Dopamine transporter (DAT) single-photon emission tomography (SPECT) with (123)Ioflupane is a widely used diagnostic tool for patients with suspected parkinsonian syndromes, as it assists with ...differentiating between Parkinson's disease (PD) or atypical parkinsonisms and conditions without a presynaptic dopaminergic deficit such as essential tremor, vascular and drug-induced parkinsonisms. Recent evidence supports its utility as in vivo proof of degenerative parkinsonisms, and DAT imaging has been proposed as a potential surrogate marker for dopaminergic nigrostriatal neurons. However, the interpretation of DAT-SPECT imaging may be challenged by several factors including the loss of DAT receptor density with age and the effect of certain drugs on dopamine uptake. Furthermore, a clear, direct relationship between nigral loss and DAT decrease has been controversial so far. Striatal DAT uptake could reflect nigral neuronal loss once the loss exceeds 50%. Indeed, reduction of DAT binding seems to be already present in the prodromal stage of PD, suggesting both an early synaptic dysfunction and the activation of compensatory changes to delay the onset of symptoms. Despite a weak correlation with PD severity and progression, quantitative measurements of DAT binding at baseline could be used to predict the emergence of late-disease motor fluctuations and dyskinesias. This review addresses the possibilities and limitations of DAT-SPECT in PD and, focusing specifically on regulatory changes of DAT in surviving DA neurons, we investigate its role in diagnosis and its prognostic value for motor complications as disease progresses.
A major goal of current clinical research in Parkinson's disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes, understanding PD ...pathophysiology, and demonstrating target engagement in clinical trials. Molecular imaging with specific dopamine-related tracers offers a practical indirect imaging biomarker of PD, serving as a powerful tool to assess the status of presynaptic nigrostriatal terminals. In this review we provide an update on the dopamine transporter (DAT) imaging in PD and translate recent findings to potentially valuable clinical practice applications. The role of DAT imaging as diagnostic, preclinical and predictive biomarker is discussed, especially in view of recent evidence questioning the incontrovertible correlation between striatal DAT binding and nigral cell or axon counts.
As neurons are highly energy-demanding cell, increasing evidence suggests that mitochondria play a large role in several age-related neurodegenerative diseases. Synaptic damage and mitochondrial ...dysfunction have been associated with early events in the pathogenesis of major neurodegenerative diseases, including Parkinson's disease, atypical parkinsonisms, and Huntington disease. Disruption of mitochondrial structure and dynamic is linked to increased levels of reactive oxygen species production, abnormal intracellular calcium levels, and reduced mitochondrial ATP production. However, recent research has uncovered a much more complex involvement of mitochondria in such disorders than has previously been appreciated, and a remarkable number of genes and proteins that contribute to the neurodegeneration cascade interact with mitochondria or affect mitochondrial function. In this review, we aim to summarize and discuss the deep interconnections between mitochondrial dysfunction and basal ganglia disorders, with an emphasis into the molecular triggers to the disease process. Understanding the regulation of mitochondrial pathways may be beneficial in finding pharmacological or non-pharmacological interventions to delay the onset of neurodegenerative diseases.
In the present study, we aimed to better investigate attention system profile of Parkinson's disease-Mild Cognitive Impairment (PD-MCI) patients and to determine if specific attentional deficits are ...associated with 123I-FP-CIT SPECT.
A total of 44 de novo drug-naïve PD patients (27) with normal cognition (PD-NC) and 17 with MCI (PD-MCI), 23 MCI patients and 23 individuals with subjective cognitive impairment (SCI) were recruited at the Clinical Neurology Unit of Santa Chiara hospital (Pisa University Medical School, Italy). They were assessed by a wide neuropsychological battery, including Visual Search Test (VST) measuring selective attention. Performances among groups were compared by non-parametric tests (i.e., Kruskal-Wallis and Mann-Whitney, Bonferroni corrected). Further, Spearman's rank correlations were performed to explore the association between neuropsychological variables and 123I-FP-CIT SPECT data in PD subgroup.
PD-MCI patients performed worse on VST than patients with PD-NC (
= 0.002), patients with MCI and individuals with SCI (
< 0.001). The performance of PD-MCI patients on VST significantly correlated with caudate nucleus 123I-FP-CIT SPECT uptake (rho = 0.582,
< 0.05), whereas a negative correlation between such test and 123I-FP-CIT SPECT uptake in the left putamen (rho = -0.529,
< 0.05) was found in PD-NC patients.
We suggest that selective attention deficit might be a trigger of cognitive decay in de novo PD-MCI patients. The VST should be routinely used to detect attentional deficits in hospital clinical practice, in the light of its closely association with dopamine depletion of basal ganglia in mildly impaired PD patients.
: Tau protein misfolding and accumulation in toxic species is a critical pathophysiological process of Alzheimer's disease (AD) and other neurodegenerative disorders (NDDs). Tau biomarkers, namely ...cerebrospinal fluid (CSF) total-tau (t-tau), 181-phosphorylated tau (p-tau), and tau-PET tracers, have been recently embedded in the diagnostic criteria for AD. Nevertheless, the role of tau as a diagnostic and prognostic biomarker for other NDDs remains controversial.
: We performed a systematical PubMed-based review of the most recent advances in tau-related biomarkers for NDDs. We focused on papers published from 2015 to 2020 assessing the diagnostic or prognostic value of each biomarker.
: The assessment of tau biomarkers in alternative easily accessible matrices, through the development of ultrasensitive techniques, represents the most significant perspective for AD-biomarker research. In NDDs, novel tau isoforms (e.g. p-tau217) or proteolytic fragments (e.g. N-terminal fragments) may represent candidate diagnostic and prognostic biomarkers and may help monitoring disease progression. Protein misfolding amplification assays, allowing the identification of different tau strains (e.g. 3 R-
. 4 R-tau) in CSF, may constitute a breakthrough for the in vivo stratification of NDDs. Tau-PET may help tracking the spatial-temporal evolution of tau pathophysiology in AD but its application outside the AD-spectrum deserves further studies.
The diagnosis of neurodegenerative diseases (NDDs) represents an increasing social burden, with the unsolved issue of disease-modifying therapies (DMTs). The failure of clinical trials treating ...Alzheimer's Disease (AD) so far highlighted the need for a different approach in drug design and patient selection. Identifying subjects in the prodromal or early symptomatic phase is critical to slow down neurodegeneration, but the implementation of screening programs with this aim will have an ethical and social aftermath. Novel minimally invasive candidate biomarkers (derived from blood, saliva, olfactory brush) or classical cerebrospinal fluid (CSF) biomarkers have been developed in research settings to stratify patients with NDDs. Misfolded protein accumulation, neuroinflammation, and synaptic loss are the pathophysiological hallmarks detected by these biomarkers to refine diagnosis, prognosis, and target engagement of drugs in clinical trials. We reviewed fluid biomarkers of NDDs, considering their potential role as screening, diagnostic, or prognostic tool, and their present-day use in clinical trials (phase II and III). A special focus will be dedicated to novel techniques for the detection of misfolded proteins. Eventually, an applicative diagnostic algorithm will be proposed to translate the research data in clinical practice and select prodromal or early patients to be enrolled in the appropriate DMTs trials for NDDs.
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