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INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.
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OBJECTIVE: The precise relationship between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is incompletely understood. The association has been described as a continuum, yet data suggest that this may be an oversimplification. Direct comparisons between patients who have behavioural variant FTD (bvFTD) with and without ALS are rare. This prospective comparative study aimed to determine whether there are phenotypic differences in cognition and behaviour between patients with FTD-ALS and bvFTD alone. METHODS: Patients with bvFTD or FTD-ALS and healthy controls underwent neuropsychological testing, focusing on language, executive functions and social cognition. Behavioural change was measured through caregiver interview. Blood samples were screened for known FTD genes. RESULTS: 23 bvFTD, 20 FTD-ALS and 30 controls participated. On cognitive tests, highly significant differences were elicited between patients and controls, confirming the tests' sensitivities to FTD. bvFTD and FTD-ALS groups performed similarly, although with slightly greater difficulty in patients with ALS-FTD on category fluency and a sentence-ordering task that assesses grammar production. Patients with bvFTD demonstrated more widespread behavioural change, with more frequent disinhibition, impulsivity, loss of empathy and repetitive behaviours. Behaviour in FTD-ALS was dominated by apathy. The C9ORF72 repeat expansion was associated with poorer performance on language-related tasks. CONCLUSIONS: Differences were elicited in cognition and behaviour between bvFTD and FTD-ALS, and patients carrying the C9ORF72 repeat expansion. The findings, which raise the possibility of phenotypic variation between bvFTD and FTD-ALS, have clinical implications for early detection of FTD-ALS and theoretical implications for the nature of the relationship between FTD and ALS.
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Esclerosis Amiotrófica Lateral/psicología , Apatía , Proteína C9orf72/genética , Demencia Frontotemporal/psicología , Conducta Impulsiva , Inhibición Psicológica , Cognición Social , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Estudios de Casos y Controles , Empatía , Función Ejecutiva , Femenino , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/genética , Demencia Frontotemporal/fisiopatología , Genotipo , Humanos , Lenguaje , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fenotipo , Estudios Prospectivos , Conducta EstereotipadaRESUMEN
The progressive aging of the world's population makes a higher prevalence of neurodegenerative diseases inevitable. The necessity for an accurate, but at the same time, inexpensive and minimally invasive, diagnostic test is urgently required, not only to confirm the presence of the disease but also to discriminate between different types of dementia to provide the appropriate management and treatment. In this study, attenuated total reflection FTIR (ATR-FTIR) spectroscopy combined with chemometric techniques were used to analyze blood plasma samples from our cohort. Blood samples are easily collected by conventional venepuncture, permitting repeated measurements from the same individuals to monitor their progression throughout the years or evaluate any tested drugs. We included 549 individuals: 347 with various neurodegenerative diseases and 202 age-matched healthy individuals. Alzheimer's disease (AD; n = 164) was identified with 70% sensitivity and specificity, which after the incorporation of apolipoprotein ε4 genotype (APOE ε4) information, increased to 86% when individuals carried one or two alleles of ε4, and to 72% sensitivity and 77% specificity when individuals did not carry ε4 alleles. Early AD cases (n = 14) were identified with 80% sensitivity and 74% specificity. Segregation of AD from dementia with Lewy bodies (DLB; n = 34) was achieved with 90% sensitivity and specificity. Other neurodegenerative diseases, such as frontotemporal dementia (FTD; n = 30), Parkinson's disease (PD; n = 32), and progressive supranuclear palsy (PSP; n = 31), were included in our cohort for diagnostic purposes. Our method allows for both rapid and robust diagnosis of neurodegeneration and segregation between different dementias.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Apolipoproteína E4/sangre , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Espectroscopía Infrarroja por Transformada de Fourier/métodosRESUMEN
OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.
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Péptidos beta-Amiloides , Afasia Progresiva Primaria/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Afasia Progresiva Primaria/genética , Apolipoproteínas E/genética , Encéfalo/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , PrevalenciaRESUMEN
In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aß, with higher levels of Aß40 promoting a more 'aggressive' form of CAA, and higher levels of Aß42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Amiloide/metabolismo , Vasos Sanguíneos/metabolismo , Síndrome de Down/genética , Síndrome de Down/patología , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas E/genética , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/patología , Femenino , Duplicación de Gen , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Placa Amiloide/genética , Placa Amiloide/patologíaRESUMEN
BACKGROUND: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments. METHODS: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death. RESULTS: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model. CONCLUSIONS: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals.
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Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Cognición , Memoria Episódica , Pruebas Neuropsicológicas , Factores de Edad , Anciano , Anciano de 80 o más Años , Apolipoproteínas E/genética , Encéfalo/patología , Femenino , Genotipo , Humanos , Inmunohistoquímica , Estudios Longitudinales , MasculinoRESUMEN
OBJECTIVE: To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease. BACKGROUND: Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible. METHODS: Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach. RESULTS: Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers. CONCLUSIONS: Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Encéfalo/metabolismo , Memoria a Corto Plazo/fisiología , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Análisis de Varianza , Apolipoproteína E4/genética , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Femenino , Fluorodesoxiglucosa F18/metabolismo , Lóbulo Frontal/metabolismo , Humanos , Lenguaje , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones/métodosRESUMEN
A failure of protein degradation may underpin Lewy body disease (LBD) where α-synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites. We investigated histological alterations in lysosomes and autophagosomes in the substantia nigra (SN) and cingulate gyrus (CG) in 34 patients with LBD employing antibodies against phosphorylated α-synuclein and lysosomal (lysosomal associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2), cathepsin D (CTSD)) and autophagosomal (microtubule-associated protein light chain 3α (LC3A)) proteins. Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining. Four LBD patients had mutations in GBA1. There was significantly less LAMP-1, LAMP-2 and CTSD immunostaining in neurons of the SN in LBD cases compared to control cases and marginally less LAMP-1 in patients with GBA1 mutations compared to those without. Loss of LAMP-1 and CTSD immunoreactivity correlated with cell loss from the SN. There were no changes in LC3A immunoreactivity in the SN, nor any major changes in the CG, or glial cell activity in the SN and CG, for any of the markers. A proportion of amyloid plaques in both the LBD and control cases was immunoreactive for LAMP-1 and LAMP-2, but not CTSD or LC3A proteins. These immunohisochemical features were seen in glial cells, which were negative for amyloid-ß. Alterations in lysosomal structure or function, but not macroautophagy, may underpin the pathogenesis of LBD.
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BACKGROUND: A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS-FTD) is indistinguishable from that of bvFTD alone. METHODS: A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment. RESULTS: A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (p<0.001), inertia (p<0.001), loss of sympathy and empathy (p=0.008), repetitive behaviours (p<0.001) and dietary changes (p<0.001). Warmth of affect demonstrated in the clinic setting was reported more often in ALS-FTD than bvFTD (p<0.001). Executive impairments occurred equally in both groups. Language impairments were more common in ALS-FTD than bvFTD: agrammatism (p<0.017) and impaired sentence comprehension (p<0.036). Psychotic features were relatively rare and did not distinguish the groups. CONCLUSIONS: Our findings suggest differences between bvFTD and ALS-FTD. In particular, while changes in social behaviour are prominent in bvFTD alone, there may be a comparatively greater degree of language impairment in ALS-FTD. Prospective exploration of the pattern of differences between these groups will be essential. Identification of a distinct neuropsychological phenotype in ALS-FTD may have clinical implications for early diagnosis, disease management and care planning and theoretical implications for our understanding of the relationship between ALS and FTD.
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Esclerosis Amiotrófica Lateral/diagnóstico , Demencia Frontotemporal/diagnóstico , Trastornos del Lenguaje/diagnóstico , Trastorno de la Conducta Social/diagnóstico , Anciano , Afasia de Broca/diagnóstico , Trastornos de la Percepción Auditiva/diagnóstico , Estudios de Cohortes , Diagnóstico Diferencial , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/diagnóstico , Pruebas Neuropsicológicas , Estudios RetrospectivosRESUMEN
INTRODUCTION: A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. METHODS: Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. RESULTS: A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal degeneration [PCA-CBD], prion disease [PCA-prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome-level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. DISCUSSION: There was strong agreement regarding the definition of the core clinico-radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single-center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.
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Encefalopatías/clasificación , Encéfalo/diagnóstico por imagen , Encefalopatías/diagnóstico por imagen , Encefalopatías/fisiopatología , Encefalopatías/psicología , HumanosRESUMEN
INTRODUCTION: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. METHODS: We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. RESULTS: We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]). DISCUSSION: We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.
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Enfermedad de Alzheimer/genética , Moléculas de Adhesión Celular Neuronal/genética , Corteza Cerebral/patología , Predisposición Genética a la Enfermedad/genética , Proteínas/genética , Semaforinas/genética , Factores de Edad , Anciano , Enfermedad de Alzheimer/complicaciones , Apolipoproteínas E/genética , Atrofia/etiología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Polimorfismo de Nucleótido Simple/genética , Polinucleotido Adenililtransferasa , Receptores de Complemento 3b/genética , Factores de RiesgoRESUMEN
AIMS: Frontotemporal lobar degeneration (FTLD) is clinically and pathologically heterogeneous. Although associated with variations in MAPT, GRN and C9ORF72, the pathogenesis of these, and of other nongenetic, forms of FTLD, remains unknown. Epigenetic factors such as histone regulation by histone deacetylases (HDAC) may play a role in the dysregulation of transcriptional activity, thought to underpin the neurodegenerative process. METHODS: The distribution and intensity of HDACs 4, 5 and 6 was assessed semi-quantitatively in immunostained sections of temporal cortex with hippocampus, and cerebellum, from 33 pathologically confirmed cases of FTLD and 27 controls. RESULTS: We found a significantly greater intensity of cytoplasmic immunostaining for HDAC4 and HDAC6 in granule cells of the dentate gyrus in cases of FTLD overall compared with controls, and specifically in cases of FTLD tau-Picks compared with FTLD tau-MAPT and controls. No differences were noted between FTLD-TDP subtypes, or between the different genetic and nongenetic forms of FTLD. No changes were seen in HDAC5 in any FTLD or control cases. CONCLUSIONS: Dysregulation of HDAC4 and/or HDAC6 could play a role in the pathogenesis of FTLD-tau associated with Pick bodies, although their lack of immunostaining implies that such changes do not contribute directly to the formation of Pick bodies.
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Giro Dentado/patología , Degeneración Lobar Frontotemporal/enzimología , Degeneración Lobar Frontotemporal/patología , Histona Desacetilasas/biosíntesis , Proteínas Represoras/biosíntesis , Anciano , Femenino , Histona Desacetilasa 6 , Histona Desacetilasas/análisis , Historia del Siglo XVI , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas Represoras/análisisRESUMEN
BACKGROUND: Clinical criteria are important for improving diagnostic accuracy and ensuring comparability of patient cohorts in research studies. OBJECTIVE: The aim was to assess the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer's disease (AD) dementia in AD and frontotemporal lobar degeneration (FTLD). METHODS: Two hundred twelve consecutive patients with pathologically confirmed AD or FTLD who were clinically assessed in a specialist cognitive unit were identified. Fifty-five patients were excluded predominantly because of insufficient clinical information. Anonymized clinical data were rated against the NIA-AA criteria by raters who were blinded to clinical and pathologic diagnosis. RESULTS: The NIA-AA AD dementia criteria had a sensitivity of 65.6% for probable and 79.5% for possible AD and a specificity of 95.2% and 94.0% for probable and possible, respectively. CONCLUSION: In patients with FTLD and predominantly early-onset AD, the NIA-AA AD dementia criteria have high specificity but lower sensitivity. The high specificity is due to the broad exclusion criteria.
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Enfermedad de Alzheimer/diagnóstico , Demencia Frontotemporal/diagnóstico , Indicadores de Salud , Anciano , Enfermedad de Alzheimer/patología , Encéfalo/patología , Estudios de Cohortes , Diagnóstico Diferencial , Reacciones Falso Negativas , Reacciones Falso Positivas , Femenino , Demencia Frontotemporal/patología , Humanos , Masculino , Persona de Mediana Edad , National Institute on Aging (U.S.) , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estados UnidosRESUMEN
INTRODUCTION: Frontotemporal lobar degeneration (FTLD) is classified mainly into FTLD-tau and FTLD-TDP according to the protein present within inclusion bodies. While such a classification implies only a single type of protein should be present, recent studies have demonstrated dual tau and TDP-43 proteinopathy can occur, particularly in inherited FTLD. METHODS: We therefore investigated 33 patients with FTLD-tau (including 9 with MAPT mutation) for TDP-43 pathological changes, and 45 patients with FTLD-TDP (including 12 with hexanucleotide expansion in C9ORF72 and 12 with GRN mutation), and 23 patients with motor neurone disease (3 with hexanucleotide expansion in C9ORF72), for tauopathy. RESULTS: TDP-43 pathological changes, of the kind seen in many elderly individuals with Alzheimer's disease, were seen in only two FTLD-tau cases--a 70-year-old male with exon 10 + 13 mutation in MAPT, and a 73-year-old female with corticobasal degeneration. Such changes were considered to be secondary and probably reflective of advanced age. Conversely, there was generally only scant tau pathology, usually only within hippocampus and/or entorhinal cortex, in most patients with FTLD-TDP or MND. The extent of tau pathology in FTLD-TDP and MND, as with amyloid ß protein, may relate to increased age and possession of Apolipoprotein ε4 allele. CONCLUSION: We find no predilection or predisposition towards an accompanying TDP-43 pathology in patients with FTLD-tau, irrespective of presence or absence of MAPT mutation, or that genetic changes associated with FTLD-TDP predispose towards excessive tauopathy. Where the two processes coexist, this is limited and probably causatively independent of each other.
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Corteza Cerebral/metabolismo , Proteínas de Unión al ADN/genética , Degeneración Lobar Frontotemporal/genética , Enfermedad de la Neurona Motora/genética , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Proteína C9orf72 , Femenino , Humanos , Cuerpos de Inclusión/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Persona de Mediana Edad , Progranulinas , Proteínas/genéticaRESUMEN
AIMS: Pathological heterogeneity within patients with frontotemporal lobar degeneration (FTLD) in general precludes the accurate assignment of diagnostic subtype in life. The aim of this study was to assess the extent of microglial cell activation in FTLD in order to determine whether it might be possible to employ this as a diagnostic marker in vivo using PET ligand [11C](R)-PK11195 in order to differentiate cases of FTLD according to histological subtype. METHODS: The distribution and extent of microglial cell activation was assessed semi-quantitatively in cortical grey and subcortical white matter of CD68 immunostained sections of frontal and temporal cortex from 78 pathologically confirmed cases of FTLD, 13 of Alzheimer's disease (AD) and 13 controls. RESULTS: Significantly higher levels of microglial cell activation than controls occurred in all four regions in FTLD, and in three of the four regions in AD. Microglial activation was greater in frontal subcortical white matter in FTLD than AD, whereas it was higher in temporal cortical grey matter in AD than FTLD. Microglial cell activation was significantly higher in temporal subcortical white matter in FTLD-MAPT than in other genetic (GRN, C9ORF72) or non-genetic forms of FTLD. CONCLUSIONS: The present study suggests that high levels of microglial cell involvement in temporal lobe (subcortical white matter) might serve as a marker of inherited FTLD associated with intronic mutations in MAPT, with a relatively intense signal in this region in PET studies using [11C](R)-PK11195 as microglial cell marker could indicate the presence of MAPT mutation in vivo.
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Encéfalo/patología , Degeneración Lobar Frontotemporal/patología , Microglía/patología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Biomarcadores , Femenino , Sustancia Gris/patología , Humanos , Masculino , Persona de Mediana Edad , Sustancia Blanca/patologíaAsunto(s)
Demencia Frontotemporal/fisiopatología , Parálisis Supranuclear Progresiva/fisiopatología , Anciano , Proteínas de Unión al ADN/metabolismo , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Parálisis Supranuclear Progresiva/complicaciones , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Delirium is common and is associated with an increased risk of dementia. However, it is not clear whether delirium confers increased risk of any particular type of dementia. We performed a retrospective study of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) to ascertain whether a suspected episode of preceding delirium was more common prior to diagnosis in either type of dementia. METHODS: The study was carried out in a tertiary referral unit for the diagnosis of dementia. Clinic letters from the first presentation to the unit of 85 cases with DLB and 95 cases of AD were reviewed for documentation of any previous episodes of suspected delirium. RESULTS: In this study, 25% of DLB cases had at least one reported episode of suspected delirium as compared to 7% of AD cases (p = 0.001). For the DLB cases who had a prior suspected delirium, 23% had more than one episode compared with 14% of the AD group. The median time between most recent suspected episode of delirium and diagnosis of dementia in both groups was less than a year CONCLUSIONS: A greater proportion of those presenting and diagnosed with DLB had a documentation of a suspected delirium than those diagnosed with AD. Delirium may lead to a higher risk of DLB as opposed to other forms of dementia, or delirium may, at least in some cases, represent the early stages of DLB. These data suggest that a diagnosis of DLB should be specifically considered in those presenting with a delirium.
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Enfermedad de Alzheimer/psicología , Delirio/epidemiología , Enfermedad por Cuerpos de Lewy/psicología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Prevalencia , Estudios Retrospectivos , RiesgoRESUMEN
BACKGROUND: Decline in verbal episodic memory is a core feature of amnestic mild cognitive impairment (aMCI). The delayed story recall (DSR) test from the Adult Memory and Information Processing Battery (AMIPB) discriminates MCI from normal aging and predicts its conversion to Alzheimer's dementia. However, there is no study that validates the Chinese version of the DSR and reports cut-off scores in the Chinese population. METHODS: A total of 631 subjects were screened in the memory clinics of Dongzhimen Hospital, Beijing University of Chinese Medicine, China. 249 were considered to have normal cognition (NC), 134 met diagnostic criteria for MCI according to the MCI Working Group of the European Consortium on Alzheimer's Disease, and 97 met criteria for probable Alzheimer's disease (AD) according to the NINCDS/ADRDA criteria, 14 exhibited vascular dementia (VaD), and 50 had a diagnosis of another type of dementia. Receiver operating characteristic (ROC) curve analyses were used to calculate the story recall cutoff score for detecting MCI and AD. Normative data in the NC group were obtained as a function of age and education. RESULTS: In this Chinese sample, the normative mean DSR score was 28.10 ± 8.54 in the 50-64 year-old group, 26.22 ± 8.38 in the 65-74 year-old group, and 24.42 ± 8.38 in the 75-85 year-old group. DSR performance was influenced by age and education. The DSR test had high sensitivity (0.899) and specificity (0.799) in the detection of MCI from NC using a cut-off score of 15.5. When the cutoff score was 10.5, the DSR test obtained optimal sensitivity (0.980) and specificity (0.938) in the discrimination of AD from NC. Cutoff scores and diagnostic values were calculated stratified by age and education. CONCLUSIONS: The Chinese version of the DSR can be used as a screening tool to detect MCI and AD with high sensitivity and specificity, and it could be used to identify people at high risk of cognitive impairment.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Tamizaje Masivo/métodos , Recuerdo Mental , Pruebas Neuropsicológicas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Pueblo Asiatico , China , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Curva ROC , Sensibilidad y Especificidad , TraducciónRESUMEN
Progressive non-fluent aphasia (PNFA) is typically associated with pathological changes consistent with frontotemporal lobar degeneration. A 65-year-old male presented with effortful speech, markedly impaired naming and features of speech apraxia, consistent with PNFA. Perceptuospatial function, calculation and executive function were intact. Brain SPECT showed left perisylvian hypoperfusion. He deteriorated profoundly over the subsequent eight months, with appearances on diffusion-weighted magnetic resonance imaging typical of sporadic Creutzfeldt-Jakob disease, which was confirmed pathologically at postmortem examination. While the presence of PNFA with speech apraxia is thought to predict underlying tauopathy, sporadic Creutzfeldt-Jakob disease may mimic this presentation and present in a highly circumscribed form not previously described.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/psicología , Afasia Progresiva Primaria no Fluente/diagnóstico , Afasia Progresiva Primaria no Fluente/psicología , Anciano , Diagnóstico Diferencial , Humanos , MasculinoRESUMEN
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.