Clinical applicability of diagnostic biomarkers in early-onset cognitive impairment.

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.

Decreased striatal dopamine transporter uptake in the non-fluent/agrammatic variant of primary progressive aphasia.

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.

Neuroimaging and biochemical markers in the three variants of primary progressive aphasia.

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-fluent/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.

Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease.

OBJECTIVES: Early-onset Alzheimer disease (EOAD) diagnosis often represents a challenge because of the high frequency of atypical presentations. Our aim was to describe the clinical features, APOE genotype, and its pathologic correlations of neuropathologic confirmed EOAD. METHODS: Retrospective review of clinical data (age at onset, family history, clinical presentation, diagnostic delay, diagnosis) and APOE genotype of patients with neuropathologically confirmed EOAD (<60 years). RESULTS: Forty cases were selected. Mean age at onset was 54.5 years (range 46-60). The mean disease duration was 11 years with a mean diagnostic delay of 3.1 years. A total of 37.5% had a nonmemory presentation. Behavioral/executive dysfunction was the most prevalent atypical presentation. Incorrect initial clinical diagnoses were common (53%) in patients with atypical presentations, but rare when anterograde amnesia was the presenting symptom (4%). The incorrect initial clinical diagnoses were 2 behavioral variant frontotemporal lobar degeneration, 2 normal pressure hydrocephalus, 1 semantic dementia, 1 primary progressive aphasia, 1 corticobasal degeneration, 1 pseudodementia with depression, and 1 unclassifiable dementia. APOE genotype was ε3/ε3 in 59%, with no significant differences between typical and atypical presentations. APOE ε4 was 3.3 times more frequent in subjects with family history of AD. A total of 97.5% of the cases presented advanced neurofibrillary pathology. A total of 45% of the patients had concomitant Lewy body pathology although localized in most cases and without a significant clinical correlate. CONCLUSION: One third of patients with pathologic confirmed EOAD presented with atypical symptoms. Patients with EOAD with nonamnestic presentations often receive incorrect clinical diagnoses.

Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile.

BACKGROUND: Williams-Beuren syndrome (WBS) is a developmental disorder with multisystemic manifestations mainly characterised by vascular stenoses, distinctive craniofacial features, mental retardation with a characteristic neurocognitive profile, and some endocrine and connective tissue abnormalities, caused by a recurrent deletion of 1.55 Mb including 26-28 genes at chromosomal region 7q11.23. The analysis of clinical-molecular correlations in a few reported atypical patients has been useful to propose several deleted genes as main contributors to specific aspects of the WBS phenotype. PATIENTS AND METHODS: Two additional families with partial phenotypes and atypical 7q11.23 deletions were studied. Deletions were precisely defined at the nucleotide level, and the expression levels of some affected and flanking genes were assessed in lymphoblastoid cell lines. RESULTS: Affected individuals presented variable cardiovascular and connective tissue manifestations, subtle craniofacial features, normal visuospatial construction abilities with low average IQ and no endocrine abnormalities. The deletion in family NW1 encompassed 817 kb with 11 genes (CLDN3-GTF2IRD1), and 610 kb with 14 genes (VPS37D-RFC2) in family NW2. All deleted genes in typical and atypical deletions revealed low expression levels in lymphoblastoid cell lines, except for GTF2IRD1. CLIP2 was also underexpressed in all patients despite being outside the deletion in NW2, while no other flanking non-deleted gene showed significantly different expression compared to controls. CONCLUSIONS: Along with previously reported cases, clinical-molecular correlations in these two families further confirm that the functional hemizygosity for the GTF2I and GTF2IRD1 genes is the main cause of the neurocognitive profile and some aspects of the gestalt phenotype of WBS.

MAPT gene duplications are not a cause of frontotemporal lobar degeneration.

Recurrent deletions of the 17q21.31 region encompassing the microtubule-associated protein tau (MAPT) gene have recently been described in patients with mental retardation. This region is flanked by segmental duplications that make it prone to inversions, deletions and duplications. Since gain-of-function mutations of the MAPT gene cause frontotemporal lobar degeneration (FTLD) characterized by deposition of tau protein, we hypothesize that MAPT duplication affecting gene dosage could also lead to disease. Gene dosage alterations have already been found to be involved in the etiology of neurodegenerative disorders caused by protein or peptide accumulation, such as Alzheimer's and Parkinson's diseases. To determine whether MAPT gene copy number variation is involved in FTLD, 70 patients with clinical diagnosis of FTLD and no MAPT mutation (including 12 patients with pathologically proven tau-positive FTLD) were screened by using multiplex ligation probe amplification (MLPA) with specific oligonucleotide probes. No copy number variation in the MAPT gene was observed in cases. Although our study was limited by the relatively small number of patients, it does not support the theory that chromosomal rearrangements in this region are a cause of FTLD.

[Williams syndrome: its clinical aspects and molecular bases]. / Síndrome de Williams: aspectos clínicos y bases moleculares.

INTRODUCTION AND DEVELOPMENT: Williams syndrome is a developmental disorder with an estimated prevalence of 1 in 7,500 newborns. Its phenotype is characterized by distinctive facial features, mild to moderate mental retardation and general cognitive deficits with a non-uniform profile, having problems in some areas (psychomotricity, visuospatial integration) and relative preservation of others (language, musicality), friendly personality, occasional hypercalcemia of infancy, and a vasculopathy with supravalvular aortic stenosis. Williams syndrome is caused by a submicroscopic deletion of 1.55 Mb in the chromosome band 7q11.23, which includes 26-28 genes. The mutational mechanism consists in a misalignment between regions of almost identical sequence and the subsequent unequal recombination. The reciprocal product of this rearrangement is the duplication of this region, causing a language specific disorder. CONCLUSIONS: Clinical-molecular correlations establishment through a good phenotypic characterization and the precise analysis of breakpoints in patients with atypical and typical deletions, altogether with the design of animal models and functional studies in vitro for the genes of the interval will be important to be able to determine the exact contribution of the genes to the phenotype, to know their pathogenesis and physiopathology, and to identify therapeutic methods.

Síndrome de Williams: aspectos clínicos y bases moleculares / Williams syndrome: its clinical aspects and molecular bases

Introducción y desarrollo. El síndrome de Williams es untrastorno del desarrollo que ocurre en 1 de cada 7.500 recién nacidos.Se caracteriza por rasgos faciales típicos, retraso mental leveo moderado y asimétrico, con déficit notables en algunas áreas(psicomotricidad, integración visuoespacial) y relativa preservaciónde otras (lenguaje, musicalidad), personalidad amigable, hipercalcemiaocasional en la infancia y vasculopatía con estenosisaórtica supravalvular. Está causado por una deleción submicroscópicade 1,55-1,83 Mb en la banda cromosómica 7q11.23, la cualincluye 26-28 genes. El mecanismo mutacional consiste en un malalineamiento entre regiones de secuencia casi idéntica y la subsiguienterecombinación desigual. El producto recíproco de este reordenamientoes la duplicación de la región, causante de un cuadrodiferente con un trastorno grave del desarrollo del lenguaje. Conclusiones.El establecimiento de correlaciones clinicomolecularesa través de una buena caracterización fenotípica, el estudio precisode los puntos de rotura en pacientes con deleciones típicas y atípicas,acompañado del diseño de modelos animales y estudios funcionalesin vitro para los genes del intervalo, permiten determinarla contribución precisa de cada gen al fenotipo, conocer su patogeniay fisiopatología, e identificar métodos terapéuticos

Introduction and development. Williams syndrome is a developmental disorder with an estimated prevalence of 1 in7,500 newborns. Its phenotype is characterized by distinctive facial features, mild to moderate mental retardation and generalcognitive deficits with a non-uniform profile, having problems in some areas (psychomotricity, visuospatial integration) andrelative preservation of others (language, musicality), friendly personality, occasional hypercalcemia of infancy, and avasculopathy with supravalvular aortic stenosis. Williams syndrome is caused by a submicroscopic deletion of 1.55 Mb in thechromosome band 7q11.23, which includes 26-28 genes. The mutational mechanism consists in a misalignment betweenregions of almost identical sequence and the subsequent unequal recombination. The reciprocal product of this rearrangement isthe duplication of this region, causing a language specific disorder. Conclusions. Clinical-molecular correlations establishmentthrough a good phenotypic characterization and the precise analysis of breakpoints in patients with atypical and typicaldeletions, altogether with the design of animal models and functional studies in vitro for the genes of the interval will beimportant to be able to determine the exact contribution of the genes to the phenotype, to know their pathogenesis and physiopathology,and to identify therapeutic methods