimer's dementia (AD). Modifiable, environmental causes of AD include potential metabolic derangements caused by dietary insufficiency and or excess that may be corrected by nutritional supplementation and or dietary modification. Many nutritional supplements contain a myriad of health promoting constituents (anti-oxidants, vitamins, trace minerals, flavonoids, lipids, …etc.) that may have novel mechanisms of action affecting cellular health and regeneration, the aging process itself, or may specifically disrupt pathogenic pathways in the development of AD. Nutritional modifications have the advantage of being cost effective, easy to implement, socially acceptable and generally safe and devoid of significant adverse events in most cases. Many nutritional interventions have been studied and continue to be evaluated in hopes of finding a successful agent, combination of agents, or dietary modifications that can be used for the prevention and or treatment of AD. The current review focuses on several key nutritional compounds and dietary modifications that have been studied in humans, and further discusses the rationale underlying their potential utility for the prevention and treatment of AD.
    Frontiers in Aging Neuroscience 10/2014; 6:282. DOI:10.3389/fnagi.2014.00282 · 2.84 Impact Factor
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    ABSTRACT: We assessed salience of subjective memory complaints (SMCs) by older individuals as a predictor of subsequent cognitive impairment while accounting for risk factors and eventual neuropathologies.
    Neurology 09/2014; DOI:10.1212/WNL.0000000000000856 · 8.30 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P926. DOI:10.1016/j.jalz.2014.07.146 · 17.47 Impact Factor
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    ABSTRACT: In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
    The Lancet Neurology 06/2014; 13(6-6):614-29. DOI:10.1016/S1474-4422(14)70090-0 · 21.82 Impact Factor
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    ABSTRACT: Mild cognitive impairment (MCI) is a neurological condition that is often the early stage of Alzheimer's disease (AD). This pilot study explores event-related multiscale entropy (MSE) measures as features for effectively discriminating between normal aging, MCI, and AD participants. Thirty two-channel scalp EEG records recorded during a working memory task from 43 age-matched participants (mean age 75.7 years)-17 normal controls (NC), 16 MCI, and 10 early ADare examined. Multiscale entropy curves are computed for responses during the working memory task. Support vector machine models are constructed to perform binary discriminations among the three groups. Leave-one-out cross-validation accuracies of 87.9% (p-value <1.322E-4) for MCI vs. NC, 88.9% (p-value <2.886E-5) for AD vs. NC, and 92.3% (p-value <4.910E-6) for MCI vs. AD are achieved. Results demonstrate links between event-related multiscale entropy dynamics of EEG and short-term memory deficits.
    2014 Annual Oak Ridge National Laboratory Biomedical Science and Engineering Center Conference (BSEC); 05/2014
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    ABSTRACT: Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.
    Acta Neuropathologica 04/2014; DOI:10.1007/s00401-014-1282-2 · 9.78 Impact Factor
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    ABSTRACT: Amnestic mild cognitive impairment (aMCI) often is an early stage of Alzheimer's disease (AD). MCI is characterized by cognitive decline departing from normal cognitive aging but that does not significantly interfere with daily activities. This study explores the potential of scalp EEG for early detection of alterations from cognitively normal status of older adults signifying MCI and AD. Resting 32-channel EEG records from 48 age-matched participants (mean age 75.7 years)—15 normal controls (NC), 16 early MCI, and 17 early stage AD—are examined. Regional spectral and complexity features are computed and used in a support vector machine model to discriminate between groups. Analyses based on three-way classifications demonstrate discrimination accuracies of 83.9%-96.8% for MCI vs. NC (p-value < 0.0029), 71.9%-96.9% for AD vs. NC (p-value < 0.0333), and 87.9%-90.9% for AD vs. MCI (p-value < 0.0136), depending on the EEG protocol condition employed. These results demonstrate the great promise for scalp EEG spectral and complexity features as noninvasive biomarkers for detection of MCI and early AD.
    Computer methods and programs in biomedicine 04/2014; DOI:10.1016/j.cmpb.2014.01.019 · 1.09 Impact Factor
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    ABSTRACT: Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease after the age of 40 years. To detect white matter (WM) changes in the brain linked to dementia, fractional anisotropy (FA) from diffusion tensor imaging was used. We hypothesized that adults with DS without dementia (DS n = 10), DS with dementia (DSAD n = 10) and age matched non-DS subjects (CTL n = 10) would show differential levels of FA and an association with scores from the Brief Praxis Test and the Severe Impairment Battery. WM integrity differences in DS compared with CTL were found predominantly in the frontal lobes. Across all DS adults, poorer Brief Praxis Test performance correlated with reduced FA in the corpus callosum as well as several association tracts, primarily within frontoparietal regions. Our results demonstrate significantly lower WM integrity in DS compared with controls, particularly in the frontal tracts. DS-related WM integrity reductions in a number of tracts were associated with poorer cognition. These preliminary results suggest that late myelinating frontal pathways may be vulnerable to aging in DS.
    Neurobiology of aging 02/2014; 35(7). DOI:10.1016/j.neurobiolaging.2014.01.137 · 4.85 Impact Factor
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    ABSTRACT: Aims: To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimer's disease (AD)-type pathological changes. Methods: Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (n = 649) were analyzed to assess the chronic effects of self-reported head injury. Results: The effect of self-reported head injury on the clinical state depended on the age at assessment: for a 1-year increase in age, the OR for the transition to clinical mild cognitive impairment (MCI) at the next visit for participants with a history of head injury was 1.21 and 1.34 for the transition from MCI to dementia. Without respect to age, head injury increased the odds of mortality (OR = 1.54). Moreover, it increased the odds of a pathological diagnosis of AD for men (OR = 1.47) but not women (OR = 1.18). Men with a head injury had higher mean amyloid plaque counts in the neocortex and entorhinal cortex than men without. Conclusions: Self-reported head injury is associated with earlier onset, increased risk of cognitive impairment and dementia, increased risk of mortality, and AD-type pathological changes. © 2013 S. Karger AG, Basel.
    Dementia and Geriatric Cognitive Disorders 12/2013; 37(5-6):294-306. DOI:10.1159/000355478 · 2.81 Impact Factor
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    ABSTRACT: This study investigated the effects of early- to midlife musical training on cognition in older adults. A musical training survey examined self-reported musical experience and objective knowledge in 237 cognitively intact participants. Responses were classified into low-, medium-, and high-knowledge groups. Linear mixed models compared the groups' longitudinal performance on the Animal Naming Test (ANT; semantic verbal fluency) and Logical Memory Story A Immediate Recall (LMI; episodic memory) controlling for baseline age, time since baseline, education, sex, and full-scale IQ. Results indicate that high-knowledge participants had significantly higher LMI scores at baseline and over time compared to low-knowledge participants. The ANT scores did not differ among the groups. Ability to read music was associated with higher mean scores for both ANT and LMI over time. Early- to midlife musical training may be associated with improved late-life episodic and semantic memory as well as a useful marker of cognitive reserve.
    American Journal of Alzheimer s Disease and Other Dementias 12/2013; 29(4). DOI:10.1177/1533317513517048 · 1.43 Impact Factor
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    ABSTRACT: Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer's Disease Centre, Nun Study, and National Alzheimer's Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case-control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P < 0.001). This enables informative evaluation of anatomical regions outside of the hippocampus. To assess the morphology of brain microvasculature far more rigorously than what is possible using semi-quantitative pathological scoring, we applied digital pathological (Aperio ScanScope) methods on a subsample of frontal cortex sections from hippocampal sclerosis of ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0.03), and larger vessel areas (P < 0.03) than controls. Unlike the arterioles, CD34-immunoreactive capillaries had dimensions that were unchanged in cases with hippocampal sclerosis of ageing versus controls. Arteriolosclerosis appears specific to hippocampal sclerosis of ageing brains, because brains with Alzheimer's disease pathology did not show the same morphological alterations. We conclude that there may be a pathogenetic change in aged human brain arterioles that impacts multiple brain areas and contributes to hippocampal sclerosis of ageing.
    Brain 11/2013; DOI:10.1093/brain/awt318 · 10.23 Impact Factor
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    ABSTRACT: Study of repeated learning mechanisms has been limited in amnestic mild cognitive impairment, a preclinical stage of Alzheimer disease modifiable by cognitive rehabilitation. We assessed repeated contextual working memory decline as an indicator of amnestic mild cognitive impairment in a sample of 45 older adults recruited from the tertiary care setting. Results indicated that contextual working memory impairment distinguished adults with preclinical disease from those without impairment despite similar overall cognitive performance, and comparison of the indicator with standard-of-care neuropsychological measures indicated discriminant validity. Contextual working memory impairment may represent a novel predictor of Alzheimer disease conversion risk.
    Journal of Clinical and Experimental Neuropsychology 09/2013; DOI:10.1080/13803395.2013.838942 · 2.16 Impact Factor

Publication Stats

6k Citations
882.34 Total Impact Points


  • 2007–2015
    • University of Kentucky
      • • Sanders-Brown Center on Aging
      • • Department of Neurology
      Lexington, Kentucky, United States
  • 2004–2008
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 1997–2002
    • Albert Einstein College of Medicine
      • Department of Pathology
      New York City, New York, United States