RESUMO
BACKGROUND AND PURPOSE: Several diagnostic biomarkers are currently available for clinical use in early-onset cognitive impairment. The decision on which biomarker is used in each patient depends on several factors such as its predictive value or tolerability. METHODS: There were a total of 40 subjects with early-onset cognitive complaints (<65 years of age): 26 with Alzheimer's disease (AD), five with frontotemporal dementia and nine with diagnostic suspicion of non-neurodegenerative disorder. Clinical and neuropsychological evaluation, lumbar puncture for cerebrospinal fluid (CSF) AD core biochemical marker determination, medial temporal atrophy evaluation on magnetic resonance imaging, amyloid-positron emission tomography (PET) and 18 F-fluorodeoxyglucose-PET were performed. Neurologists provided pre- and post-biomarker diagnosis, together with diagnostic confidence and clinical/therapeutic management. Patients scored the tolerability of each procedure. RESULTS: Cerebrospinal fluid biomarkers and amyloid-PET increased diagnostic confidence in AD (77.4%-86.2% after CSF, 92.4% after amyloid-PET, P < 0.01) and non-neurodegenerative conditions (53.6%-75% after CSF, 95% after amyloid-PET, P < 0.05). Biomarker results led to diagnostic (32.5%) and treatment (32.5%) changes. All tests were well tolerated. CONCLUSIONS: Biomarker procedures are well tolerated and have an important diagnostic/therapeutic impact on early-onset cognitive impairment.
Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Demência Frontotemporal/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodosRESUMO
BACKGROUND AND PURPOSE: Patients with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) may develop atypical parkinsonian syndromes. However, there is no current biomarker to assess which patients are at high risk of developing parkinsonism. 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT)-SPECT detects striatal dopamine dysfunction in vivo. The objective of the present study was to study whether non-fluent/agrammatic patients without parkinsonism at baseline present decreased striatal 123I-FP-CIT uptake. METHODS: Visual and semi-quantitative assessments of the striatal 123I-FP-CIT uptake ratio were carried out in 15 patients with nfvPPA, eight patients with the logopenic variant of PPA (lvPPA) and 18 controls. To rule out progranulin mutations or underlying Alzheimer's disease (AD), serum progranulin levels and cerebrospinal fluid (CSF) biomarkers of AD (Aß42 , total-tau, phosphorylated-tau181 ) were determined. A second 123I-FP-CIT-SPECT analysis in the biomarker-enriched groups was also carried out. RESULTS: Patients with nfvPPA presented reduced striatal 123I-FP-CIT binding, especially in the left hemisphere (P = 0.002), compared with controls. All lvPPA patients had normal striatal 123I-FP-CIT uptake. 123I-FP-CIT striatal binding in nfvPPA patients with normal progranulin and CSF biomarker levels (nfvPPA/bio-) was also significantly reduced (P < 0.05) compared with lvPPA patients with positive AD biomarkers. Sixty-four per cent (9/14) of nfvPPA patients and 80% of nfvPPA/bio- patients (8/10) showed a diminished individual left striatal 123I-FP-CIT uptake ratio. On follow-up, seven nfvPPA/bio- patients developed parkinsonism (median 1.9 years; range 1.2-2.9), six of them with baseline reduced 123I-FP-CIT uptake. CONCLUSIONS: Reduced striatal tracer uptake in nfvPPA patients prior to clinical parkinsonism can be detected by 123I-FP-CIT-SPECT, especially in those with nfvPPA/bio-, suggesting subclinical nigrostriatal degeneration. Decreased striatal 123I-FP-CIT binding might identify PPA patients at increased risk of developing atypical parkinsonian syndromes, probably related to tau-pathology.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neostriado/metabolismo , Doença de Parkinson/metabolismo , Afasia Primária Progressiva não Fluente/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tropanos , Idoso , Biomarcadores , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Afasia Primária Progressiva não Fluente/diagnóstico por imagemRESUMO
BACKGROUND/AIM: To investigate in variants of primary progressive aphasia (PPA) the association between current clinical and neuroimaging criteria and biochemical/genetic markers at the individual level. METHODS: Thirty-two PPA patients were classified as non-ï¬uent/agrammatic (nfvPPA), semantic (svPPA), or logopenic variant (lvPPA) or as unclassifiable (uPPA). In all patients, we evaluated the neuroimaging criteria (magnetic resonance imaging and/or single photon emission computed tomography/positron emission tomography) of each variant and studied serum progranulin levels, APOE genotype and Alzheimer's disease (AD)-cerebrospinal fluid (CSF) biomarkers. Cases with a first-degree family history of early-onset dementia were genetically tested. RESULTS: Ten of 15 (66%) nfvPPA, 5/5 (100%) svPPA and 7/7 (100%) lvPPA patients showed at least one positive neuroimaging-supported diagnostic criterion. All lvPPA and 3/5 (60%) uPPA patients presented AD-CSF biomarkers, which were absent in nfvPPA and svPPA cases. Four (27%) nfvPPA patients had dementia-causing mutations: 2 carried a GRN mutation and 2 the C9ORF72 hexanucleotide expansion. CONCLUSIONS: There was an excellent association between clinical criteria and neuroimaging-supported biomarkers in svPPA and lvPPA, as well as with AD-CSF biochemical markers in the lvPPA. Neuroimaging, biochemical and genetic findings in nfvPPA were heterogeneous. Incorporating biochemical/genetic markers into the PPA clinical diagnosis would allow clinicians to improve their predictions of PPA neuropathology, especially in nfvPPA and uPPA cases.
Assuntos
Afasia Primária Progressiva/patologia , Biomarcadores/sangue , Neuroimagem/métodos , Idade de Início , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/psicologia , Afasia Primária Progressiva/metabolismo , Afasia Primária Progressiva/psicologia , Apolipoproteínas E/sangue , Estudos de Coortes , Expansão das Repetições de DNA , Escolaridade , Feminino , Marcadores Genéticos , Variação Genética , Humanos , Processamento de Imagem Assistida por Computador , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Progranulinas , Fatores Socioeconômicos , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
We describe a patient who presented a progressive asymmetrical parietal syndrome including ideomotor apraxia, hemiinattention, unilateral limb dystonia and myoclonus. The clinical picture of this patient supported the clinical diagnosis of corticobasal degeneration (CBD). However, the neuropathologic examination revealed abundant cortical betaA4-amyloid deposits, and phosphorylated tau accumulation in neuritic plaques, neurofibrillary tangles and neuropil threads corresponding to Alzheimer's disease (AD) stage V of Braak and Braak. This case supports the clinical heterogeneity in AD and the existence of a clinical overlap between AD and CBD.
Assuntos
Doença de Alzheimer/complicações , Mioclonia/diagnóstico , Mioclonia/etiologia , Doenças Neurodegenerativas/diagnóstico , Lobo Parietal/patologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Córtex Cerebral/patologia , Diagnóstico Diferencial , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
A novel mutation (V89L) in the presenilin 1 (PSEN1) gene is described in a family with pathologically confirmed Alzheimer's disease. The mutation was identified in two affected members with early onset Alzheimer's disease characterised by early and marked behavioural disturbances. The mutation is located on the same side of the helix as other described mutations in the first transmembrane domain and its relation to other mutations in this helix suggests that they share a common pathogenic mechanism.
Assuntos
Doença de Alzheimer/genética , Proteínas de Membrana/genética , Transtornos Mentais/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Encéfalo/patologia , Cromossomos Humanos Par 14 , Análise Mutacional de DNA , Éxons , Seguimentos , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Mutação/genética , Testes Neuropsicológicos , Linhagem , Presenilina-1RESUMO
The authors describe a novel missense mutation in the presenilin 2 (PSEN2) gene at residue 439 that predicts an aspartate-to-alanine substitution (D439A). This mutation was found in a 58-year old patient who displayed a progressive dementia at the age of 52. The mutation was absent in his cognitively normal relatives. Haplotype analysis indicated that his affected mother was the most probable mutation carrier. The D439A mutation is located near the C-terminal end of the PS2 protein, a region critical for endoproteolytic processing.
Assuntos
Doença de Alzheimer/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Alanina/genética , Doença de Alzheimer/diagnóstico , Substituição de Aminoácidos/genética , Ácido Aspártico/genética , Triagem de Portadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Presenilina-2 , EspanhaRESUMO
In a family with early-onset Alzheimer disease (EOAD) from Spain we found a mutation in the presenilin 1 (PS1) gene that predicts a methionine-to-threonine change at the PS1 residue 139 (M139T). This mutation was previously reported in a independent French family. The age of onset of the disease was similar in the affected members from both families, suggesting a specific age of expression (range 47-50 years). The detection of the M139T mutation in an independent EOAD family strongly supports the pathogenicity of this mutation in familial Alzheimer disease (AD).
Assuntos
Doença de Alzheimer/genética , Proteínas de Membrana/genética , Mutação Puntual/genética , Encéfalo/patologia , Encéfalo/fisiopatologia , Cromossomos Humanos Par 14/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Presenilina-1 , Espanha/epidemiologiaRESUMO
The effect of L-ethionine, the ethyl analog of the essential amino acid methionine, on the SOS system of Escherichia coli was studied. This compound does not induce either inhibition of cell division nor cessation of cell respiration in a RecA+ Met+ RelA+ strain, nor in RecA+ Met- RelA+ or RecA+ Met- RelA- mutants. Nevertheless, L-ethionine blocks the expression of both cited SOS functions in a recA441 mutant when it is growing at the restrictive temperature of 42 degrees C. Furthermore, the inhibitory effect of the L-ethionine on the induction of the SOS system in this mutant is increased when the cells are preincubated for several hours in the presence of the analog, before the temperature shift. Moreover, cultures of the recA441 mutant incubated at 42 degrees C in the presence of both L-ethionine and L-methionine present the same behaviour as the cultures of this mutant growing at the same temperature but without either amino acid. On the other hand, L-ethionine does not have any effect on the expression of the two mentioned SOS functions when these are induced by UV-irradiation in a RecA+ strain even if this compound is added to the cells several hours before irradiation.