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1.  Dementia with Lewy Bodies versus Alzheimer's Disease and Parkinson's Disease Dementia: A Comparison of Cognitive Profiles 
Background and Purpose
It is particularly difficult to differentiate dementia with Lewy bodies (DLB) from the related dementias of Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Few studies have been designed to comparatively analyze detailed neuropsychological assessments of DLB patients and patients with AD and PDD.
Three groups of patients participated in this study: 10 with DLB, 76 with AD, and 17 with PDD, who had been diagnosed as probable DLB, AD, and PDD, respectively, according to the clinical criteria of the consortium on DLB, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorder Association, and the clinical diagnostic criteria for PDD. All patients were evaluated by careful neurological examination with detailed neuropsychological testing.
Significant differences among the three groups were found for attention, memory, and executive function, which included tasks of backward digit span, three-word recall, verbal delayed recall, and the Stroop test. Post hoc analysis revealed that the deficiencies of attention on the digit span task were greater in the DLB group than in the AD and PDD groups. The scores for episodic verbal memory tasks were significantly lower in the DLB and AD groups than in the PDD group. The performance in frontal executive function, as indicated by the Stroop test, was significantly worse in the DLB and PDD groups than in the AD group.
The results of the present study show that the pattern of cognitive dysfunction, in terms of attention, episodic memory, and executive functions, differ between patients with DLB and patients with AD and PDD.
PMCID: PMC3079155  PMID: 21519522
dementia with lewy bodies; Alzheimer's disease; Parkinson's disease dementia; cognition; neuropsychology
2.  Severe Episodic Memory Impairment in a Patient With Clinical Features Compatible With Corticobasal Degeneration 
Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder characterized by asymmetric parkinsonism associated with apraxia, cortical sensory loss, and alien-limb phenomenon. Neuropsychological testing in patients with CBD typically shows deficits in executive functions, praxis, language, and visuospatial functioning, but not in memory. We report a CBD patient with severely impaired memory function but relatively mild motor symptoms. Detailed neuropsychological assessment showed significant verbal and visual memory deficits accompanied by frontal executive dysfunctions. Our observations indicate that CBD can in rare cases present with severe episodic memory impairment associated with frontal executive dysfunctions in the early stage of illness.
PMCID: PMC2686868  PMID: 19513310
Corticobasal degeneration; Episodic memory; PET
3.  Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease 
The New England journal of medicine  2014;371(6):530-539.
Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating.
To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons.
PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine.
Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute quantities of PrPSc. (Funded by the National Institutes of Health and others.)
PMCID: PMC4162740  PMID: 25099577
4.  Clinical and Neuropsychological Characteristics of a Nationwide Hospital-Based Registry of Frontotemporal Dementia Patients in Korea: A CREDOS-FTD Study 
We investigated the demographic, clinical, and neuropsychological characteristics of frontotemporal dementia (FTD) from the Clinical Research Center for Dementia of South Korea (CREDOS)-FTD registry.
A total of 200 consecutive patients with FTD recruited from 16 neurological clinics in Korea were evaluated by cognitive and functional assessments, a screening test for aphasia, behavioral questionnaires, motor assessments, and brain MRI or PET.
In our registry, 78 patients were classified as having been diagnosed with behavioral-variant FTD (bvFTD), 70 with semantic dementia (SD), 33 with progressive nonfluent aphasia (PNFA), and 8 with motor neuron disease plus syndrome (MND-plus). The patients with language variants of dementia were older than those with bvFTD. There were no differences in sex ratio, duration of illness, or level of education among the four subgroups. Overall, the patients with bvFTD showed a significantly better performance in cognitive tests. A higher frequency of motor symptoms and a lower frequency of behavioral symptoms were found in PNFA than in bvFTD and SD. The Global Language Index was significantly lower in SD than in bvFTD and PNFA. The MND-plus group had a poorer performance than all the others in all cognitive domains.
The neuropsychological, behavioral, motor, and language characteristics of the four subtypes are comparable with those from other series. However, the proportion of SD (37.0%), which was similar to that of bvFTD (41.3%), was higher in our registry than in other series.
PMCID: PMC4132251  PMID: 25177333
Frontotemporal dementia; Demography; Epidemiology; Asia; Korea
5.  Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans 
PLoS Genetics  2013;9(3):e1003351.
Prion proteins can adopt self-propagating alternative conformations that account for the infectious nature of transmissible spongiform encephalopathies (TSEs) and the epigenetic inheritance of certain traits in yeast. Recent evidence suggests a similar propagation of misfolded proteins in the spreading of pathology of neurodegenerative diseases including Alzheimer's or Parkinson's disease. Currently there is only a limited number of animal model systems available to study the mechanisms that underlie the cell-to-cell transmission of aggregation-prone proteins. Here, we have established a new metazoan model in Caenorhabditis elegans expressing the prion domain NM of the cytosolic yeast prion protein Sup35, in which aggregation and toxicity are dependent upon the length of oligopeptide repeats in the glutamine/asparagine (Q/N)-rich N-terminus. NM forms multiple classes of highly toxic aggregate species and co-localizes to autophagy-related vesicles that transport the prion domain from the site of expression to adjacent tissues. This is associated with a profound cell autonomous and cell non-autonomous disruption of mitochondrial integrity, embryonic and larval arrest, developmental delay, widespread tissue defects, and loss of organismal proteostasis. Our results reveal that the Sup35 prion domain exhibits prion-like properties when expressed in the multicellular organism C. elegans and adapts to different requirements for propagation that involve the autophagy-lysosome pathway to transmit cytosolic aggregation-prone proteins between tissues.
Author Summary
Alzheimer's, Parkinson's, Huntington's, frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and prion diseases are all age-related, fatal neurodegenerative disorders. Hallmarks of these diseases include the expression of toxic protein species. The ability to spread and infect naive cells was thought to be limited to prions but has recently been observed for other disease-linked protein aggregates in tissue culture cells and transgenic mice. The underlying cellular pathways of this cell-to-cell transmission, however, remain elusive. We have developed a new prion model in the roundworm Caenorhabditis elegans and show that the appearance of aggregate species is associated with cellular toxicity, not only in the expressing cell but as well as in adjacent tissues. We monitored in real time the spreading of prion domains by autophagy-derived lysosomal vesicles from cell-to-cell. Given that autophagy and lysosomal degradation have a role in several neurodegenerative diseases, this cellular pathway might be the basis of amyloid infectivity in general.
PMCID: PMC3610634  PMID: 23555277
6.  Prion protein in Caenorhabditis elegans 
Prion  2011;5(1):28-38.
The infectious agent of prion diseases is believed to be nucleic acid-free particles composed of misfolded conformational isomers of a host protein known as prion protein (PrP). Although this “protein-only” concept is generally accepted, decades of extensive research have not been able to elucidate the mechanisms by which PrP misfolding leads to neurodegeneration and infectivity. The challenges in studying prion diseases relate in part to the limitations of mammalian prion models, which include the long incubation period post-infection until symptoms develop, the high expense of maintaining mammals for extended periods, as well as safety issues. In order to develop prion models incorporating a genetically tractable simple system with a well-defined neuronal system, we generated transgenic C. elegans expressing the mouse PrP behind the pan-neuronal ric-19 promoter (Pric-19). We show here that high expression of Pric-19::PrP in C. elegans can result in altered morphology, defective mobility and shortened lifespan. Low expression of Pric-19::PrP, however, does not cause any detectable harm. Using the dopamine neuron specific promoter Pdat-1, we also show that expression of the murine BAX, a pro-apoptotic member of the Bcl-2 family, causes dopamine neuron destruction in the nematode. However, co-expression of PrP inhibits BAX-mediated dopamine neuron degeneration, demonstrating for the first time that PrP has anti-BAX activity in living animals. Thus, these distinct PrP-transgenic C. elegans lines recapitulate a number of functional and neuropathological features of mammalian prion models and provide an opportunity for facile identification of genetic and environmental contributors to prion-associated pathology.
PMCID: PMC3038003  PMID: 21084837
prion; C. elegans; protein misfolding; cytoprotection; BAX; neurodegeneration
7.  Cytoplasmic Expression of Mouse Prion Protein Causes Severe Toxicity in C. elegans 
To test if Caenorhabditis elegans could be established as a model organism for prion study, we created transgenic C. elegans expressing the cytosolic form of the mouse prion .protein, MoPrP(23-231), which lacks the N-terminal signal sequence and the C-terminal glycosylphosphatidylinisotol (GPI) anchor site. We report here that transgenic worms expressing MoPrP(23-231)–CFP exhibited a wide range of distinct phenotypes: from normal growth and development, reduced mobility and development delay, complete paralysis and development arrest, to embryonic lethality. Similar levels of MoPrP (23-231)-CFP were produced in animals exhibiting these distinct phenotypes, suggesting that MoPrP (23-231)-CFP might have misfolded into distinct toxic species. In combining with the observation that mutations in PrP that affect prion pathogenesis also affect the toxic phenotypes in C. elegans, we conclude that the prion protein folding mechanism is similar in mammals and C. elegans. Thus, C. elegans can be a useful model organism for prion research.
PMCID: PMC2587115  PMID: 18519028
prion; C. elegans; toxicity; aggregation; protein misfolding; neurodegeneration
8.  Newly identified prion linked to the chromatin-remodeling factor Swi1 in Saccharomyces cerevisiae 
Nature genetics  2008;40(4):460-465.
SWI/SNF, an evolutionarily conserved ATP-dependent chromatin-remodeling complex, has an important role in transcriptional regulation1. In Saccharomyces cerevisiae, SWI/SNF regulates the expression of ~6% of total genes through activation or repression2. Swi1, a subunit of SWI/SNF, contains an N-terminal region rich in glutamine and asparagine, a notable feature shared by all characterized yeast prions—a group of unique proteins capable of self-perpetuating changes in conformation and function3. Here we provide evidence that Swi1 can become a prion, [SWI+]. Swi1 aggregates in [SWI+] cells but not in nonprion cells. Cells bearing [SWI+] show a partial loss-of-function phenotype of SWI/SNF. [SWI+] can be eliminated by guanidine hydrochloride treatment, HSP104 deletion or loss of Swi1. Moreover, we show [SWI+] is dominantly and cytoplasmically transmitted. Our findings reveal a novel mechanism of ‘protein-only’ inheritance that results in modification of chromatin-remodeling and, ultimately, global gene regulation.
PMCID: PMC2633598  PMID: 18362884

Results 1-8 (8)