•We evaluated iron deposition in N1 in HC and patients with early PD (ePD) and iRBD.•N1 aspect was pathological in T2*-w images in 45% of iRBD patients and in most ePD.•ePD N1 χ was higher than iRBD ...and HC χ but had no correlation with disease duration.•N1 χ in iRBD was similar to HC but increased with disease duration.•N1 χ may be a presymptomatic biomarker for neurodegeneration in prodromal PD.
Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, such as Parkinson's disease (PD), which are characterized by the loss of dopaminergic neurons in substantia nigra, associated with abnormal iron load. The assessment of presymptomatic biomarkers predicting the onset of neurodegenerative disorders is critical for monitoring early signs, screening patients for neuroprotective clinical trials and understanding the causal relationship between iron accumulation processes and disease development. Here, we used Quantitative Susceptibility Mapping (QSM) and 7T MRI to quantify iron deposition in Nigrosome 1 (N1) in early PD (ePD) patients, iRBD patients and healthy controls and investigated group differences and correlation with disease progression. We evaluated the radiological appearance of N1 and analyzed its iron content in 35 ePD, 30 iRBD patients and 14 healthy controls via T2*-weighted sequences and susceptibility (χ) maps. N1 regions of interest (ROIs) were manually drawn on control subjects and warped onto a study-specific template to obtain probabilistic N1 ROIs. For each subject the N1 with the highest mean χ was considered for statistical analysis. The appearance of N1 was rated pathological in 45% of iRBD patients. ePD patients showed increased N1 χ compared to iRBD patients and HC but no correlation with disease duration, indicating that iron load remains stable during the early stages of disease progression. Although no difference was reported in iron content between iRBD and HC, N1 χ in the iRBD group increases as the disease evolves. QSM can reveal temporal changes in N1 iron content and its quantification may represent a valuable presymptomatic biomarker to assess neurodegeneration in the prodromal stages of PD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Spastic Paraplegia type 7 (SPG7) is one of the most common autosomal recessive Hereditary Spastic Paraplegias (HSP); Spastic Paraplegias (SPGs) can present as hereditary ataxias. ...However, ataxia is frequently the symptom of presentation of many other hereditary/sporadic disorders, such as Multiple system atrophy type C (MSA-C), an α-synuclein sporadic neurodegenerative disorder, in which cerebellar ataxia is one of the main clinical features. Dopamine Transporter imaging (DAT-SCAN), associated with clinical features, can be a helpful tool in order to distinguish MSA-C from other causes of ataxia.
Case-presentation
We present the case of a 70-year-old man with gait difficulties over a period of 3 years and frequent backward/lateral falls. He also reported urinary urge incontinence, but no symptoms that are compatible with orthostatic hypotension. On neurological examination he showed ataxic gait, spasticity in the left lower limb and trunk and limb ataxia, especially on the left side. Mild hypokinesia was found in all 4 limbs, especially in the left foot. MRI revealed atrophy of the cerebellar hemispheres and vermis. DAT-SCAN imaging revealed bilateral nigro-striatal degeneration, which was compatible with a diagnosis of possible MSA-C. Considering the atypical disease course (the patient walked without any support after 3 years), we carried out a genetic investigation for Ataxia, and a mutation in
SPG7
was found.
Conclusions
DAT-SCAN imaging, evaluated together with the clinical findings, can be useful for differentiating MSA from other possible causes of adult-onset Ataxia. Indeed, patients with MSA-C generally show a decreased uptake of dopamine transporters in DAT-SCAN imaging. Ours is the first case reported in the literature of a patient with
SPG7
mutation with nigrostriatal degeneration and a clinical presentation of a possible MSA-C. Performing genetic investigations in patients with an atypical disease course is important to avoid MSA-mimicries.
Identifying the correct diagnosis is important not only for prognostic reasons, but also for possible future genetic therapies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Differential diagnosis between Parkinson's disease (PD) and Atypical Parkinsonisms, mainly Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA), remains challenging. The low ...sensitivity of macroscopic findings at imaging might limit early diagnosis. The availability of iron-sensitive MR techniques and high magnetic field MR scanners provides new insights in evaluating brain structures in degenerative parkinsonisms. Quantitative Susceptibility Mapping (QSM) allows quantifying tissue iron content and could be sensitive to microstructural abnormalities which precede the appearence of regional atrophy. We measured the magnetic susceptibility (χ) of nigral and extranigral regions in patients with PD, PSP and MSA to evaluate the potential utility of the QSM technique for differential diagnosis.
65 patients (36 PD, 14 MSA, 15 PSP) underwent clinical and radiological evaluation with 3 T MRI. QSM maps were obtained from GRE sequences. ROI were drawn on substantia nigra (SN), red nucleus (RN), subthalamic nucleus (STN), putamen, globus pallidus and caudate. χ values were compared to detect inter-group differences.
The highest diagnostic accuracy for PSP (area under the ROC curve, AUC, range 0.9–0.7) was observed for increased χ values in RN, STN and medial part of SN whereas in MSA (AUC range 0.8–0.7) iron deposition was significantly higher in the putamen, according to the patterns of pathological involvement that characterize the different diseases.
QSM could be used for iron quantification of nigral and extranigral structures in all degenerative parkinsonisms and should be tested longitudinally in order to identify early microscopical changes.
•The qualitative evaluation of the SN failed to discriminate PD and atypical parkinsonisms.•QSM showed increased susceptibility values within nigral and extranigral regions in AP.•In MSA susceptibility values of putamen, STN and RN were higher than in PD.•In PSP susceptibility values of medial SN, STN, RN and putamen were higher than in PD.•QSM seems to be a promising tool in distinguishing PD from AP and MSA from PSP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid
(Aβ
) and tau, in both brain and peripheral ...tissues. In addition to oligomers, the role of the interactions of α-syn with Aβ or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as a valid peripheral model for the study of aging-related pathologies. Herein, a small cohort (
= 28) of patients affected by Parkinson's disease (PD) and age-matched controls were enrolled to detect the content of α-syn (total and oligomeric), Aβ
and tau (total and phosphorylated) in RBCs. Moreover, the presence of α-syn association with tau and Aβ
was explored by co-immunoprecipitation/western blotting in the same cells, and quantitatively confirmed by immunoenzymatic assays. For the first time, PD patients were demonstrated to exhibit α-syn heterocomplexes with Aβ
and tau in peripheral tissues; interestingly, α-syn-Aβ
concentrations were increased in PD subjects with respect to healthy controls (HC), and directly correlated with disease severity and motor deficits. Moreover, total-α-syn levels were decreased in PD subjects and inversely related to their motor deficits. Finally, an increase of oligomeric-α-syn and phosphorylated-tau was observed in RBCs of the enrolled patients. The combination of three parameters (total-α-syn, phosphorylated-tau and α-syn-Aβ
concentrations) provided the best fitting predictive index for discriminating PD patients from controls. Nevertheless further investigations should be required, overall, these data suggest α-syn hetero-aggregates in RBCs as a putative tool for the diagnosis of PD.
To investigate dopaminergic function in a large cohort of patients with corticobasal syndrome (CBS) and describe its relationship with clinical features in comparison to Parkinson's disease and ...healthy control subjects. In addition, we assessed prevalence and features of individuals with CBS and in vivo evidence of preserved nigral neuronal density.
Substantia nigra pars compacta (SNc) neuronal degeneration is a mandatory pathological criterion for definite corticobasal degeneration, though sporadic autopsy-proven cases with ante-mortem imaging evidence of preserved nigral terminals have been recently described.
In this multicenter study, we investigated presynaptic nigrostriatal function in 36 outpatients fulfilling clinical criteria for "probable corticobasal degeneration" (age 71±7.3 years; disease duration 3.9±1.6 years), 37 PD and 24 healthy control subjects using FP-CIT single photon emission computed tomography. Clinical, neuropsychological, and magnetic resonance imaging assessment was performed to characterize CBS patients. Linear discriminant analysis was used to categorize normal vs. pathological scans.
FP-CIT binding reduction in patients with CBS was characterized by larger variability, more uniform reduction throughout the striatum and greater hemispheric asymmetry compared to PD. Moreover, there was no significant correlation between tracer uptake values and clinical features such as disease duration and severity. Despite all CBS subjects showed obvious bilateral extrapyramidal signs, FP-CIT uptake was found to be normal bilaterally in four CBS patients and only unilaterally in other four cases. Extensive clinical, neuropsychological and imaging assessment did not reveal remarkable differences between CBS subjects with normal vs. pathological FP-CIT uptake.
Our findings support the hypothesis that extrapyramidal motor symptoms in CBS are not invariably associated with SNc neuronal degeneration and that supranigral factors may play a major role in several cases. CBS individuals with normal FP-CIT uptake do not show any clinical or cognitive feature suggesting a different pathology than CBD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Objective:
To verify the association of midbrain-based MRI measures as well as cortical volumes with disease core features and progression in patients with Progressive Supranuclear Palsy (PSP).
...Methods:
Sixty-seven patients (52.2% with Richardson's syndrome) were included in the present analysis. Available midbrain-based MRI morphometric assessments as well as cortical lobar volumes were computed. Ocular, gait and postural involvement at the time of MRI was evaluated with the PSP rating scale. Specific milestones or death were used to estimate disease progression up to 72 months follow up. Hierarchical regression models and survival analysis were used for analyzing cross-sectional and longitudinal data, respectively.
Results:
Multivariate models showed vertical supranuclear gaze palsy was associated with smaller midbrain area (OR: 0.02, 95% CI 0.00–0.175,
p
= 0.006). Cox regression adjusted for age, disease duration, and phenotype demonstrated that lower midbrain area (HR: 0.122, 95% CI 0.030–0.493,
p
= 0.003) and diameter (HR: 0.313, 95% CI 0.112–0.878,
p
= 0.027), higher MR Parkinsonism Index (HR: 6.162, 95% CI 1.790–21.209,
p
= 0.004) and larger third ventricle width (HR: 2.755, 95% CI 1.068–7.108,
p
= 0.036) were associated with higher risk of dependency on wheelchair.
Conclusions:
Irrespective of disease features and other MRI parameters, reduced midbrain size is significantly associated with greater ocular motor dysfunction at the time of MRI and more rapid disease progression over follow up. This is the first comprehensive study to systematically assess the association of available midbrain-based MRI measures and cortical volumes with disease severity and progression in a large cohort of patients with PSP in a real-world setting.
The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature ...could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD.
The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio OR 0.73; 95% confidence interval CI 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29).
The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives
To support the cognitive model of Freezing of Gait (FoG) we investigated FoG in a cohort of patients with Dementia with Lewy Bodies (DLB).
Materials and Methods
We assessed FoG frequency ...in 19 DLB patients compared to 19 control PD patients within 2 years from symptom onset and with at least 5 years follow‐up. The two groups were matched by age and motor presentation at onset, severity of parkinsonism and disease duration. The presence and severity of FoG was identified as those with a score of 1 or greater on subitem 14 of the Unified Parkinson's Disease Rating Scale Part II (UPDRS II).
Results
At T0, 68.4% DLB and 10.5% PD patients experienced FoG ≥1. The prevalence of FoG increased with disease progression (94.7% DLB and 47.3% PD subjects had FoG ≥1 at T5). DLB also showed a more severe FoG (FoG ≥2) than PD (21% vs. 0% at T0 and 52.6% vs. 10.5% at T5), consistently with previous studies reporting FoG prevalence in DLB.
Conclusion
This is the first study looking specifically at FoG in DLB, identifying it as a frequent and early feature of DLB and emphasizing the crucial role of cognitive impairment in the occurrence of this mysterious phenomenon.
FoG frequency was assessed in 19 DLB patients compared to 19 control matched PD patients. At the first examination (T0), 68.4% DLB and 10.5% PD patients experienced FoG. The prevalence of FoG increased with disease progression. DLB also showed a more severe FoG than PD (21% at T0 and 52.6% vs. 10.5% at T5), consistently with previous studies reporting FoG prevalence in DLB. This is the first study looking specifically at FoG in DLB, identifying it as a frequent and early feature of DLB and emphasizing the crucial role of cognitive impairment in the occurrence of this mysterious phenomenon.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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