RESUMO
PURPOSE OF REVIEW: Molecular imaging has traditionally been used and interpreted primarily in the context of localized and relatively static neurochemical processes. New understanding of brain function and development of novel molecular imaging protocols and analysis methods highlights the relevance of molecular networks that co-exist and interact with functional and structural networks. Although the concept and evidence of disease-specific metabolic brain patterns has existed for some time, only recently has such an approach been applied in the neurotransmitter domain and in the context of multitracer and multimodal studies. This review briefly summarizes initial findings and highlights emerging applications enabled by this new approach. RECENT FINDINGS: Connectivity based approaches applied to molecular and multimodal imaging have uncovered molecular networks with neurodegeneration-related alterations to metabolism and neurotransmission that uniquely relate to clinical findings; better disease stratification paradigms; an improved understanding of the relationships between neurochemical and functional networks and their related alterations, although the directionality of these relationships are still unresolved; and a new understanding of the molecular underpinning of disease-related alteration in resting-state brain activity. SUMMARY: Connectivity approaches are poised to greatly enhance the information that can be extracted from molecular imaging. While currently mostly contributing to enhancing understanding of brain function, they are highly likely to contribute to the identification of specific biomarkers that will improve disease management and clinical care.
Assuntos
Encéfalo , Doenças Neurodegenerativas , Tomografia por Emissão de Pósitrons , Humanos , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismoRESUMO
INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doenças de Pequenos Vasos Cerebrais , Hipocampo , Tomografia por Emissão de Pósitrons , Humanos , Hipocampo/patologia , Hipocampo/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/patologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Masculino , Idoso , Feminino , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Substância Branca/patologia , Substância Branca/diagnóstico por imagem , Atrofia/patologia , Imageamento por Ressonância Magnética , Idoso de 80 Anos ou mais , Neuroimagem , Estudos de CoortesRESUMO
Several genetic pathogenic variants increase the risk of Parkinson's disease (PD) with pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene being among the most common. A joint pattern analysis based on multi-set canonical correlation analysis (MCCA) was utilized to extract PD and LRRK2 pathogenic variant-specific spatial patterns in relation to healthy controls (HCs) from multi-tracer Positron Emission Tomography (PET) data. Spatial patterns were extracted for individual subject cohorts, as well as for pooled subject cohorts, to explore whether complementary spatial patterns of dopaminergic denervation are different in the asymptomatic and symptomatic stages of PD. The MCCA results are also compared to the traditional univariate analysis, which serves as a reference. We identified PD-induced spatial distribution alterations common to DAT and VMAT2 in both asymptomatic LRRK2 pathogenic variant carriers and PD subjects. The inclusion of HCs in the analysis demonstrated that the dominant common PD-induced pattern is related to an overall dopaminergic terminal density denervation, followed by asymmetry and rostro-caudal gradient with deficits in the less affected side still being the best marker of disease progression. The analysis was able to capture a trend towards PD-related patterns in the LRRK2 pathogenic variant carrier cohort with increasing age in line with the known increased risk of this patient cohort to develop PD as they age. The advantage of this method thus resides in its ability to identify not only regional differences in tracer binding between groups, but also common disease-related alterations in the spatial distribution patterns of tracer binding, thus potentially capturing more complex aspects of disease induced alterations.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Tomografia por Emissão de Pósitrons , Humanos , Doença de Parkinson/genética , Doença de Parkinson/diagnóstico por imagem , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Tomografia por Emissão de Pósitrons/métodos , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Adulto , Heterozigoto , Encéfalo/diagnóstico por imagem , Proteínas Vesiculares de Transporte de Monoamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genéticaRESUMO
Parkinson's disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [11C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson's disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [11C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [11C](+)DTBZ to assess dopaminergic denervation and [11C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [11C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [11C]PBB3 and [11C]PBR28 binding in nigrostriatal regions. [11C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [11C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.