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1.  Dementia in Down’s syndrome: an MRI comparison with Alzheimer’s disease in the general population 
Down’s syndrome (DS) is the most common genetic cause of intellectual disability. People with DS are at an increased risk of Alzheimer’s disease (AD) compared to the general population. Neuroimaging studies of AD have focused on medial temporal structures; however, to our knowledge, no in vivo case–control study exists comparing the anatomy of dementia in DS to people with AD in the general population. We therefore compared the in vivo brain anatomy of people with DS and dementia (DS+) to those with AD in the general population.
Using MRI in 192 adults, we compared the volume of whole brain matter, lateral ventricles, temporal lobes and hippocampus in DS subjects with and without dementia (DS+, DS-), to each other and to three non-DS groups. These included one group of individuals with AD and two groups of controls (each age-matched for their respective DS and general population AD cohorts).
AD and DS+ subjects showed significant reductions in the volume of the whole brain, hippocampus and temporal lobes and a significant elevation in the volume of the lateral ventricle, compared to their non-demented counterparts. People with DS+ had a smaller reduction in temporal lobe volume compared to individuals with AD.
DS+ and AD subjects have a significant reduction in volume of the same brain regions. We found preliminary evidence that DS individuals may be more sensitive to tissue loss than others and have less ‘cognitive reserve’.
PMCID: PMC3765707  PMID: 23962297
Dementia; Imaging; Intellectual disability
2.  Cognitive and Anatomic Contributions of Metabolic Decline in Alzheimer Disease and Cerebrovascular Disease 
Archives of neurology  2008;65(5):650-655.
Alzheimer disease and cerebrovascular disease affect elderly persons through alterations in brain structure and metabolism that produce cognitive decline. Understanding how each disease contributes to dementia is essential from both a pathophysiologic and diagnostic perspective.
To elucidate how baseline cognitive function (episodic memory and executive function) and brain anatomy (white matter hyperintensities and hippocampal volume) are associated with baseline (positron emission tomography-1 [PET1]) and longitudinal (PET2) glucose metabolism in 38 subjects older than 55 years ranging from normal cognition, cognitive impairment without dementia, and dementia.
Cross-sectional regression analyses across subjects.
Multicenter, university-based study of subcortical vascular dementia.
Main Outcome Measures:
Regional cerebral glucose metabolism was the primary outcome, with the major hypotheses that memory and hippocampal volume are related to temporoparietal hypometabolism while executive function and white matter hyperintensities correlate with frontal lobe hypometabolism.
Low baseline hippocampal volume predicted longitudinal development (PET2) of medial temporal hypometabolism. Lower memory was associated with parietal and cingulate hypometabolism at PET1, which increased at the 2-year-follow-up (PET2). Executive function was associated with frontal and temporoparietal hypometabolism at PET1 but only with frontal hypometabolism at follow-up. White matter hyperintensities predicted hypometabolism over time in the frontoparietal regions, predicting a rate of metabolic change (PET1−PET2/time).
Low baseline episodic memory and hippocampal volume predict the metabolic alterations associated with Alzheimer disease, whereas elevated baseline white matter hyperintensities predict a different pattern of metabolic decline that is plausibly associated with cerebrovascular disease.
PMCID: PMC2556212  PMID: 18474742
3.  Another VCP interactor: NF is enough 
The Journal of Clinical Investigation  2011;121(12):4627-4630.
Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. How missense mutations in this abundant, ubiquitously expressed, multifunctional protein lead to the degeneration of disparate tissues is unclear. VCP participates in diverse cellular functions by associating with an expanding collection of substrates and cofactors that dictate its functionality. In this issue of the JCI, Wang and colleagues have further expanded the VCP interactome by identifying neurofibromin-1 (NF1) as a novel VCP interactor in the CNS. IBMPFD-associated mutations disrupt binding of VCP to NF1, resulting in reduced synaptogenesis. Thus, aberrant interactions between VCP and NF1 may explain the dementia phenotype and cognitive delay observed in patients with IBMPFD and neurofibromatosis type 1.
PMCID: PMC3226341  PMID: 22105166
4.  A Case of Generalized Auditory Agnosia with Unilateral Subcortical Brain Lesion 
Annals of Rehabilitation Medicine  2012;36(6):866-870.
The mechanisms and functional anatomy underlying the early stages of speech perception are still not well understood. Auditory agnosia is a deficit of auditory object processing defined as a disability to recognize spoken languages and/or nonverbal environmental sounds and music despite adequate hearing while spontaneous speech, reading and writing are preserved. Usually, either the bilateral or unilateral temporal lobe, especially the transverse gyral lesions, are responsible for auditory agnosia. Subcortical lesions without cortical damage rarely causes auditory agnosia. We present a 73-year-old right-handed male with generalized auditory agnosia caused by a unilateral subcortical lesion. He was not able to repeat or dictate but to perform fluent and comprehensible speech. He could understand and read written words and phrases. His auditory brainstem evoked potential and audiometry were intact. This case suggested that the subcortical lesion involving unilateral acoustic radiation could cause generalized auditory agnosia.
PMCID: PMC3546192  PMID: 23342322
Auditory agnosia; Unilateral subcortical lesion
5.  Utilizing Descriptive Statements from the Biodiversity Heritage Library to Expand the Hymenoptera Anatomy Ontology 
PLoS ONE  2013;8(2):e55674.
Hymenoptera, the insect order that includes sawflies, bees, wasps, and ants, exhibits an incredible diversity of phenotypes, with over 145,000 species described in a corpus of textual knowledge since Carolus Linnaeus. In the absence of specialized training, often spanning decades, however, these articles can be challenging to decipher. Much of the vocabulary is domain-specific (e.g., Hymenoptera biology), historically without a comprehensive glossary, and contains much homonymous and synonymous terminology. The Hymenoptera Anatomy Ontology was developed to surmount this challenge and to aid future communication related to hymenopteran anatomy, as well as provide support for domain experts so they may actively benefit from the anatomy ontology development. As part of HAO development, an active learning, dictionary-based, natural language recognition tool was implemented to facilitate Hymenoptera anatomy term discovery in literature. We present this tool, referred to as the ‘Proofer’, as part of an iterative approach to growing phenotype-relevant ontologies, regardless of domain. The process of ontology development results in a critical mass of terms that is applied as a filter to the source collection of articles in order to reveal term occurrence and biases in natural language species descriptions. Our results indicate that taxonomists use domain-specific terminology that follows taxonomic specialization, particularly at superfamily and family level groupings and that the developed Proofer tool is effective for term discovery, facilitating ontology construction.
PMCID: PMC3575469  PMID: 23441153
6.  Speech Recognition as a Transcription Aid: A Randomized Comparison With Standard Transcription 
Objective. Speech recognition promises to reduce information entry costs for clinical information systems. It is most likely to be accepted across an organization if physicians can dictate without concerning themselves with real-time recognition and editing; assistants can then edit and process the computer-generated document. Our objective was to evaluate the use of speech-recognition technology in a randomized controlled trial using our institutional infrastructure.
Design. Clinical note dictations from physicians in two specialty divisions were randomized to either a standard transcription process or a speech-recognition process. Secretaries and transcriptionists also were assigned randomly to each of these processes.
Measurements. The duration of each dictation was measured. The amount of time spent processing a dictation to yield a finished document also was measured. Secretarial and transcriptionist productivity, defined as hours of secretary work per minute of dictation processed, was determined for speech recognition and standard transcription.
Results. Secretaries in the endocrinology division were 87.3% (confidence interval, 83.3%, 92.3%) as productive with the speech-recognition technology as implemented in this study as they were using standard transcription. Psychiatry transcriptionists and secretaries were similarly less productive. Author, secretary, and type of clinical note were significant (p < 0.05) predictors of productivity.
Conclusion. When implemented in an organization with an existing document-processing infrastructure (which included training and interfaces of the speech-recognition editor with the existing document entry application), speech recognition did not improve the productivity of secretaries or transcriptionists.
PMCID: PMC150361  PMID: 12509359
7.  Total hip arthroplasty in developmental dysplasia of the hip: Review of anatomy, techniques and outcomes 
World Journal of Orthopedics  2012;3(5):42-48.
Total hip arthroplasty (THA) in developmental dysplasia of the hip (DDH) presents many challenges to the reconstructive surgeon. The complex femoral and acetabular anatomy makes standard reconstruction technically challenging. Acetabular coverage can be improved by medialization of the component or augmentation of the deficient areas with bone graft. Femoral shortening osteotomies are considered in cases of severe dysplasia and frankly dislocated hips. Each patient’s unique anatomy dictates what options of reconstruction are available. The functional outcomes of THA in DDH are generally excellent, though higher rates of mechanical failure have been reported in this group. This article reviews the anatomy, classification, technical considerations, and outcomes of THA in patients with DDH.
PMCID: PMC3364316  PMID: 22655221
Developmental dysplasia of the hip; Total hip arthroplasty; Hip; Arthritis; Hip replacement
8.  MR Imaging Anatomy in Neurodegeneration: A Robust Volumetric Parcellation Method of the Frontal Lobe Gyri with Quantitative Validation in Patients with Dementia 
Brain volumetry is widely used for evaluating tissue degeneration; however, the parcellation methods are rarely validated and use arbitrary planes to mark boundaries of brain regions. The goal of this study was to develop, validate, and apply an MR imaging tracing method for the parcellation of 3 major gyri of the frontal lobe, which uses only local landmarks intrinsic to the structures of interest, without the need for global reorientation or the use of dividing planes or lines.
Studies were performed on 25 subjects—healthy controls and subjects diagnosed with Lewy body dementia and Alzheimer disease—with significant variation in the underlying gyral anatomy and state of atrophy. The protocol was evaluated by using multiple observers tracing scans of subjects diagnosed with neurodegenerative disease and those aging normally, and the results were compared by spatial overlap agreement. To confirm the results, observers marked the same locations in different brains. We illustrated the variabilities of the key boundaries that pose the greatest challenge to defining consistent parcellations across subjects.
The resulting gyral volumes were evaluated, and their consistency across raters was used as an additional assessment of the validity of our marking method. The agreement on a scale of 0–1 was found to be 0.83 spatial and 0.90 volumetric for the same rater and 0.85 spatial and 0.90 volumetric for 2 different raters. The results revealed that the protocol remained consistent across different neurodegenerative conditions.
Our method provides a simple and reliable way for the volumetric evaluation of frontal lobe neurodegeneration and can be used as a resource for larger comparative studies as well as a validation procedure of automated algorithms.
PMCID: PMC1829312  PMID: 16971629
9.  Molecular Characterization of Novel Progranulin (GRN) Mutations in Frontotemporal Dementia 
Human mutation  2008;29(4):512-521.
Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6–2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.
PMCID: PMC2756561  PMID: 18183624
Frontotemporal dementia; FTD; granulin; progranulin; GRN; PGRN
10.  Frail elderly patients with dementia go too fast 
The reason why patients with dementia fall more often and sustain more fractures than patients without dementia remains unclear. Therefore, the relationship between dementia and gait velocity as a marker for mobility and falls in a cohort of frail elderly (mean age of 77.3 years) inpatients was assessed. Patients with dementia were expected to walk slower than patients without dementia. A trend was indeed observed: absolute gait velocity of 0.59 m/s in patients with dementia (n = 63) versus 0.65 m/s in patients without dementia (n = 62; p = 0.19). After adjustment for parkinsonism and walking aids, however, patients with dementia walked 0.44 m/s faster than patients without dementia (p = 0.02). Probable explanations are frontal lobe disinhibition and lack of insight, causing patients with dementia to walk relatively too fast in the context of their frailty. Therefore, the high risk of falls in dementia may be partially explained by the loss of control of gait velocity.
PMCID: PMC2117489  PMID: 16788015
11.  Neurotrophin-3–enhanced Nerve Regeneration Selectively Improves Recovery of Muscle Fibers Expressing Myosin Heavy Chains 2b  
The Journal of Cell Biology  1997;139(3):709-715.
The purpose of this study was to evaluate the effect of neurotrophin 3 (NT-3) enhanced nerve regeneration on the reinnervation of a target muscle. Muscle fibers can be classified according to their mechanical properties and myosin heavy chain (MHC) isoform composition. MHC1 containing slow-type and MHC2a or 2b fast-type fibers are normally distributed in a mosaic pattern, their phenotype dictated by motor innervation. After denervation, all fibers switch to fast-type MHC2b expression and also undergo atrophy resulting in loss of muscle mass. After regeneration, discrimination between fast and slow fibers returns, but the distribution and fiber size change according to the level of reinnervation.
In this study, rat gastrocnemius muscles (ipsilateral and contralateral to the side of nerve injury) were collected up to 8 mo after nerve repair, with or without local delivery of NT-3. The phenotype changes of MHC1, 2a, and 2b were analyzed by immunohistochemistry, and fiber type proportion, diameter, and grouping were assessed by computerized image analysis. At 8 mo, the local delivery of NT-3 resulted in significant improvement in gastrocnemius muscle weight compared with controls (NT-3 group 47%, controls 39% weight of contralateral normal muscle; P < 0.05). NT-3 delivery resulted in a significant increase in the proportion (NT-3 43.3%, controls 35.7%; P < 0.05) and diameter (NT-3 87.8 μm, controls 70.8 μm; P < 0.05) of fast type 2b fibers after reinnervation. This effect was specific to type 2b fibers; no normalization was seen in other fiber types.
This study indicates that NT-3–enhanced axonal regeneration has a beneficial effect on the motor target organ. Also, NT-3 may be specifically affecting a subset of motoneurons that determine type 2b muscle fiber phenotype. As NT-3 was topically applied to cut nerves, our data suggest a discriminating effect of the neurotrophin on neuro–muscular interaction. These results would imply that muscle fibers may be differentially responsive to other neurotrophic factors and indicate the potential clinical role of NT-3 in the prevention of muscle atrophy after nerve injury.
PMCID: PMC2141699  PMID: 9348287
12.  Anterolateral Thigh Flow-Through Flap in Hand Salvage 
Eplasty  2013;13:e19.
Objective: Hand salvage and reconstruction following trauma and oncologic resection often dictates the use of innovative reconstructive techniques. Preservation of functional anatomy is paramount to success in this clinical setting. Further constraints are placed on the reconstructive surgeon in the setting of the aging US population. We report a case of successful hand salvage in an elderly patient using a free anterolateral thigh flow-through flap. Methods: A retrospective chart review was performed on prospectively entered data to examine the case in detail. Indications, radiographs, and follow-up visits were reviewed. A free anterolateral thigh flap was harvested and used to provide soft tissue coverage as well as reconstruction of the palmar arch. Results: The free anterolateral thigh flap not only reconstructed the unique soft tissue envelope of the hand but also restored functional vascular anatomy by reconstituting the interrupted superficial palmar arch. The patient had an uneventful hospital course and was discharged without complications. Conclusions: The free anterolateral thigh flap is a versatile flap that can be used as an innovative solution for hand salvage where vascular anatomy and soft tissue need to be restored.
PMCID: PMC3624776  PMID: 23641298
13.  Analgesic use, pain and daytime sedation in people with and without dementia in aged care facilities: a cross-sectional, multisite, epidemiological study protocol 
BMJ Open  2014;4(6):e005757.
People living with dementia may experience and express pain in different ways to people without dementia. People with dementia are typically prescribed fewer analgesics than people without dementia indicating a potential difference in how pain is identified and treated in these populations. The objectives of this study are to (1) investigate the prevalence of analgesic load, pain and daytime sedation in people with and without dementia in Australian residential aged care facilities (RACFs), and (2) investigate the clinical and diagnostic associations between analgesic load, pain and daytime sedation in people with and without dementia in Australian RACFs.
This will be a cross-sectional study of 300 permanent residents of up to 10 low-level and high-level RACFs in South Australia with and without dementia. Trained study nurses will administer validated and dementia-specific assessments of self-reported and clinician-observed pain, sedation and other clinical and humanistic outcomes. Medicine-use data will be extracted directly from each resident's medication administration chart. Binary and multinominal logistic regression will be used to compute unadjusted and adjusted ORs and 95% CIs for factors associated with pain, analgesic load and daytime sedation. These factors will include dementia severity, behavioural and psychological symptoms, quality of life, resident satisfaction, attitudes towards medicines, activities of daily living and nutritional status.
Ethics and dissemination
Institutional ethics approval has been granted. The findings will be disseminated through public lectures, professional and scientific conferences and in peer-reviewed journal articles. The findings of this study will allow for a better understanding of the prevalence and factors associated with analgesic use, pain and other outcomes in residential care. The findings of this study will be used to inform the development and implementation of strategies to improve the quality of life of people with dementia.
PMCID: PMC4067818  PMID: 24948752
Epidemiology; Geriatric Medicine; Pain Management
14.  A novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family☆ 
Neurobiology of Aging  2013;34(12):2890.e1-2890.e5.
Triggering receptor expressed on myeloid cells 2 (TREM2) homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has recently been shown to cause frontotemporal dementia (FTD) without the presence of any bone phenotype. Here, we further confirm the association of TREM2 mutations with FTD-like phenotypes by reporting the first compound heterozygous mutation in a Turkish family.
PMCID: PMC3898264  PMID: 23870839
TREM2; Nasu-Hakola; Frontotemporal dementia; Compound heterozygous
15.  Survival of people with clinical diagnosis of dementia in primary care: cohort study 
Objectives To estimate survival after a diagnosis of dementia in primary care, compared with people without dementia, and to determine incidence of dementia.
Design Cohort study using data from The Health Improvement Network (THIN), a primary care database.
Setting 353 general practices in the United Kingdom providing data to THIN.
Participants All adults aged 60 years or over with a first ever code for dementia from 1990 to 2007 (n=22 529); random sample of five participants without dementia for every participant with dementia matched on practice and time period (n=112 645).
Main outcome measures Median survival by age and sex; mortality rates; incidence of dementia by age, sex, and deprivation.
Results The median survival of people with dementia diagnosed at age 60-69 was 6.7 (interquartile range 3.1-10.8) years, falling to 1.9 (0.7-3.6) years for those diagnosed at age 90 or over. Adjusted mortality rates were highest in the first year after diagnosis (relative risk 3.68, 95% confidence interval 3.44 to 3.94). This dropped to 2.49 (2.29 to 2.71) in the second year. The incidence of recorded dementia remained stable over time (3-4/1000 person years at risk). The incidence was higher in women and in younger age groups (60-79 years) living in deprived areas.
Conclusions Median survival was much lower than in screened populations. These clinically relevant estimates can assist patients and carers, clinicians, and policy makers when planning support for this population. The high risk of death in the first year after diagnosis may reflect diagnoses made at times of crisis or late in the disease trajectory. Late recording of diagnoses of dementia in primary care may result in missed opportunities for potential early interventions.
PMCID: PMC2917003  PMID: 20688840
16.  Patterns of striatal degeneration in frontotemporal dementia 
Behavioral variant frontotemporal dementia and semantic dementia have been associated with striatal degeneration, but few studies have delineated striatal subregion volumes in vivo or related them to clinical phenotype. We traced caudate, putamen, and nucleus accumbens on MR images to quantify volumes of these structures in behavioral variant frontotemporal dementia, semantic dementia, Alzheimer’s disease, and healthy controls (n = 12 per group). We further related these striatal volumes to clinical deficits and neuropathological findings in a subset of patients. Behavioral variant frontotemporal dementia and semantic dementia showed significant overall striatal atrophy compared with controls. Moreover, behavioral variant frontotemporal dementia showed panstriatal degeneration whereas semantic dementia featured a more focal pattern involving putamen and accumbens. Right-sided striatal atrophy, especially in the putamen, correlated with overall behavioral symptom severity and with specific behavioral domains. At autopsy, patients with behavioral variant frontotemporal dementia and semantic dementia showed striking and severe tau or TAR DNA-binding protein of 43 kDa pathology, especially in ventral parts of the striatum. These results demonstrate that ventral striatum degeneration is a prominent shared feature in behavioral variant frontotemporal dementia and semantic dementia and may contribute to social-emotional deficits common to both disorders.
PMCID: PMC3389579  PMID: 22367382
17.  Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort 
Neurology  2009;73(22):1866-1872.
The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population.
A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia.
A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7.
Stroke patients with cognitive impairment no dementia (CIND) moderate are at higher risk of developing dementia, while CIND mild patients are not at increased risk of developing dementia.
= Alzheimer disease;
= area under the curve;
= confidence interval;
= cognitive impairment no dementia;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= European Australasian Stroke Prevention in Reversible Ischemia Trial;
= European Australasian Stroke Prevention in Reversible Ischemia Trial, cognitive substudy;
= hazard ratio;
= lacunar infarct;
= mild cognitive impairment;
= modified Rankin scale;
= no cognitive impairment;
= Oxfordshire Community Stroke Project;
= partial anterior circulation infarct;
= posterior circulation infarct;
= receiver operating curve;
= total anterior circulation infarct;
= vascular dementia;
= Wechsler Adult Intelligence Scale–Revised;
= Wechsler Memory Scale–Revised.
PMCID: PMC2788800  PMID: 19949033
18.  Impact of Dementia on Payments for Long-term and Acute Care in an Elderly Cohort 
Medical care  2013;51(7):575-581.
Older people with dementia have increased risk of nursing home (NH) use and higher Medicaid payments. Dementia’s impact on acute care use and Medicare payments is less well understood.
Identify trajectories of incident dementia and NH use, and (2) compare Medicare and Medicaid payments for persons having different trajectories.
Research Design
Retrospective cohort of older patients who were screened for dementia in 2000–2004 and were tracked for five years. Trajectories were identified with latent class growth analysis.
3673 low-income persons age 65 or older without dementia at baseline.
Incident dementia diagnosis, comorbid conditions, dual eligibility, acute and long-term care use and payments based on Medicare and Medicaid claims, medical record systems, and administrative data.
Three trajectories were identified based on dementia incidence and short and long-term NH use: (1) high incidence of dementia with heavy NH use (5% of the cohort) averaging $56,111/year ($36,361 Medicare, $19,749 Medicaid); (2) high incidence of dementia with little or no NH use (16% of the cohort) averaging $16,206/year ($14,644 Medicare, $1,562 Medicaid); and (3) low incidence of dementia and little or no NH use (79% of the cohort) averaging $8,475/year ($7,558 Medicare, $917 Medicaid).
Dementia and its interaction with NH utilization are major drivers of publicly financed acute and long-term care payments. Medical providers in accountable care organizations and other health care reform efforts must effectively manage dementia care across the care continuum if they are to be financially viable.
PMCID: PMC3680786  PMID: 23756644
dementia; nursing home; acute care; payment
19.  Students' perception of anatomy education at a Korean medical college with respect to time and contents 
Anatomy & Cell Biology  2013;46(2):157-162.
Among medical education institutions worldwide, the time allotted for anatomy instruction has decreased without any reasonable time optimization suggestions. In addition, the utility of cadaver dissection has long been debated. Herein, we surveyed students' perceptions of anatomy education with respect to time and hands-on cadaver dissection, at Seoul National University College of Medicine. With the help of a questionnaire, we surveyed third- and fourth-year students at our institute who had completed the anatomy module as freshmen as well as their clinical clerkship. At our institute, students complete 50 hours of anatomy lectures and 120 hours of dissection laboratory during their first year. According to the survey responses, they generally considered these durations to be adequate for achieving their anatomy education goals. Almost all the students regarded the dissection laboratory as an essential and most helpful modality. Thus, we suggest that these ranges of time along with cadaver dissection could be useful guidelines for optimized anatomy education. The survey data also indicated that a more clinically oriented anatomy education could improve students' results.
PMCID: PMC3713280  PMID: 23869263
Anatomy education; Cadaver dissection; Korean medical college
20.  Prominent Phenotypic Variability Associated with Mutations in Progranulin 
Neurobiology of aging  2007;30(5):739-751.
Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer’s disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.
PMCID: PMC3164546  PMID: 17949857
Frontotemporal dementia; FTDP-17; Progranulin; PGRN; MRI
21.  Where Vascular meets Neurodegenerative Disease 
Stroke; a journal of cerebral circulation  2010;41(10 Suppl):S144-S146.
Vascular and neurodegenerative disease commonly co-occur in older persons. We review findings from the Rush Religious Orders Study and Memory and Aging Project. Both studies enroll subjects without diagnosed dementia, perform annual evaluations and obtain autopsies proximate to death. We found that macroscopic infarcts are common, lower the threshold for cognitive impairment, and often coexist with Alzheimer’s disease (AD) pathology. We also found that vascular pathology may be associated with memory impairment and may be difficult to distinguish from clinical AD. Finally, because dementia in older persons often results from mixed pathology and the clinical phenotypes overlap, some risk factors may increase risk for clinical AD through an increase in vascular pathology.
PMCID: PMC2967303  PMID: 20876491
22.  Checklist for the Structural Description of the Deep Phenotype in Disorders of Sexual Development 
This paper addresses the question, how the variations of the deep phenotype in disorders of sex development (DSD) are appropriately described. This is a relevant question, because extensive phenotypic variability occurs in gonads and sex ducts. With the advance of video endoscopy and laparoscopy, fresh insight in gonadal and sex duct anatomy is emerging. So far, an attempt to standardize the diagnostic approach and, in particular, how to document these findings has not been published. We propose a standardized examination schedule for these procedures. It consists of 5 pictures of relevant anatomic features. For laparoscopy, it includes two pictures each of gonads and sex ducts on either side and an image of the retrovesical space. For endoscopy, the examination of the ureteric orifices, the posterior urethra, and the urogenital sinus derivates is recommended. Adherence of a standardized schedule and image storing enhances patient autonomy, because they can carry their examination for a second opinion without need for repeated examination. Physicians and scientists create a structured image library that facilitates the comparison of clinical outcomes, research on genotype phenotype associations and may lead to better classifications.
PMCID: PMC3320020  PMID: 22536235
23.  Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI 
NeuroImage  2011;56(3):1251-1258.
With increasing efforts to develop and utilize mouse models of a variety of neuro-developmental diseases, there is an urgent need for sensitive neuroimaging methods that enable in vivo analysis of subtle alterations in brain anatomy and function in mice. Previous studies have shown that the brains of Fibroblast Growth Factor 17 null mutants (Fgf17−/−) have anatomical abnormalities in the inferior colliculus (IC)–the auditory midbrain–and minor foliation defects in the cerebellum. In addition, changes in the expression domains of several cortical patterning genes were detected, without overt changes in forebrain morphology. Recently, it has also been reported that Fgf17−/− mutants have abnormal vocalization and social behaviors, phenotypes that could reflect molecular changes in the cortex and/or altered auditory processing / perception in these mice. We used manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) to analyze the anatomical phenotype of Fgf17−/− mutants in more detail than achieved previously, detecting changes in IC, cerebellum, olfactory bulb, hypothalamus and frontal cortex. We also used MEMRI to characterize sound-evoked activity patterns, demonstrating a significant reduction of the active IC volume in Fgf17−/− mice. Furthermore, tone-specific (16- and 40-kHz) activity patterns in the IC of Fgf17−/− mice were observed to be largely overlapping, in contrast to the normal pattern, separated along the dorsal-ventral axis. These results demonstrate that Fgf17 plays important roles in both the anatomical and functional development of the auditory midbrain, and show the utility of MEMRI for in vivo analyses of mutant mice with subtle brain defects.
PMCID: PMC3085550  PMID: 21356319
MEMRI; DBM; IC; activity mapping; auditory; tonotopic map
24.  Neuropsychological Predictors of Decision-Making Capacity over 9 Months in Mild-to-Moderate Dementia 
Older adults with dementia may have diminished capacity to make medical treatment decisions.
To examine rates and neuropsychological predictors of treatment decision making, or consent capacity, among older adults with dementia over 9 months.
Consent capacity was assessed initially and 9 months later in subjects with and without dementia using a longitudinal repeated measures design.
Fifty-three older adults with dementia and 53 similarly aged adults without dementia.
A standardized measure MacArthur Competence Assessment Tool-Treatment of 4 legal standards for capacity (Understanding, Appreciation, Reasoning, and Expressing a Choice) and a neuropsychological battery.
In the dementia group, 9.4% had impaired capacity initially, and 26.4% had impaired capacity at 9 months. Mean scores in the dementia group were impaired relative to controls initially and at 9 months for Understanding (initial t=2.49, P=.01; 9-month t=3.22, P<.01) and Reasoning (initial t=2.18, P=.03; 9-month t=4.77, P<.01). Declining capacity over 9 months was attributable to a further reduction in Reasoning (group × time F=9.44, P=.003). Discriminant function analysis revealed that initial scores on naming, delayed Logical Memory, and Trails B were associated with impaired capacity at 9 months.
Some patients with mild-to-moderate dementia develop a clinically relevant impairment of consent capacity within a year. Consent capacity in adults with mild-to-moderate dementia should be reassessed periodically to ensure that it is adequate for each specific informed consent situation. Interventions that maximize Understanding and Reasoning by supporting naming, memory, and flexibility may help to optimize capacity in this patient group.
PMCID: PMC1484610  PMID: 16423129
dementia; consent; capacity; competency
25.  Early epileptic seizures after stroke are associated with increased risk of new‐onset dementia 
Subclinical vascular or degenerative lesions occur in the brain before the clinical expression of dementia. Those lesions in a brain that just experienced a stroke may have lower thresholds for early epileptic seizures. Therefore, epileptic seizures may be a marker of subclinical brain lesions, which may lead to dementia.
To test the hypothesis that patients with stroke who have epileptic seizures without dementia have an increased risk of new‐onset dementia.
169 consecutive patients with stroke without pre‐existing dementia recruited in the Lille Stroke/Dementia Study were investigated (90 men; 150 ischaemic strokes; median age 73 years). Pre‐stroke cognitive functions were evaluated with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), with a cut‐off of 104 for the diagnosis of dementia. The patients were followed up over a 3‐year period. Dementia was diagnosed with International Classification of Diseases, 10th revision criteria in survivors who underwent neurological visits, and with the IQCODE score in those who could not. The relationship between epileptic seizures and new‐onset dementia was studied within 3 years, using life‐table methods.
9 patients (5.3%; 95% CI 2.9 to 8.7%) had early seizures. Epileptic seizures were independent predictors of new‐onset dementia within 3 years after stroke (HR 3.81; 95% CI 1.13 to 12.82), with increasing age (HR 1.04; 95% CI 1.01 to 1.08), IQCODE scores at admission (HR 1.08; 95% CI 1.02 to 1.13) and diabetes mellitus (HR 3.52; 95% CI 1.46 to 8.47).
Patients with stroke who have epileptic seizures may be at increased risk of dementia. Whether cognitive follow‐up should be systematically performed in those patients remains to be validated.
PMCID: PMC2117834  PMID: 17435186

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