Adolfo Jiménez-Huete

Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues

We have investigated the proteolytic cleavage of the cellular (PrPC) and pathological (PrPSc) isoforms of the human prion protein (PrP) in normal and prion-affected brains and in tonsils and platelets from neurologically intact individuals. The various PrP species were resolved after deglycosylation according to their electrophoretic mobility, immunoreactivity, Sarkosyl solubility, and, as a novel approach, resistance to endogenous proteases. First, our data show that PrPC proteolysis in brain originates amino-truncated peptides of 21 to 22 and 18 (C1) kd that are similar in different regions and are not modified by the PrP codon 129 genotype, a polymorphism that affects the expression of prion disorders. Second, this proteolytic cleavage of PrPC in brain is blocked by inhibitors of metalloproteases. Third, differences in PrPC proteolysis, and probably in Asn glycosylation and glycosylphosphatidylinositol anchor composition, exist between neural and non-neural tissues. Fourth, protease-resistant PrPSc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis. Fifth, the profile of endogenous proteolytic PrPSc peptides is characteristic of each disorder studied, thus permitting the molecular classification of these prion diseases without the use of proteinase K and even a recognition of PrPSc heterogeneity within type 2 CJD patients having different codon 129 genotype and neuropathological phenotype. This does not exclude the role of additional factors in phenotypic expression; in particular, differences in glycosylation that may be especially relevant in the new variant CJD. Proteolytic processing of PrP may play an important role in the neurotropism and phenotypic expression of prion diseases, but it does not appear to participate in disease susceptibility.

Senile dementia associated with amyloid β protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-ε4 allele

Abstract Amyloid β protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer’s disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipoprotein E (APOE)-ɛ4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-ɛ4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid β protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide form of amyloid β protein was that terminating at residue Val40, as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. DNA sequence analysis of the Amyloid Precursor Protein gene and Presenilin-1 (PS-1) gene revealed no mutations. In these APOE-ɛ4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid β protein angiopathy, neurofibrillary tangles, some cortical Lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid β protein deposition.

Clinical-Genetic Correlations in Familial Alzheimer's Disease Caused by Presenilin 1 Mutations

We describe the clinical phenotype of nine kindred with presenile Alzheimers disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

Impact of the clinical context on the 14-3-3 test for the diagnosis of sporadic CJD.

BackgroundThe 14-3-3 test appears to be a valuable aid for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in selected populations. However, its usefulness in routine practice has been challenged. In this study, the influence of the clinical context on the performance of the 14-3-3 test for the diagnosis of sCJD is investigated through the analysis of a large prospective clinical series.MethodsSix hundred seventy-two Spanish patients with clinically suspected sCJD were analyzed. Clinical classification at sample reception according to the World Health Organizations (WHO) criteria (excluding the 14-3-3 test result) was used to explore the influence of the clinical context on the pre-test probabilities, and positive (PPV) and negative (NPV) predictive values of the 14-3-3 test.ResultsPredictive values of the test varied greatly according to the initial clinical classification: PPV of 98.8%, 96.5% and 45.0%, and NPV of 26.1%, 66.6% and 100% for probable sCJDi (n = 115), possible sCJDi (n = 73) and non-sCJDi (n = 484) cases, respectively. According to multivariate and Bayesian analyses, these values represent an improvement of diagnostic certainty compared to clinical data alone.ConclusionIn three different contexts of sCJD suspicion, the 14-3-3 assay provides useful information complementary to clinical and electroencephalographic (EEG) data. The test is most useful supporting a clinical impression, whilst it may show deceptive when it is not in agreement with clinical data.

Small temporal pole encephalocele: A hidden cause of “normal” MRI temporal lobe epilepsy

Small temporal pole encephalocele (STPE) can be the pathologic substrate of epilepsy in a subgroup of patients with noninformative magnetic resonance imaging (MRI). Herein, we analyzed the clinical, neurophysiologic, and radiologic features of the epilepsy found in 22 patients with STPE, and the frequency of STPE in patients with refractory focal epilepsy (RFE).

Diversity of Senile Plaques in Alzheimers Disease as Revealed by a New Monoclonal Antibody that Recognizes an Internal Sequence of the Aβ Peptide

In order to have more specific tools available to approach amyloidogenesis in Alzheimers disease (AD), we have produced several polyclonal and monoclonal antibodies that recognize specific sequences of the amyloid beta (Abeta) peptide. Here we present results that demonstrate that our monoclonal antibody EM5 recognizes an internal sequence (residues 11-16) of the Abeta peptide. This strategic localization of the epitope allowed us to employ this antibody, together with two previously reported polyclonal antibodies (EM2 and EM3, specific for AbetaX-40 and AbetaX-42, respectively), in an immunohistochemical study aimed at exploring the differential distribution of longer (AbetaX-40/42) and shorter (Abeta17-X) peptides along the various types of amyloid deposits of AD. This antibody panel was used in six AD brains, on sections from associative neocortex, striatum and cerebellar cortex. Single and double immunostaining revealed specific staining of vascular amyloid deposits and neuritic plaques by EM5 antibody, with high co-localization of EM2. Our results suggest that EM5 antibody recognizes pathogenic forms of Abeta deposits (amyloid angiopathy and neuritic plaques) and reveals the existence of a subset of plaques with a profile similar to vascular deposits. Additionally, our results show that diffuse plaques in AD brains may contain Abeta17-X peptides as its principal component. EM5 may be a useful tool in research both on human and transgenic mice tissue that may aid in the study of molecular heterogeneity of plaques in AD.

Florbetapir (18F) for brain amyloid positron emission tomography: Highlights on the European marketing approval

Florbetapir (18F) for brain amyloid positron emission tomography (PET) imaging has been recently approved in Europe to estimate β‐amyloid neuritic plaque density in the brain when the subject is still alive. Such density is one of the key issues for the definitive diagnosis of Alzheimers disease (AD) at autopsy. This capability of florbetapir (18F) is regarded as a significant improvement in the diagnostic procedures for adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive impairment. The current paper highlights the specific characteristics of the European marketing authorization of florbetapir (18F).

Subjective evaluation of mood and cognitive functions in a general neurology clinic: patients versus informants

Background and Purpose We aimed to determine the correlation between subjective evaluations of mood and cognitive functions by patients and informants, and the findings of a battery of neuropsychological tests. Methods We analyzed 74 subjects recruited from a general neurology clinic, comprising 37 patients with cognitive complaints and 37 informants (either relatives or caregivers in close contact with the patients). Four ordinal scales concerning recent memory, verbal expression, initiative, and mood were correlated with the findings of a series of neuropsychological tests and questionnaires using the tau b coefficient. Results The scores for the patients on the scales were most strongly correlated with scores on the 15-item Geriatric Depression Scale (GDS-15), while the scores for the informants were most strongly correlated with scores on GDS-15, the Informant Questionnaire on Cognitive Decline, and the Functional Activities Questionnaire (FAQ). The most significant correlation was between the initiative scale from informants and FAQ (tau b=-0.591, p<0.001), and it was the only one that remained significant after correcting for multiple testing (p Holm=0.013). Conclusions Cognitive complaints from patients mainly reflect their mood, whilst informant reports mainly reflect both the functional ability and mood of the patients.

Efficacy and safety of eslicarbazepine acetate monotherapy for partial-onset seizures: Experience from a multicenter, observational study

Eslicarbazepine acetate (ESL, Aptiom™) is a once-daily anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). Historical-controlled trials investigating the use of ESL as monotherapy have demonstrated a favorable efficacy and tolerability profile in patients with POS. This prospective, non-interventional study recruited POS patients in 17 hospitals in Spain. After a 3-month baseline period, ESL therapy was initiated as 400mg QD and up-titrated to an optimal maintenance dose based on clinical response and tolerance. The incidence of seizures was assessed via seizure calendars and the nature and severity of adverse events (AEs) were also recorded. A total of 117 patients (aged 9-87years) enrolled in the study and were treated with ESL at either 400mg/day (3.4% patients), 800mg/day (61% patients), 1200mg/day (27.1% patients) or 1600mg/day (8.5% patients). At 3months, 82.0% (n=72) of patients achieved a ≥50% reduction in seizure frequency, compared to 79.7% (n=67) of patients at 6months and 83.0% (n=49) at 12months. Patients who suffered secondary generalized tonic-clonic (SGTC) seizures had seizure-free rates of 71% (n=27), 69.6% (n=29), and 72.7% (n=16) at 3, 6, and 12months, respectively. Overall, 18 patients (15.3%) reported AEs of instability and dizziness (n=9), somnolence (n=3), mild hyponatremia (n=3), headache (n=1), hypertriglyceridemia (n=1), and allergic reaction (n=1), which caused ESL discontinuation of ESL treatment. ESL is effective and well tolerated as monotherapy for patients with POS, which supports previous findings. Early use is supported by its frequent use as monotherapy in this study and lack of severe side effects.

Differential Diagnosis of Degenerative Dementias Using Basic Neuropsychological Tests Multivariable Logistic Regression Analysis of 301 Patients

Background: The validity of neuropsychological tests for the differential diagnosis of degenerative dementias may depend on the clinical context. We constructed a series of logistic models taking into account this factor. Methods: We retrospectively analyzed the demographic and neuropsychological data of 301 patients with probable Alzheimer’s disease (AD), frontotemporal degeneration (FTLD), or dementia with Lewy bodies (DLB). Nine models were constructed taking into account the diagnostic question (eg, AD vs DLB) and subpopulation (incident vs prevalent). Results: The AD versus DLB model for all patients, including memory recovery and phonological fluency, was highly accurate (area under the curve = 0.919, sensitivity = 90%, and specificity = 80%). The results were comparable in incident and prevalent cases. The FTLD versus AD and DLB versus FTLD models were both inaccurate. Conclusion: The models constructed from basic neuropsychological variables allowed an accurate differential diagnosis of AD versus DLB but not of FTLD versus AD or DLB.