RESUMEN
The olfactory bulb is involved early in the pathophysiology of Parkinson's disease (PD), which is consistent with the early onset of olfactory dysfunction. Identifying the molecular mechanisms through which PD affects the olfactory bulb could lead to a better understanding of the pathophysiology and etiology of olfactory dysfunction in PD. We specifically aimed to assess gene expression changes, affected pathways and co-expression network by whole transcriptomic profiling of the olfactory bulb in subjects with clinicopathologically defined PD. Bulk RNA sequencing was performed on frozen human olfactory bulbs of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative disorders and the Brain and Body Donation Program. Differential expression analysis (19 PD vs 19 controls) revealed 2164 significantly differentially expressed genes (1090 upregulated and 1074 downregulated) in PD. Pathways enriched in downregulated genes included oxidative phosphorylation, olfactory transduction, metabolic pathways, and neurotransmitters synapses while immune and inflammatory responses as well as cellular death related pathways were enriched within upregulated genes. An overrepresentation of microglial and astrocyte-related genes was observed amongst upregulated genes, and excitatory neuron-related genes were overrepresented amongst downregulated genes. Co-expression network analysis revealed significant modules highly correlated with PD and olfactory dysfunction that were found to be involved in the MAPK signaling pathway, cytokine-cytokine receptor interaction, cholinergic synapse, and metabolic pathways. LAIR1 (leukocyte associated immunoglobulin like receptor 1) and PPARA (peroxisome proliferator activated receptor alpha) were identified as hub genes with a high discriminative power between PD and controls reinforcing an important role of neuroinflammation in the olfactory bulb of PD subjects. Olfactory identification test score positively correlated with expression of genes coding for G-coupled protein, glutamatergic, GABAergic, and cholinergic receptor proteins and negatively correlated with genes for proteins expressed in glial olfactory ensheathing cells. In conclusion, this study reveals gene alterations associated with neuroinflammation, neurotransmitter dysfunction, and disruptions of factors involved in the initiation of olfactory transduction signaling that may be involved in PD-related olfactory dysfunction.
Asunto(s)
Trastornos del Olfato , Bulbo Olfatorio , Enfermedad de Parkinson , Análisis de Secuencia de ARN , Humanos , Bulbo Olfatorio/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Masculino , Trastornos del Olfato/genética , Femenino , Anciano , Análisis de Secuencia de ARN/métodos , Persona de Mediana Edad , Anciano de 80 o más Años , Perfilación de la Expresión Génica/métodos , TranscriptomaRESUMEN
BACKGROUND: While preclinical studies have shown that alpha-synuclein can spread through cell-to-cell transmission whether it can be transmitted between humans is unknown. OBJECTIVES: The aim was to assess the presence of a synucleinopathy in autopsied conjugal couples. METHODS: Neuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies. RESULTS: Ninety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD. CONCLUSIONS: This large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society.
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Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Sinucleinopatías , Humanos , Femenino , Masculino , Anciano de 80 o más Años , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/metabolismo , Anciano , Sinucleinopatías/patología , Autopsia , alfa-Sinucleína/metabolismo , Esposos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Cuerpos de Lewy/patologíaRESUMEN
Synaptic transmission is essential for nervous system function and the loss of synapses is a known major contributor to dementia. Alzheimer's disease dementia (ADD) is characterized by synaptic loss in the mesial temporal lobe and cerebral neocortex, both of which are brain areas associated with memory and cognition. The association of synaptic loss and ADD was established in the late 1980s, and it has been estimated that 30-50% of neocortical synaptic protein is lost in ADD, but there has not yet been a quantitative profiling of different synaptic proteins in different brain regions in ADD from the same individuals. Very recently, positron emission tomography (PET) imaging of synapses is being developed, accelerating the focus on the role of synaptic loss in ADD and other conditions. In this study, we quantified the densities of two synaptic proteins, the presynaptic protein Synaptosome Associated Protein 25 (SNAP25) and the postsynaptic protein postsynaptic density protein 95 (PSD95) in the human brain, using enzyme-linked immunosorbent assays (ELISA). Protein was extracted from the cingulate gyrus, hippocampus, frontal, primary visual, and entorhinal cortex from cognitively unimpaired controls, subjects with mild cognitive impairment (MCI), and subjects with dementia that have different levels of Alzheimer's pathology. SNAP25 is significantly reduced in ADD when compared to controls in the frontal cortex, visual cortex, and cingulate, while the hippocampus showed a smaller, non-significant reduction, and entorhinal cortex concentrations were not different. In contrast, all brain areas showed lower PSD95 concentrations in ADD when compared to controls without dementia, although in the hippocampus, this failed to reach significance. Interestingly, cognitively unimpaired cases with high levels of AD pathology had higher levels of both synaptic proteins in all brain regions. SNAP25 and PSD95 concentrations significantly correlated with densities of neurofibrillary tangles, amyloid plaques, and Mini Mental State Examination (MMSE) scores. Our results suggest that synaptic transmission is affected by ADD in multiple brain regions. The differences were less marked in the entorhinal cortex and the hippocampus, most likely due to a ceiling effect imposed by the very early development of neurofibrillary tangles in older people in these brain regions.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/metabolismo , Ovillos Neurofibrilares/metabolismo , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Proteínas tau/metabolismo , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: We examined the progression of extrapyramidal symptoms and signs in autopsy-confirmed dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Alzheimer's disease dementia (AD). METHODS: Longitudinal data were obtained from Arizona Study of Aging and Neurodegenerative Disease, with PDD (n = 98), AD (n = 47) and DLB (n = 48) further sub-grouped as with or without parkinsonism (DLB+ and DLB-). Within-group Unified Parkinson's Disease Rating Scale (UPDRS) -II and UPDRS-III trajectories were analyzed using non-linear mixed effects models. RESULTS: In DLB, 65.6% had parkinsonism. Baseline UPDRS-II and III scores (off-stage) were highest (P < 0.001) for PDD (mean ± SD 14.3 ± 7.8 and 27.4 ± 16.3), followed by DLB+ (6.0 ± 8.8 and 17.2 ± 17.1), DLB- (1.1 ± 1.3 and 3.3 ± 5.5) and AD (3.2 ± 6.1 and 8.2 ± 13.6). Compared to PDD, the DLB+ group had faster UPDRS-III progression over 8-years (Cohen's-d range 0.98 to 2.79, P < 0.001), driven by gait (P < 0.001) and limb bradykinesia (P = 0.02) subscales. DISCUSSION: Motor deficits progress faster in DLB+ than PDD, providing insights about expected changes in motor function. HIGHLIGHTS: Dementia with Lewy bodies has faster motor progression than Parkinson's disease dementia Linear and non-linear mixed modeling analysis of longitudinal data was utilized Findings have implications for clinical prognostication and trial design.
Asunto(s)
Enfermedad de Alzheimer , Demencia , Enfermedad por Cuerpos de Lewy , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , AutopsiaRESUMEN
The Alzheimer's Questionnaire (AQ) is an informant-based screening tool with good diagnostic accuracy for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). The aim of this study is to validate the AQ with AD-associated neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology. Data from 205 prospectively followed autopsy cases clinically classified as AD (n = 90), aMCI (n = 42), or cognitively unimpaired (CU, n = 73) were used. Semi-quantitative measures of NP and NFT pathology were correlated with the AQ, Clinical Dementia Rating Sum of Boxes (CDR-SOB), and the Mini-Mental State Exam (MMSE). The AQ correlated significantly (p < 0.001) with NP load (r = 0.37) and NFT load (r = 0.57). The MMSE and CDR-SOB showed similar correlations with NP load (r = - 0.37, r = 0.35, respectively) and NFT load (r = - 0.58, r = 0.55, respectively). The AQ correlates well with NP and NFT pathology of AD, which provides additional confidence to clinicians using the AQ to screen for AD-related cognitive impairment.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Pruebas de Estado Mental y Demencia , Disfunción Cognitiva/diagnóstico , Autopsia , Encuestas y CuestionariosRESUMEN
OBJECTIVE: There are few neuropathological studies on Parkinson's disease with mild cognitive impairment (PD-MCI). Those published reveal coexisting Lewy body and Alzheimer's disease pathology. Our objective is to determine the pathology that underlies PD-MCI. METHODS: We used data from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study. Of 736 autopsied subjects with standardized movement and cognitive assessments, 25 had PD-MCI. Neuropathological findings, including Lewy body and Alzheimer's disease pathology, were compared in PD subjects with amnestic MCI (A-MCI) and nonamnestic MCI (NA-MCI). RESULTS: Significant pathological heterogeneity within PD-MCI was found. This included varying Lewy body stages, Alzheimer's disease pathology, and cerebral amyloid angiopathy. There was a significant increase in the severity of Lewy body pathology (meeting The Unified Staging System for Lewy Body disorders neocortical stage) in nonamnestic MCI (7/1, 63%) when compared with amnestic MCI (3/14, 21%, P = 0.032). CONCLUSION: Although a small study, distinct pathological changes may contribute to PD-MCI phenotype. © 2020 International Parkinson and Movement Disorder Society.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Disfunción Cognitiva/etiología , Humanos , Cuerpos de Lewy , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiologíaRESUMEN
OBJECTIVE: Identify clinical features predictive of Lewy body pathology in Alzheimer's disease (AD) patients in an ongoing longitudinal clinicopathologic study. MATERIAL AND METHODS: We queried the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) database for dementia cases with AD pathology (1997-2015). Subjects received longitudinal comprehensive clinical evaluations including motor/neuropsychological assessment and Apo-E4 genotyping. All cases were autopsied and had standard neuropathological assessments for AD and Lewy-type synucleinopathy (LTS). Subjects were categorized based on standardized pathological criteria with AD cases that had LTS but did not meet DLB pathologic criteria being categorized as ADLB. We performed pairwise comparison between the different diagnoses and multivariable modelling to identify clinical symptoms that predict the pathological diagnosis. RESULTS: We identified 32 DLB/AD, 54 ADLB, 70 AD only and 41 PDD/AD cases. AD subjects with LTS pathology had higher UPDRS II and III total scores as well as generally higher individual scores compared to AD alone. While depression scales and Trail-making Test A correlated significantly with LTS, other neuropsychological variables were not significantly different. Apo E4 occurrence was similar in all groups (40%-49%). CONCLUSIONS: Our study suggests that the presence (or absence) of LTS influences motor and non-motor clinical findings in AD patients. These findings may lead to biomarkers that allow for more targeted treatment of AD.
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Enfermedad de Alzheimer/patología , Encéfalo/patología , Cuerpos de Lewy/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Bases de Datos Factuales , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Estudios Prospectivos , Escalas de Valoración PsiquiátricaRESUMEN
Amyloid-positron emission tomography (PET) imaging of the brain detects elevated amyloid-beta (amyloid-ß) neuritic plaques in vivo, which can be helpful in appropriately selected cases of mild cognitive impairment (MCI) and dementia, when Alzheimer's disease remains a possible etiology, after a comprehensive clinical evaluation. We reviewed cases of cognitively impaired patients who underwent amyloid-PET imaging because of diagnostic uncertainty. Pre- and post-PET elements of diagnosis and management were first compared, to assess impact of scan results on clinical decision-making, and then an analysis of those decisions was undertaken in appropriate clinical situations, to delineate the added value and limitations of amyloid-PET imaging. The potential benefits and limitations of this diagnostic tool are important to understand in an era when the utility of such scans in clinical practice is evolving.
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Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Demencia/diagnóstico por imagen , Demencia/metabolismo , Tomografía de Emisión de Positrones , Anciano , Compuestos de Anilina/metabolismo , Glicoles de Etileno/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Rapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear. METHODS: Parkinson's disease subjects in a longitudinal clinicopathologic study were screened for probable RBD with the Mayo Sleep Questionnaire. After death, semiquantitative analyses were conducted for synuclein, amyloid, neurofibrillary tangles, and cerebrovascular lesions. RESULTS: Forty cases had probable RBD (PD+RBD), and 41 did not (PD-RBD). Despite similar age at death (â¼80 y) and disease duration (â¼14.5 y), PD+RBD had increased synuclein deposition in all regions examined, with nine of 10 regions significantly different. The Lewy body 10-region total score (scale = 0-40) was 29.5 in PD+RBD versus 24.5 in PD-RBD (Cohen-d effect size = 0.79, P = 0.002). Cerebrovascular lesion burden was slightly higher in PD-RBD. CONCLUSIONS: Although overlap occurs between groups, PD patients with probable RBD may have greater density and range of synuclein pathology on autopsy.
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Enfermedad de Parkinson/metabolismo , Trastorno de la Conducta del Sueño REM/metabolismo , alfa-Sinucleína/metabolismo , Anciano , Anciano de 80 o más Años , Autopsia , Estudios de Cohortes , Femenino , Humanos , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/patología , Trastorno de la Conducta del Sueño REM/etiología , Trastorno de la Conducta del Sueño REM/patologíaRESUMEN
BACKGROUND: Although there are studies investigating the pathologic origins of mild cognitive impairment (MCI), they have revolved around comparisons to normal elderly individuals or those with Alzheimer's disease (AD) or other dementias. There are few studies directly comparing the comprehensive neuropathology of amnestic (aMCI) and nonamnestic (naMCI) MCI. METHODS: The database of the Brain and Body Donation Program ( www.brainandbodydonationprogram.org ), a longitudinal clinicopathological study of normal aging and neurodegenerative disorders, was queried for subjects who were carrying a diagnosis of aMCI or naMCI at the time of autopsy. Neuropathological lesions, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy bodies (LBs), infarcts, cerebral white matter rarefaction (CWMR), cerebral amyloid angiopathy (CAA), and concurrent major clinicopathological diagnoses, including Parkinson's disease (PD) were analyzed. RESULTS: Thirty four subjects with aMCI and 15 naMCI met study criteria. Subjects with aMCI were older at death (88 vs. 83 years of age, p = 0.03). Individuals with naMCI had higher densities of LBs within the temporal lobe (p = 0.04) while subjects with aMCI had a propensity for increased NFTs in parietal and temporal lobes (p values = 0.07). After adjusting for age at death, the only significant difference was greater densities of temporal lobe NFTs within the aMCI group. Other regional pathology scores for plaques, NFTs, and LBs were similar between groups. Subjects met clinico-pathological criteria for co-existent PD in 24 % aMCI and 47 % naMCI while neuropathological criteria for AD were met in equal percentages of aMCI and of naMCI cases (53 %); these proportional differences were not significant (p values > 0.35). Furthermore, regardless of amnestic status, there was a greater presence of CAA (71 % of MCI with executive dysfunction vs. 39 % without p = 0.03) and a greater presence of CWMR (81 % of MCI with executive dysfunction and 54 % without p = 0.046) in MCI cases with executive dysfunction. CONCLUSIONS: No single pathologic entity strongly dichotomized MCI groups, perhaps due to the pathologic heterogeneity found within both entities. However, these data suggest the possibility for naMCI to have a propensity for increased LBs and aMCI for increased NFTs in select anatomic regions.
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Amnesia/patología , Encéfalo/patología , Disfunción Cognitiva/patología , Cuerpos de Lewy/patología , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Anciano , Anciano de 80 o más Años , Amnesia/complicaciones , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/patología , Infarto Cerebral/complicaciones , Infarto Cerebral/patología , Disfunción Cognitiva/complicaciones , Femenino , Humanos , Leucoencefalopatías/complicaciones , Leucoencefalopatías/patología , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/patología , Lóbulo Temporal/patologíaRESUMEN
The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.
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Envejecimiento/patología , Encéfalo/patología , Enfermedades Neurodegenerativas/patología , Bancos de Tejidos , Obtención de Tejidos y Órganos , Anciano de 80 o más Años , Arizona , Autopsia , Biomarcadores , Femenino , Humanos , Masculino , Preservación de Órganos , Cambios Post Mortem , Donantes de Tejidos , Supervivencia TisularRESUMEN
BACKGROUND: Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption. AIMS: To characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms. METHODS: A longitudinal, observational study of 51 subjects with FM (range 55-95 years) and 81 control subjects (58-95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment. RESULTS: Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin. DISCUSSION: In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated. CONCLUSIONS: Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.
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Fibromialgia/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/uso terapéutico , Cognición , Femenino , Fibromialgia/fisiopatología , Fibromialgia/psicología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pregabalina/uso terapéuticoRESUMEN
INTRODUCTION: Down syndrome (DS) is associated with amyloid b (Ab) deposition. METHODS: We characterized imaging measurements of regional fibrillar Ab burden, cerebral metabolic rate for glucose (rCMRgl), gray matter volumes (rGMVs), and age associations in 5 DS with dementia (DS/AD1), 12 DS without dementia (DS/AD2), and 9 normal controls (NCs). RESULTS: There were significant group differences in mean standard uptake value ratios (SUVRs) for florbetapir with DS/AD1 having the highest, followed by DS/AD2, followed by NC. For [18F]-fluorodeoxyglucose positron emission tomography, posterior cingulate rCMRgl in DS/AD1 was significantly reduced compared with DS/AD2 and NC. For volumetric magnetic resonance imaging (vMRI), hippocampal volumes were significantly reduced for the DS/AD1 compared with DS/AD2 and NC. Age-related SUVR increases and rCMRgl reductions were greater in DS participants than in NCs. DISCUSSION: DS is associated with fibrillar Ab, rCMRgl, and rGMV alterations in the dementia stage and before the presence of clinical decline. This study provides a foundation for the studies needed to inform treatment and prevention in DS.
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Compuestos de Anilina/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Síndrome de Down/patología , Glicoles de Etileno/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Adulto , Enfermedad de Alzheimer/complicaciones , Síndrome de Down/complicaciones , Servicios de Urgencia Psiquiátrica , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
The Alzheimer Questionnaire (AQ) has been established as a valid and accurate informant-based screening questionnaire for Alzheimer disease and amnestic mild cognitive impairment. Although the AQ's validity and diagnostic accuracy has been established, its performance in comparison with other instruments has not. Thirty-nine amnestic mild cognitive impairment cases and 34 Alzheimer disease cases were matched on the basis of age, education, and sex to 73 cognitively normal individuals. The sample had a mean age of 82.54±7.77 years and a mean education level of 14.61±2.61 years. The diagnostic accuracy of the CDR Sum of Boxes, Mini Mental State Exam (MMSE), and Montreal Cognitive Assessment (MoCA) were compared with the AQ. The AQ correlated strongly with the CDR Sum of Boxes (r=0.79) and demonstrated similar diagnostic accuracy with the MoCA and MMSE. These results suggest that the AQ is comparable with other established informant-based and patient-based measures.
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Enfermedad de Alzheimer/diagnóstico , Pruebas Neuropsicológicas , Encuestas y Cuestionarios , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
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Progresión de la Enfermedad , Cuerpos de Lewy , Enfermedad por Cuerpos de Lewy , alfa-Sinucleína , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , alfa-Sinucleína/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Tronco Encefálico/patología , Tronco Encefálico/metabolismo , Cuerpos de Lewy/patología , Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/metabolismo , Bulbo Olfatorio/patología , Bulbo Olfatorio/metabolismoRESUMEN
To date there is no validated peripheral biomarker to assist with the clinical diagnosis of Alzheimer's disease (AD). Platelet proteins have been studied as AD biomarkers with relative success. In this study, we investigated whether platelet BACE1 levels differ between AD and cognitively normal (CN) control patients. Using a newly developed ELISA method, we found that BACE1 levels were significantly lower in AD compared to CN subjects. These data were supported by the observation that several BACE1 isoforms, identified by Western blotting, were also lower in AD platelets. This proof-of-concept study provides evidence for testing platelet BACE1 levels as a peripheral AD biomarker using a novel, sensitive and inexpensive method.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Plaquetas/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Isoformas de ProteínasRESUMEN
Introduction: Sex differences in Alzheimer's disease (AD) may contribute to disease heterogeneity and affect prevalence, risk factors, disease trajectories and outcomes. Depression impacts a large number of patients with AD and has been reported to be more prevalent in women. We aimed to better understand the interaction between sex, depression and AD neuropathology, which could have implications for detection of symptoms, earlier diagnosis, therapeutic management, and enhanced quality of life. Methods: We compared 338 cases with clinicopathologically confirmed AD (46% women) to 258 control cases (50% women), without dementia, parkinsonism or a significant pathological diagnosis. Depression was assessed both, using the Hamilton Depression Scale (HAM-D), and as being reported in their medical history combined with treatment with antidepressant medication. Results: In the control group, women showed a higher depression severity, and a higher proportion of women were found to meet the cut-off score for depression on the HAM-D (32 vs. 16%) and having an history of depression (33 vs. 21%), while these sex differences were not observed in AD. Further, in both groups, female sex independently predicted the presence of depression, with covariates for age and cognitive status. AD subjects had higher mean HAM-D scores, were more likely to meet cutoff scores for depression (41 vs. 24%) and have a history of depression than controls (47 vs. 27%). When comparing the increase in frequency of depression in controls versus AD, the difference was significantly greater in men (AD men - control men: 24%) than in women (AD women - control women: 9%). Although subjects with depression were more likely to have higher levels of AD neuropathology, these differences were not observed when investigating the control or AD group separately. Discussion: Control women had a higher likelihood and severity of depression than control men, but this sex difference was not noted when considering only those with pathologically defined AD, emphasizing the importance of considering sex in aging studies. AD was associated with higher rates of depression and men may be more likely to report or be diagnosed with depression once they develop AD indicating the importance of more frequent depression screenings in men.
RESUMEN
The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100â000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (â¼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate.
Asunto(s)
Trastornos Parkinsonianos , Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico , Parálisis Supranuclear Progresiva/epidemiología , Parálisis Supranuclear Progresiva/patología , Incidencia , AutopsiaRESUMEN
Lewy body (LB) disorders, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. By applying data-driven disease progression modelling to regional neuropathological LB density scores from 814 brain donors, we describe three inferred trajectories of LB pathology that were characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) showed earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) exhibited the first abnormalities in brainstem regions. Early limbic pathology was associated with Alzheimer's disease-associated characteristics. Meanwhile, brainstem-first pathology was associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in LBDs.
RESUMEN
Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.