RESUMEN
The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer's disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer's disease (n = 17), primary tauopathies (n = 8), synucleinopathies (n = 27), frontotemporal lobar degeneration (n = 8), mixed pathology (n = 11), other neurodegenerative diseases (n = 6), and cognitively normal controls (n = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer's disease, primary tauopathies and controls with Alzheimer's disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (n = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (n = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (n = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (n = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates associated with the main neurodegenerative disease. These findings indicate that with appropriate retinal imaging techniques, retinal biomarkers have the potential to become highly accurate indicators for diagnosing the major neurodegenerative diseases of the brain.
Asunto(s)
Enfermedades Neurodegenerativas , Retina , Proteínas tau , Humanos , Anciano , Femenino , Masculino , Retina/patología , Retina/metabolismo , Anciano de 80 o más Años , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/metabolismo , Proteínas tau/metabolismo , Persona de Mediana Edad , alfa-Sinucleína/metabolismo , Autopsia , Tauopatías/patología , Tauopatías/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas de Unión al ADN/metabolismoRESUMEN
The biological definition of Alzheimer's disease using CSF biomarkers requires abnormal levels of both amyloid (A) and tau (T). However, biomarkers and corresponding cutoffs may not always reflect the presence or absence of pathology. Previous studies suggest that up to 32% of individuals with autopsy-confirmed Alzheimer's disease show normal CSF p-tau levels in vivo, but these studies are sparse and had small sample sizes. Therefore, in three independent autopsy cohorts, we studied whether or not CSF A+T- excluded Alzheimer's disease based on autopsy. We included 215 individuals, for whom ante-mortem CSF collection and autopsy had been performed, from three cohorts: (i) the Amsterdam Dementia Cohort (ADC) [n = 80, 37 (46%) Alzheimer's disease at autopsy, time between CSF collection and death 4.5 ± 2.9 years]; (ii) the Antwerp Dementia Cohort (DEM) [n = 92, 84 (91%) Alzheimer's disease at autopsy, time CSF collection to death 1.7 ± 2.3 years]; and (iii) the Alzheimer's Disease Neuroimaging Initiative (ADNI) [n = 43, 31 (72%) Alzheimer's disease at autopsy, time CSF collection to death 5.1 ± 2.5 years]. Biomarker profiles were based on dichotomized CSF Aß1-42 and p-tau levels. The accuracy of CSF AT profiles to detect autopsy-confirmed Alzheimer's disease was assessed. Lastly, we investigated whether the concordance of AT profiles with autopsy diagnosis improved when CSF was collected closer to death in 9 (10%) DEM and 30 (70%) ADNI individuals with repeated CSF measurements available. In total, 50-73% of A+T- individuals and 100% of A+T+ individuals had Alzheimer's disease at autopsy. Amyloid status showed the highest accuracy to detect autopsy-confirmed Alzheimer's disease (accuracy, sensitivity and specificity in the ADC: 88%, 92% and 84%; in the DEM: 87%, 94% and 12%; and in the ADNI cohort: 86%, 90% and 75%, respectively). The addition of CSF p-tau did not further improve these estimates. We observed no differences in demographics or degree of Alzheimer's disease neuropathology between A+T- and A+T+ individuals with autopsy-confirmed Alzheimer's disease. All individuals with repeated CSF measurements remained stable in Aß1-42 status during follow-up. None of the Alzheimer's disease individuals with a normal p-tau status changed to abnormal; however, four (44%) DEM individuals and two (7%) ADNI individuals changed from abnormal to normal p-tau status over time, and all had Alzheimer's disease at autopsy. In summary, we found that up to 73% of A+T- individuals had Alzheimer's disease at autopsy. This should be taken into account in both research and clinical settings.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Proteínas tau , Biomarcadores , Sensibilidad y Especificidad , Fragmentos de PéptidosRESUMEN
BACKGROUND: Phosphorylated tau (p-tau) accumulation, a hallmark of Alzheimer's disease (AD), can also be found in the retina. However, it is uncertain whether it is linked to AD or another tauopathy. METHODS: Retinas from 164 individuals, with and without AD, were analyzed for p-tau accumulation and its relationship with age, dementia, and vision impairment. RESULTS: Retinal p-tau pathology showed a consistent pattern with four stages and a molecular composition distinct from that of cerebral tauopathies. The stage of retinal p-tau pathology correlated with age (r = 0.176, P = 0.024) and was associated with AD (odds ratio [OR] 3.193; P = 0.001), and inflammation (OR = 2.605; P = 0.001). Vision impairment was associated with underlying eye diseases (ß = 0.292; P = 0.001) and the stage of retinal p-tau pathology (ß = 0.192; P = 0.030) in a linear regression model. CONCLUSIONS: The results show the presence of a primary retinal tauopathy that is distinct from cerebral tauopathies.
Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Humanos , Tauopatías/patología , Proteínas tau , Enfermedad de Alzheimer/patología , RetinaRESUMEN
The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer's disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies.
Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Humanos , Enfermedad de Alzheimer/patología , Fosforilación , Proteínas tau/metabolismo , Tauopatías/patología , Encéfalo/patología , Retina/patología , EpítoposRESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia, and due to increasing life expectancy the number of patients is expected to grow. The diagnosis of AD involves the use of biomarkers determined by an amyloid PET scan or cerebrospinal fluid analyses that are either invasive or expensive, and not available in each hospital, thus limiting their usage as a front-line screener. The TearAD study aims to use tear fluid as a potential source for AD biomarkers. In previous reports, we demonstrated that AD biomarkers amyloid-beta and tau, are measurable in tear fluid and are associated with disease severity and neurodegeration. This study aims to validate previous results in a larger cohort and evaluate the diagnostic accuracy of tear biomarkers to discriminate between individuals with and without neurodegeneration as determined by hippocampal atrophy. METHODS: The TearAD study is an observational longitudinal multi-center study that will enroll 50 cognitively healthy controls, 50 patients with subjective cognitive decline, 50 patients with mild cognitive impairment and 50 patients with AD dementia from the memory clinic. Participants will be examined at baseline, after one year, and after two years follow-up. Study assessments include neuropsychological tests and ophthalmic examination. All participants will receive a MRI scan, and a subset of the study population will undergo cerebral spinal fluid collection and an amyloid PET scan. Tear fluid will be collected with Schirmer strips and levels of Aß38, Aß40, Aß42, t-tau and p-tau in tear fluid will be determined using multiplex immunoassays. Blood samples will be collected from all participants. Images of the retina will be obtained with a standard, hyperspectral and ultra-wide field fundus camera. Additionally, macular pigment optical density will be measured with the macular pigment reflectometer, and cross-sectional images of the retina will be obtained through optical coherence tomography imaging. DISCUSSION: The TearAD study will provide insight into the potential diagnostic use of tear biomarkers as a minimally invasive and low cost tool for the screening and diagnosis of AD. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov (NCT05655793).
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Pigmento Macular , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Disfunción Cognitiva/psicología , Biomarcadores/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Fragmentos de PéptidosRESUMEN
Cognitive deficits in Alzheimer's disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The cholinergic nucleus within the basal forebrain, the nucleus basalis of Meynert, exhibits local atrophy and reduced cortical tract integrity on MRI, and reveals amyloid-ß and phosphorylated-tau pathology at autopsy. To understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimer's disease, we used a combined post-mortem in situ MRI and histopathology approach. A total of 19 Alzheimer's disease (10 amnestic and nine non-amnestic) and nine non-neurological control donors underwent 3 T T1-weighted MRI for anatomical delineation and volume assessment of the nucleus basalis of Meynert, and diffusion-weighted imaging for microstructural assessment of the nucleus and its projections. At subsequent brain autopsy, tissue dissection and immunohistochemistry were performed for amyloid-ß, phosphorylated-tau and choline acetyltransferase. Compared to controls, we observed an MRI-derived volume reduction and altered microstructural integrity of the nucleus basalis of Meynert in Alzheimer's disease donors. Furthermore, decreased cholinergic cell density was associated with reduced integrity of the nucleus and its tracts to the temporal lobe, specifically to the temporal pole of the superior temporal gyrus, and the parahippocampal gyrus. Exploratory post hoc subgroup analyses indicated that cholinergic cell density could be associated with cortical tract alterations in amnestic Alzheimer's disease donors only. Our study illustrates that in Alzheimer's disease, cholinergic degeneration in the nucleus basalis of Meynert may contribute to damaged cortical projections, specifically to the temporal lobe, leading to cognitive deterioration.
Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Péptidos beta-Amiloides , Atrofia , Núcleo Basal de Meynert , Recuento de Células , Colinérgicos , HumanosRESUMEN
INTRODUCTION: We aim to study the effect of a more precise diagnosis, by means of amyloid positron emission tomography (PET), on institutionalization, mortality, and health-care costs. METHODS: Between October 27, 2014 and December 31, 2016, we offered amyloid PET to all patients as part of their diagnostic work-up. Patients who accepted to undergo amyloid PET (n = 449) were propensity score matched with patients without amyloid PET (n = 571, i.e., no PET). Matched groups (both n = 444) were compared on rate of institutionalization, mortality, and health-care costs in the years after diagnosis. RESULTS: Amyloid PET patients had a lower risk of institutionalization (10% [n = 45] vs. 21% [n = 92]; hazard ratio [HR] = 0.48 [0.33-0.70]) and mortality rate (11% [n = 49] vs. 18% [n = 81]; HR = 0.51 [0.36-0.73]) and lower health-care costs in the years after diagnosis compared to matched no-PET patients (ß = -4573.49 [-6524.76 to -2523.74], P-value < 0.001). DISCUSSION: A more precise diagnosis in tertiary memory clinic patients positively influenced the endpoints of institutionalization, death, and health-care costs.
Asunto(s)
Enfermedad de Alzheimer , Tomografía de Emisión de Positrones , Humanos , Tomografía de Emisión de Positrones/métodos , Amiloide , Proteínas Amiloidogénicas , Institucionalización , Péptidos beta-Amiloides , Enfermedad de Alzheimer/diagnóstico por imagenRESUMEN
INTRODUCTION: Computer tools based on artificial intelligence could aid clinicians in memory clinics by supporting diagnostic decision-making and communicating diagnosis and prognosis. We aimed to identify preferences of end-users, and barriers and facilitators for using computer tools in memory clinics. METHODS: Between July and October 2020, we invited European clinicians (n=109, age 45±10y; 47% female) to participate in an online questionnaire. A second questionnaire was sent to patients (n=50, age 73±8y, 34% female) with subjective cognitive complaints (SCD, n=21), mild cognitive impairment (MCI, n=16) and dementia (n=13) and care partners (n=46, 65±12y, 54% female). RESULTS: The vast majority (75%) of all participants positively valued the use of computer tools in memory clinics. Facilitating factors included user-friendliness and increased diagnostic accuracy. Barriers included (doubts relating) reliability and validity of the tool and loss of clinical autonomy. The participants believe that tools should be used in addition to the current working method and not as a replacement. DISCUSSION: Our results provide an important step in the iterative process of developing computer tools for memory clinics in co-creation with end-users and could guide successful implementation.
Asunto(s)
Inteligencia Artificial , Cuidadores , Humanos , Femenino , Anciano , Anciano de 80 o más Años , Masculino , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , ComputadoresRESUMEN
AIMS: The loss of von Economo neurons (VENs) and GABA receptor subunit theta (GABRQ) containing neurons is linked to early changes in social-emotional cognition and is seen in frontotemporal dementia (FTD) due to C9orf72 repeat expansion. We investigate the vulnerability of VENs and GABRQ-expressing neurons in sporadic and genetic forms of FTD with different underlying molecular pathology and their association with the presence and severity of behavioural symptoms. METHODS: We quantified VENs and GABRQ-immunopositive neurons in the anterior cingulate cortex (ACC) in FTD with underlying TDP43 (FTLD-TDP) (n = 34), tau (FTLD-tau) (n = 24) or FUS (FTLD-FUS) (n = 8) pathology, neurologically healthy controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we quantified VENs and the GABRQ-expressing population in relation to presence of behavioural symptoms in the first years of disease onset. RESULTS: The number of VENs and GABRQ-expressing neurons and the ratio of VENs and GABRQ-expressing neurons over total Layer 5 neuronal population decreased in FTLD-TDP and FTLD-FUS, but not in FTLD-tau, compared to control and AD. The severity of early behavioural symptoms in all donors correlated with a lower VEN and GABRQ neuronal count. CONCLUSION: We show that in FTD, a loss of VENs together with GABRQ-expressing pyramidal neurons is associated with TDP43 and FUS pathology. No significant loss was found in donors with FTLD-tau pathology; however, this could be due to the specific MAPT mutation studied and small sporadic FTLD-tau sample size. Overall, we show the GABRQ-expressing population correlates with behavioural changes and suggest they are key in modulating behaviour in FTD.
Asunto(s)
Enfermedad de Alzheimer , Demencia Frontotemporal , Enfermedad de Alzheimer/patología , Síntomas Conductuales , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Giro del Cíngulo/patología , Humanos , Neuronas/patología , Células Piramidales/patología , Receptores de GABA-A/genéticaRESUMEN
INTRODUCTION: The impact of amyloid positron emission tomography (PET) imaging on patient health outcomes for individuals with dementia is unknown. In the present study, we explored the association between diagnostic outcome and clinician's level of certainty with quality of life (QoL) after [18F]flutemetamol PET results were disclosed in young onset dementia patients in a memory clinic cohort. METHODS: In 154 patients suspected of dementia, QoL was measured before and after [18F]flutemetamol PET results were disclosed. Multiple regression analyses were conducted with (changed) general and disease-specific QoL measures as dependent factors [QoL-Alzheimer disease (AD) and EQ-5D Dutch tariff] and etiological diagnosis and clinician's certainty as independent factors. RESULTS: (Change in) diagnosis of AD was associated to QOL in 2 of the 4 analyses (utility-based QoL ß=0.15, P=0.010; disease-specific QoL ß=2.0, P=0.037). Diagnostic certainty was associated to QOL in 1 of the 4 analyses (generic QoL ß=0.002, P=0.028). DISCUSSION: The diverse results in this explorative analysis do not reflect a univocal association between diagnosis, certainty, and QoL. Nevertheless, this result could be interpreted as a possible potential for advanced diagnostic technologies for AD, which requires confirmation in future research.
Asunto(s)
Enfermedad de Alzheimer , Calidad de Vida , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide , Revelación , Humanos , Tomografía de Emisión de Positrones/métodosRESUMEN
In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico por imagen , Retina/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Biomarcadores , Encéfalo/diagnóstico por imagen , Humanos , Persona de Mediana EdadRESUMEN
Alzheimer's disease (AD) is characterized by amyloid-beta (Aß) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aß deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aß-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aß-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrPC), Aß isoform composition (Aß40, Aß42, AßN3pE, pSer8Aß), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aß40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aß40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aß plaque-type associated with EOAD. Differences in Aß processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aß deposits. Disentangling specific Aß deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.
Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Placa Amiloide/patología , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Capilares/patología , Angiopatía Amiloide Cerebral/genética , Femenino , Humanos , Masculino , Neuritas/patologíaRESUMEN
BACKGROUND: The development of novel diagnostics enables increasingly earlier diagnosis of Alzheimer's disease (AD). Timely diagnosis may benefit patients by reducing their uncertainty regarding the cause of symptoms, yet does not always provide patients with the desired certainty. OBJECTIVE: To examine, using both quantitative and qualitative methods, uncertainty communicated by memory clinic clinicians in post-diagnostic testing consultations with patients and their caregivers. METHODS: First, we identified all uncertainty expressions of 22 clinicians in audiotaped post-diagnostic testing consultations with 78 patients. Second, we statistically explored relationships between patient/clinician characteristics and uncertainty expressions. Third, the transcribed uncertainty expressions were qualitatively analysed, determining the topic to which they pertained, their source and initiator/elicitor (clinicians/patients/caregivers). RESULTS: Within 57/78 (73%) consultations, clinicians expressed in total 115 uncertainties, of which 37% elicited by the patient or caregiver. No apparent relationships were found between patient/clinician characteristics and whether or not, and how often clinicians expressed uncertainty. Uncertainty expressions pertained to ten different topics, most frequently patient's diagnosis and symptom progression. Expressed uncertainty was mostly related to the unpredictability of the future and limits to available knowledge. DISCUSSION AND CONCLUSIONS: The majority of clinicians openly discussed the limits of scientific knowledge and diagnostic testing with patients and caregivers in the dementia context. Noticeably, clinicians did not discuss uncertainty in about one quarter of consultations. More evidence is needed on the beneficial and/or harmful effects on patients of discussing uncertainty with them. This knowledge can be used to support clinicians to optimally convey uncertainty and facilitate patients' uncertainty management.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Comunicación , Pruebas Diagnósticas de Rutina , Revelación , Personal de Salud/estadística & datos numéricos , Pacientes/estadística & datos numéricos , Incertidumbre , Anciano , Instituciones de Atención Ambulatoria , Cuidadores/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Pacientes/psicología , Investigación CualitativaRESUMEN
OBJECTIVES: Memory clinics (MCs) have been established to improve diagnosis and treatment of cognitive disorders, including dementia. The aim of this study was to determine the characteristics and working methods of MCs in the Netherlands in 2016. More insight into different working methods can be used to improve the quality of care in Dutch MCs. Additionally, the findings will be compared with earlier results to investigate the development of MCs since 1998. METHODS: A survey was sent in 1998, 2004, 2009, and 2017 to all operational Dutch MCs with questions about organization, collaboration, patients, and diagnostic procedures. RESULTS: From 1998 to 2016, the number of MCs increased substantially from 12 to 91. The capacity increased from 1560 patients to 24,388. In 1998, most patients received a dementia diagnosis (85%), while in 2016, half of the patients were diagnosed with milder cognitive problems. MCs are more often part of regional care chains and are better embedded within regional care organizations. Diagnostic tools, such as blood tests (97%), neuropsychological assessment (NPA) (95%), and neuroimaging (92%), were used in nearly all MCs. The number of patients in whom these tools were used differed greatly between MCs (NPA: 5%-100%, neuroimaging: 10%-100%, and CSF: 0.5%-80%). There was an increase in the use of NPA, while the use of neuroimaging, CSF, and EEG/ECG decreased by 8% to 15% since 2009. CONCLUSIONS: Since 1998, MCs have developed substantially and outgrown the primarily research-based university settings. They are now accepted as regular care facilities for people with cognitive problems.
Asunto(s)
Trastornos del Conocimiento/terapia , Centros Comunitarios de Salud Mental/organización & administración , Trastornos de la Memoria/terapia , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/diagnóstico , Centros Comunitarios de Salud Mental/tendencias , Femenino , Humanos , Masculino , Trastornos de la Memoria/diagnóstico , Persona de Mediana Edad , Países Bajos , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: While most patients with Alzheimer's disease (AD) present with memory complaints, 30% of patients with early disease onset present with non-amnestic symptoms. This atypical presentation is thought to be caused by a different spreading of neurofibrillary tangles (NFT) than originally proposed by Braak and Braak. Recent studies suggest a prominent role for neuroinflammation in the spreading of tau pathology. METHODS: We aimed to explore whether an atypical spreading of pathology in AD is associated with an atypical distribution of neuroinflammation. Typical and atypical AD cases were selected based on both NFT distribution and amnestic or non-amnestic clinical presentation. Immunohistochemistry was performed on the temporal pole and superior parietal lobe of 10 typical and 9 atypical AD cases. The presence of amyloid-beta (N-terminal; IC16), pTau (AT8), reactive astrocytes (GFAP), microglia (Iba1, CD68, and HLA-DP/DQ/DR), and complement factors (C1q, C3d, C4b, and C5b-9) was quantified by image analysis. Differences in lobar distribution patterns of immunoreactivity were statistically assessed using a linear mixed model. RESULTS: We found a temporal dominant distribution for amyloid-beta, GFAP, and Iba1 in both typical and atypical AD. Distribution of pTau, CD68, HLA-DP/DQ/DR, C3d, and C4b differed between AD variants. Typical AD cases showed a temporal dominant distribution of these markers, whereas atypical AD cases showed a parietal dominant distribution. Interestingly, when quantifying for the number of amyloid-beta plaques instead of stained surface area, atypical AD cases differed in distribution pattern from typical AD cases. Remarkably, plaque morphology and localization of neuroinflammation within the plaques was different between the two phenotypes. CONCLUSIONS: Our data show a different localization of neuroinflammatory markers and amyloid-beta plaques between AD phenotypes. In addition, these markers reflect the atypical distribution of tau pathology in atypical AD, suggesting that neuroinflammation might be a crucial link between amyloid-beta deposits, tau pathology, and clinical symptoms.
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Enfermedad de Alzheimer/patología , Citocinas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Lóbulo Parietal/metabolismo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Autopsia , Proteínas de Unión al Calcio , Proteínas del Sistema Complemento/metabolismo , Femenino , Humanos , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Ovillos Neurofibrilares/metabolismo , Proteínas tau/metabolismoRESUMEN
OBJECTIVE: To investigate whether subcortical grey matter atrophy predicts progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), and to compare subcortical volumes between AD, MCI and controls. To assess the correlation between subcortical grey matter volumes and severity of cognitive impairment. METHODS: We included 773 participants with three-dimensional T1-weighted MRI at 3 T, made up of 181 controls, who had subjective memory symptoms with normal cognition, 201 MCIs and 391 AD. During follow-up (2.0 ± 0.9 years), 35 MCIs converted to AD (progressive MCI) and 160 MCIs remained stable (stable MCI). We segmented volumes of six subcortical structures of the amygdala, thalamus, caudate nucleus, putamen, globus pallidus and nucleus accumbens, and of the hippocampus, using FMRIBs integrated registration and segmentation tool. RESULTS: Analysis of variances, adjusted for sex and age, showed that all structures, except the globus pallidus, were smaller in AD than in controls. In addition, the amygdala, thalamus, putamen, nucleus accumbens and hippocampus were smaller in MCIs than in controls. Across groups, all subcortical greymatter volumes, except the globus pallidus, showed a positive correlation with cognitive function, as measured by Mini Mental State Examination (MMSE) (0.16Asunto(s)
Enfermedad de Alzheimer/patología
, Disfunción Cognitiva/patología
, Sustancia Gris/patología
, Factores de Edad
, Anciano
, Anciano de 80 o más Años
, Enfermedad de Alzheimer/psicología
, Atrofia
, Disfunción Cognitiva/psicología
, Progresión de la Enfermedad
, Escolaridad
, Femenino
, Humanos
, Procesamiento de Imagen Asistido por Computador
, Imagen por Resonancia Magnética
, Masculino
, Memoria
, Persona de Mediana Edad
, Pruebas Neuropsicológicas
, Factores Sexuales
RESUMEN
BACKGROUND: We aimed to assess the impact of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease on decision making and patient management in a tertiary memory clinic. METHODS: We included all patients, for 1 year, visiting the VUmc Alzheimer Center for cognitive screening. Neurologists completed questionnaires before and after CSF disclosure. We assessed the change of diagnosis, diagnostic confidence, and impact on patient management. RESULTS: A total of 438 patients (age 63 ± 8 years, 39% women) were included, of whom 351 (80%) underwent lumbar puncture. After the disclosure of CSF 23/351 diagnoses (7%) were changed. Diagnostic confidence increased from 84% to 89% (P < .001). There were consequences for management in 44/351 patients (13%) with CSF, and 13/87 patients (15%) because of unavailable CSF. There was no effect of age on these results. CONCLUSIONS: CSF biomarkers aid clinicians with decision making during diagnostic work-up of cognitive disorders. This study may be useful for developing guidelines for the implementation of CSF biomarkers in daily practice.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/complicaciones , Análisis de Varianza , Trastornos del Conocimiento/etiología , Función Ejecutiva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Escalas de Valoración Psiquiátrica , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-ß1-42 (Aß42), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimer's disease (AD). METHODS: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). RESULTS: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/Aß42 ratio and 0.08 for the p-tau/Aß42 ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/Aß42 ratio. CONCLUSIONS: A tau/Aß42 ratio of >0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.