Pseudo-anticipation in Creutzfeldt-Jakob disease is due to a rhomboid-shaped artifact.

BACKGROUND AND PURPOSE: Previous studies have reported conflicting results regarding possible anticipation in familial E200K Creutzfeldt-Jakob disease (fCJD). Our objective was to use a large database to assess the age of disease onset (AODO) in CJD. METHODS: The study population included 477 CJD patients [266 with fCJD, 145 with sporadic CJD (sCJD) and 66 patients of Libyan origin but negative family history] from the Israeli registry of CJD conducted since 1954. In all patients, AODO in relatives and family trees was documented. Comparison of AODO was done using a paired t test and regression using Pearson correlation for birth and year of onset. RESULTS: The initial analysis in 52/73 families in which more than one generation was affected revealed an AODO of 63.30 ± 9.44 in the first generation compared to 56.96 ± 8.99 in the second generation (P < 0.001). However, inspection of individual AODO values plotted by year of birth showed a clear rhomboid methodological artifact generated by missing data of many young onset CJD patients who died before the database began to function in 1954 and of many late onset CJD patients missing at the present time since they will only develop the disease in the future. The 'generation' effect completely disappears if analysis is performed by year of disease onset or for the periods in which complete data are available. CONCLUSIONS: In this very large dataset, true anticipation in fCJD patients was not detected. It is plausible that previous reports supporting the presence of anticipation are biased by a rhomboid-shaped data availability artifact.

Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease.

BACKGROUND AND PROPOSE: Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. The typical presenting symptoms include cognitive decline, behavioral changes and gait disturbances; however, some patients may have an unusual presentation such as a stroke-like presentation, alien hand syndrome or visual disturbances. The aim of this paper is to describe uncommon presentations in our series of consecutive patients with E200K fCJD. METHODS: The study group included consecutive fCJD patients followed up as part of a longitudinal prospective study ongoing since 2003 or hospitalized since 2005. The clinical diagnosis of probable CJD was based on accepted diagnostic criteria and supported by typical magnetic resonance imaging, electroencephalographic findings, elevated cerebrospinal fluid tau protein levels and by genetic testing for the E200K mutation. Disease symptoms and signs were retrieved from the medical files. RESULTS: The study population included 77 patients (42 men) with a mean age of disease onset of 60.6 ± 7.2 years. The most prevalent presenting symptoms were cognitive decline followed by gait impairment and behavioral changes. However, six patients had an unusual presentation including auditory agnosia, monoparesis, stroke-like presentation, facial nerve palsy, pseudobulbar syndrome and alien hand syndrome. CONCLUSIONS: Our case series illustrates the wide phenotypic variability of the clinical presentation of patients with fCJD and widens the clinical spectrum of the disease. A high level of clinical suspicion may prove useful in obtaining early diagnosis and therefore avoiding costly and inefficient diagnostic and therapeutic strategies.

CSF tau correlates with CJD disease severity and cognitive decline.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans. The clinical diagnosis of CJD is supported by a combination of electroencephalogram, MRI, and the presence in the CSF of biomarkers. CSF tau is a marker for neuronal damage and tangle pathology, and is correlated with cognitive status in Alzheimer's disease (AD). OBJECTIVES: The aim of this study was to test whether tau levels in the CSF also correlate with the degree of the neurological deficit and cognitive decline in patients with CJD as reflected by various clinical scales that assess disease severity and cognitive performance. METHODS: Consecutive patients with familial CJD (fCJD) were examined by a neurologist who performed several tests including minimental status examination (MMSE), frontal assessment battery (FAB), NIH stroke scale (NIHSS), CJD neurological scale (CJD-NS), and the expanded disability status scale (EDSS). CSF tau was tested as part of the workout, and the correlation was tested using Pearson correlation. RESULTS: Fifty-two patients with fCJD were recruited to the study (35 males, mean age 59.4 ± 5.7, range 48-75 years). A significant negative correlation was found between CSF tau levels and the cognitive performance of the patients as reflected by their MMSE and FAB scores. In addition, a significant positive correlation was found between tau levels and the clinical disease severity scales of CJD-NS, NIHSS, and EDSS. CONCLUSION: The correlation between tau levels and the disease severity and degree of cognitive decline in patients with fCJD suggests that tau can be a biomarker reflecting the extent of neuronal damage.

Health professions and risk of sporadic Creutzfeldt-Jakob disease, 1965 to 2010.

In 2009, a pathologist with sporadic Creutzfeldt-Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD. Five countries reported 15 physicians and 68 other health professionals among 2,968 controls or non-cases, suggesting no relative excess of sCJD among healthcare professionals. A literature review revealed: (i) 12 case or small case-series reports of 66 health professionals with sCJD, and (ii) five analytical studies on health-related occupation and sCJD, where statistically significant findings were solely observed for persons working at physicians' offices (odds ratio: 4.6 (95 CI: 1.2-17.6)). We conclude that a wide spectrum of medical specialities and health professions are represented in sCJD cases and that the data analysed do not support any overall increased occupational risk for health professionals. Nevertheless, there may be a specific risk in some professions associated with direct contact with high human-infectivity tissue.

The Creutzfeldt-Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression.

OBJECTIVES: To develop a scale sensitive for the neurological manifestations of Creutzfeldt-Jakob disease (CJD). METHODS: A 26-item CJD neurological status scale (CJD-NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first-degree relatives of the patients and 14 elderly patients with Parkinson's disease (PD). RESULTS: The mean TSS (±SD) was significantly higher in patients with CJD (13.19 ± 5.63) compared with normal controls (0.41 ± 0.78) and PD patients (9.71 ± 3.05). The mean SIS was also significantly different between the CJD (5.19 ± 1.22) and PD (2.78 ± 1.18 P ≤ 0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS > 4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3-9 months revealed a time-dependent increase in both the TSS and the SIS reflecting the scale's ability to track disease progression. CONCLUSIONS: The CJD-NS scale is sensitive to neurological signs and their progression in CJD patients.

Rapidly progressive Creutzfeldt-Jakob disease in patients with Familial Mediterranean Fever.

BACKGROUND: The largest cluster of familial Creutzfeldt-Jakob disease (fCJD) exists in Jews of Libyan origin. Familial Mediterranean fever (FMF) is an inflammatory disease also common in this population. OBJECTIVES: We hypothesized that FMF, as a pro-inflammatory condition, may affect the course of CJD. METHODS: Three hundred and seventy-two consecutive patients diagnosed clinically and genetically as CJD were included in the study. Two hundred and thirty-six had fCJD, and 136 had sporadic disease (sCJD). Review of the patient's records revealed three patients with FMF-CJD co-morbidity. In addition, 50 DNA samples of patients with CJD were genotyped as homozygote, heterozygote, and non-carriers of the FMF mutation. The demographic and clinical variables of the groups were compared. RESULTS: The three patients with FMF had an earlier age of onset and significantly shorter disease duration than the patients without FMF. Heterozygote carriers did not differ in disease onset and duration from patients without FMF. CONCLUSIONS: The shorter disease duration of CJD patients with FMF may indicate the importance of pro-inflammatory factors in the disease.

Fast collapse but slow formation of secondary structure elements in the refolding transition of E. coli adenylate kinase.

The various models proposed for protein folding transition differ in their order of appearance of the basic steps during this process. In this study, steady state and time-resolved dynamic non-radiative excitation energy transfer (FRET and trFRET) combined with site specific labeling experiments were applied in order to characterize the initial transient ensemble of Escherichia coli adenylate kinase (AK) molecules upon shifting conditions from those favoring denaturation to refolding and from folding to denaturing. Three sets of labeled AK mutants were prepared, which were designed to probe the equilibrium and transient distributions of intramolecular segmental end-to-end distances. A 176 residue section (residues 28-203), which spans most of the 214 residue molecule, and two short secondary structure chain segments including an alpha-helix (residues 169-188) and a predominantly beta-strand region (residues 188-203), were labeled. Upon fast change of conditions from denaturing to folding, the end-to-end distance of the 176 residue chain section showed an immediate collapse to a mean value of 26 A. Under the same conditions, the two short secondary structure elements did not respond to this shift within the first ten milliseconds, and retained the characteristics of a fully unfolded state. Within the first 10 ms after changes of the solvent from folding to denaturing, only minor changes were observed at the local environments of residues 203 and 169. The response of these same local environments to the shift of conditions from denaturing to folding occurred within the dead time of the mixing device. Thus, the response of the CORE domain of AK to fast transfer from folding to unfolding conditions is slow at all three conformational levels that were probed, and for at least a few milliseconds the ensemble of folded molecules is maintained under unfolding conditions. A different order of the changes was observed upon initiation of refolding. The AK molecules undergo fast collapse to an ensemble of compact structures where the local environment of surface probes seems to be native-like but the two labeled secondary structure elements remain unfolded.

Primary antiphospholipid antibody syndrome masquerading as progressive supranuclear palsy.

We report a case of a patient with clinical features of progressive supranuclear palsy and raised titres of anticardiolipin antibodies in blood, thrombocytopenia and livedo reticularis on skin. Magnetic resonance imaging of brain and isotope scan of brain were distinctive of vascular disorder.

A general strategy for site-specific double labeling of globular proteins for kinetic FRET studies.

Site-directed mutagenesis provides a straightforward means of creating specific targets for chemical modifications of proteins. This capability enhanced the applications of spectroscopic methods adapted for addressing specific structural questions such as the characterization of partially folded and transient intermediate structures of globular proteins. Some applications such as the steady state or time-resolved fluorescence resonance energy transfer (FRET) detection of the kinetics of protein folding require relatively large quantities (approximately 10-100 mg) of site-specific doubly labeled protein samples. Engineered cysteine residues are common targets for labeling of proteins. The challenge here is to develop methods for selective modification of one of two reactive sulfhydryl groups in a protein molecule. A general systematic procedure for selective labeling of each of two cysteine residues in a protein molecule was developed, using Escherichia coli adenylate kinase (AKe) as a model protein. Potential sites for insertion of cysteine residues were selected by examination of the crystal structure of the protein. A series of single-cysteine mutants was prepared, and the rates of the reaction of each engineered cysteine residue with a reference reagent [5,5'-dithiobis(2-nitrobenzoic acid) (DTNB)] were determined. Two-cysteine mutants were prepared by selection of pairs of sites for which the ratio of this reaction rate constant was high (>80). The conditions for the selective labeling reaction were optimized. In a first cycle of labeling, the more reactive cysteine residue was labeled with a fluorescent probe (donor). The second probe was attached to the less reactive site under unfolding conditions in the second cycle of labeling. The doubly and singly labeled mutants retained full enzymatic activity and the capacity for a reversible folding-unfolding transition. High yields (70-90%) of the preparation of the pure, site-specific doubly labeled AK mutant were obtained. The procedure described herein is a general outline of procedures, which can meet the double challenge of both site specificity and large-scale preparation of doubly labeled proteins.

The natively helical chain segment 169-188 of Escherichia coli adenylate kinase is formed in the latest phase of the refolding transition.

The refolding transition of Escherichia coli adenylate kinase (AK) was investigated by monitoring the refolding kinetics of a selected 20 residue helical segment in the CORE domain of the protein. Residues 169 and 188 were labeled by 1-acetamido-methyl-pyrene, and by bimane, respectively. The experiment combines double-jump stopped-flow fast mixing initiation of refolding and time-resolved Förster energy transfer spectroscopy for monitoring the conformational transitions (double-kinetics experiment). Two kinetic phases were found in the denaturant-induced unfolding of AK. In the first phase, the fluorescence quantum yields of both probes decreased. The distribution of the distances between them transformed from the native state's narrow distribution with the mean distance corresponding to the distance in the crystal structure, to a distribution compatible with an unordered structure. In the second, slow step of denaturation, neither the fluorescence parameters of the probes nor the distance distribution between them changed. This step appeared to be a transformation of the fast-folding species formed in the first phase, to the slow-folding species. Refolding of the fast-folding species of the denatured state of AK was also a two-phase process. During the first fast phase, within less than 5ms, the fluorescence emission of both probes increased, but the distance distribution between the labeled sites was unchanged. Only during the second slow refolding step did the intramolecular distance distribution change from the characteristic of the denatured state to the narrow distribution of the native state. This experiment shows that for the case of the CORE domain of AK, the large helical segment of residues 169-188 was not formed in the first compaction step of refolding. The helical conformation of this segment is established only in the second, much slower, refolding phase, simultaneously with the completion of the native structure.

Successful aging among people with HIV/AIDS.

With advances made in the treatment of people with HIV/AIDS, there is an increasing number of persons who are reaching old age. This is a heterogeneous group. Yet, all of these diverse patients share in common the challenge of aging successfully despite their condition. There is little room in most gerontological conceptualizations for consideration of success for older persons unfortunate enough to live with chronic and particularly life-threatening illnesses in late life. Ideals of successful aging certainly leave little room for older adults with HIV/AIDS, a highly stigmatized, life-threatening, and disabling condition. In this article, we briefly review a new model of successful aging that we have developed, and show how it can be meaningfully applied to expectations of successful aging even among disabled and chronically ill populations of older adults such as persons with HIV/AIDS.

History and mobility exam index to identify community-dwelling elderly persons at risk of falling.

BACKGROUND: Falls are common in community-dwelling elderly persons and are a frequent source of morbidity. Simple indices to prospectively stratify people into categories at different fall-risk would be useful to health care practitioners. Our goal was to develop a fall-risk index that discriminated between people at high and low risk of falling. METHODS: We evaluated the risk of falling over a one-year period in 557 elderly persons (mean age 81.6) living in a retirement community. On the baseline interview, we asked subjects if they had fallen in the previous year and evaluated risk factors in six additional conceptual categories. On the follow-up interview one year later, we again asked subjects if they had fallen in the prior year. We evaluated risk factors in the different conceptual categories and used logistic regression to determine the independent predictors of falling over a one-year period. We used these independent predictors to create a fall-risk index. We compared the ability of a prior falls history with other risk factors and with the combination of a falls history and other risk factors to discriminate fallers from nonfallers. RESULTS: A fall in the previous year (OR = 2.42, 95% CI = 1.49-3.93), a symptom of either balance difficulty or dizziness (OR = 1.83, 95% CI = 1.16-2.89), or an abnormal mobility exam (OR = 2.64, 95% CI = 1.64-4.26) were independent predictors of falling over the subsequent year. These three risk factors together (c statistic =.71) discriminated fallers from nonfallers better than previous history of falls alone (c statistic =.61) or the symptomatic and exam risk factors alone (c statistic =.68). When combined into a risk index, the three independent risk factors stratify people into groups whose risk for falling over the subsequent year ranges from 10% to 51%. CONCLUSION: A history of falling over the prior year, a risk factor that can be obtained from a clinical history (balance difficulty or dizziness), and a risk factor that can be obtained from a physical exam (mobility difficulty) stratify people into groups at low and high risk of falling over the subsequent year. This risk index may provide a simple method of assessing fall risk in community-dwelling elderly persons. However, it requires validation in other subjects before it can be recommended for widespread use.

Outcome of infants with unilateral Sturge-Weber syndrome and early onset seizures.

Patients with Sturge-Weber syndrome often present with seizures during the first year of life. Currently, only patients with clinically significant seizures who do not respond to medical treatment are candidates for early epileptic surgery. However, a delay of surgical treatment may result in cognitive deterioration. We studied the correlation between parameters and outcome of seizures to re-examine the criteria for early epilepsy surgery. We performed a retrospective chart review combined with telephone interviews of parents of all Israeli infants with unilateral Sturge-Weber syndrome and early onset seizures, and we examined whether age of seizure onset and seizure intensity were correlated with cognitive level and the degree of hemiparesis at follow-up. We recruited a total of 15 patients with unilateral Sturge-Weber syndrome and early onset seizures, five of whom underwent epilepsy surgery. The mean follow-up period of all the patients was 15 years: six patients had normal intelligence, four had borderline cognitive level, three had mild mental retardation and two had moderate mental retardation. Eight of the ten non-operated patients still experience seizures at follow-up. Cognitive delay was significantly correlated with seizure intensity in the early period, but not with the age of seizures onset, the degree of hemiparesis, or the presence of ongoing seizures. We conclude that high seizure intensity in young patients with Sturge-Weber syndrome is a prognostic marker for mental deterioration.

Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features.

The cluster in Jews of Libyan origin of limb-girdle muscular dystrophy type 2B due to a dysferlin 1624delG mutation is described. The carrier frequency of this mutation is calculated to be approximately 10% in this population, in which the disease prevalence is at least 1 per 1300 adults. Twenty-nine patients from 12 families were all homozygous for the same mutation. However, clinical features were heterogeneous even within the same family: in half of the patients onset was in the distal muscles of the legs, which is similar to Miyoshi myopathy, while in others onset was in the proximal musculature, which is similar to other forms of limb-girdle dystrophies. Age at onset varied from 12 to 28 years (mean 20.3 +/- 5.5 years). One patient was presymptomatic at age 28 years. Progression was slow regardless of age of onset, patients remaining ambulatory until at least 33 years. Five patients described subacute, painful enlarged calves as an early, unusual feature. The variable features in this ethnic cluster contribute to the definition of the clinical spectrum of dysferlinopathies in general. The cause of the observed heterogeneity remains unclear.

Epidemiologic studies of multiple sclerosis: a review.

There is evidence for genetic factors in multiple sclerosis (MS). The evidence come from epidemiologic studies, racial predilection, risk in family members (sibs, half sibs, adoptees) and twins studies. MS is not a Mendelian inherited disease; only the susceptibility to the disease is inherited, the risk of MS being also related to an environmental factor. Many candidate genes were screened, and there are four research groups trying to study the whole genome. MS seem to be an oligo- or multigenic disorder with an apparently similar phenotype for the different genes involved.

Creutzfeldt-Jakob disease profile in patients homozygous for the PRNP E200K mutation.

We identified 70 Creutzfeldt-Jakob disease patients with the previously described E200K mutation in the prion protein gene. The purpose of this study was to define the clinical features of E200K homozygous patients (n = 5), compared with heterozygotes. We found a statistically significant younger age at disease onset for the homozygous patients, although the average age at onset in this group was still in midlife. Disease features were not statistically different in the two groups. Possible explanations are discussed.

Altruistic moral judgment among older adults.

This study investigated altruistic moral judgment among the elderly, and examined its relationships to demographic and personality variables, self-reported helping, and subjective social integration (the perception that one is integrated into one's social milieu). The moral judgment interview included three stories, each of which contained a moral dilemma. Participants solved each dilemma and gave reasons for their solutions. The moral dilemmas and scoring system emphasized the positive, prosocial aspects of morality, rather than a prohibition-oriented approach. The categories used most often were, in descending order of frequency 1) pragmatic needs-of-others oriented reasons, 2) empathy-based reasons, 3) reasons based on internalized and/or abstract moral principles, and 4) hedonistic reasons. Of the higher levels of moral judgment, only reasoning based on abstract internalized principles had significant positive relationships with self-reported helping, the personality correlates of helping, and with subjective social integration into one's social milieu.

Preliminary evidence for anticipation in genetic E200K Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) linked to the E200K mutation of the prion protein (PrP) gene presents within a wide range of phenotypic heterogeneity, including the age at disease onset. We report an earlier disease onset for mutation carriers of the offspring generation when compared with that of their parents, suggesting the possibility of anticipation. A still unidentified environmental or genetic element may affect the age at onset in mutation carriers of different generations.

Depressive symptoms and 3-year mortality in older hospitalized medical patients.

BACKGROUND: Depressive symptoms are common in hospitalized older persons. However, their relation to long-term mortality is unclear because few studies have rigorously considered potential confounders of the relation between depression and mortality, such as comorbid illness, functional impairment, and cognitive impairment. OBJECTIVE: To measure the association between depressive symptoms and long-term mortality in hospitalized older persons. DESIGN: Prospective cohort study. SETTING: General medical service of a teaching hospital. PATIENTS: 573 patients 70 years of age or older. MEASUREMENTS: Depressive symptoms (Geriatric Depression Scale score), severity of acute illness (Acute Physiology and Chronic Health Evaluation II score), burden of comorbid illness (Charlson comorbidity index score), physical function (a nurse assessed dependence in six activities of daily living), and cognitive function (modified Mini-Mental State Examination) were measured at hospital admission. Mortality over the 3 years after admission was determined from the National Death Index. Mortality rates among patients with six or more depressive symptoms were compared with those among patients with five or fewer symptoms. RESULTS: The mean age of the patients was 80 years; 68% of patients were women. Patients with six or more depressive symptoms had greater comorbid illness, functional impairment, and cognitive impairment at admission than patients with fewer depressive symptoms. Three-year mortality was higher in patients with six or more depressive symptoms (56% compared with 40%; hazard ratio, 1.56 [95% CI, 1.22 to 2.00]; P < 0.001). After adjustment for age, acute illness severity, comorbid illness, functional impairment, and cognitive impairment at the time of admission, patients with six or more depressive symptoms continued to have a higher mortality rate during the 3 years after admission (hazard ratio, 1.34 [CI, 1.03 to 1.73]). Although depressive symptoms contributed less to the mortality rate than did the total burden of comorbid medical illnesses, the excess mortality rate associated with depressive symptoms was greater than that conferred by one additional comorbid medical condition. CONCLUSIONS: Depressive symptoms are associated with long-term mortality in older patients hospitalized with medical illnesses. This association is not fully explained by greater levels of comorbid illness, functional impairment, and cognitive impairment in patients with more depressive symptoms.

Evidence for the genetic role of human leukocyte antigens in low frequency DRB1*1501 multiple sclerosis patients in Israel.

A strong association exists between multiple sclerosis (MS) and the DRB1*1501 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on chromosome 6p21 has previously been observed in DRB1*1501 positive MS families. A group of 13 Israeli multiplex MS families with a very low frequency of DRB1*1501 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB1*1501 effect of HLA on susceptibility for MS. MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRB1, DQA1 and DQB1, BAT-2, MIB and D6S248. Data analyses included: (a) an association study comparing the patient group with both healthy relative, and healthy control groups (b) a transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families, and (c) multipoint non-parametric linkage (NPL) and parametric LOD score analyses using the GENEHUNTER program. The DRB1*1303 allele was significantly more frequent among the MS patients. There was a trend towards transmission disequilibrium of DRB1*1303, but was not statistically significant. Allele sharing and LOD score analyses revealed no evidence for linkage. The high frequency of DRB1*1303 observed in our family patients provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patients. Thus, DRB1*1303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRB1*1501 patients.