Investigating the aspect of asymmetry in brain-first versus body-first Parkinson's disease.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Recent literature has proposed two subgroups of PD. The "body-first subtype" is associated with a prodrome of isolated REM-sleep Behavior Disorder (iRBD) and a relatively symmetric brain degeneration. The "brain-first subtype" is suggested to have a more asymmetric degeneration and a prodromal stage without RBD. This study aims to investigate the proposed difference in symmetry of the degeneration pattern in the presumed body and brain-first PD subtypes. We analyzed 123I-FP-CIT (DAT SPECT) and 18F-FDG PET brain imaging in three groups of patients (iRBD, n = 20, de novo PD with prodromal RBD, n = 22, and de novo PD without RBD, n = 16) and evaluated dopaminergic and glucose metabolic symmetry. The RBD status of all patients was confirmed with video-polysomnography. The PD groups did not differ from each other with regard to the relative or absolute asymmetry of DAT uptake in the putamen (p = 1.0 and p = 0.4, respectively). The patient groups also did not differ from each other with regard to the symmetry of expression of the PD-related metabolic pattern (PDRP) in each hemisphere. The PD groups had no difference in symmetry considering mean FDG uptake in left and right regions of interest and generally had the same degree of symmetry as controls, while the iRBD patients had nine regions with abnormal left-right differences (p < 0.001). Our findings do not support the asymmetry aspect of the "body-first" versus "brain-first" hypothesis.

Brain Hemisphere Dissimilarity, a Self-Supervised Learning Approach for alpha-synucleinopathies prediction with FDG PET.

Idiopathic Rem sleep Behavior Disorder (iRBD) is a significant biomarker for the development of alpha-synucleinopathies, such as Parkinson's disease (PD) or Dementia with Lewy bodies (DLB). Methods to identify patterns in iRBD patients can help in the prediction of the future conversion to these diseases during the long prodromal phase when symptoms are non-specific. These methods are essential for disease management and clinical trial recruitment. Brain PET scans with 18F-FDG PET radiotracers have recently shown promise, however, the scarcity of longitudinal data and PD/DLB conversion information makes the use of representation learning approaches such as deep convolutional networks not feasible if trained in a supervised manner. In this work, we propose a self-supervised learning strategy to learn features by comparing the brain hemispheres of iRBD non-convertor subjects, which allows for pre-training a convolutional network on a small data regimen. We introduce a loss function called hemisphere dissimilarity loss (HDL), which extends the Barlow Twins loss, that promotes the creation of invariant and non-redundant features for brain hemispheres of the same subject, and the opposite for hemispheres of different subjects. This loss enables the pre-training of a network without any information about the disease, which is then used to generate full brain feature vectors that are fine-tuned to two downstream tasks: follow-up conversion, and the type of conversion (PD or DLB) using baseline 18F-FDG PET. In our results, we find that the HDL outperforms the variational autoencoder with different forms of inputs.

A kinetics-based approach to amyloid PET semi-quantification.

PURPOSE: To develop and validate a semi-quantification method (time-delayed ratio, TDr) applied to amyloid PET scans, based on tracer kinetics information. METHODS: The TDr method requires two static scans per subject: one early (~ 0-10 min after the injection) and one late (typically 50-70 min or 90-100 min after the injection, depending on the tracer). High perfusion regions are delineated on the early scan and applied onto the late scan. A SUVr-like ratio is calculated between the average intensities in the high perfusion regions and the late scan hotspot. TDr was applied to a naturalistic multicenter dataset of 143 subjects acquired with [18F]florbetapir. TDr values are compared to visual evaluation, cortical-cerebellar SUVr, and to the geometrical semi-quantification method ELBA. All three methods are gauged versus the heterogeneity of the dataset. RESULTS: TDr shows excellent agreement with respect to the binary visual assessment (AUC = 0.99) and significantly correlates with both validated semi-quantification methods, reaching a Pearson correlation coefficient of 0.86 with respect to ELBA. CONCLUSIONS: TDr is an alternative approach to previously validated ones (SUVr and ELBA). It requires minimal image processing; it is independent on predefined regions of interest and does not require MR registration. Besides, it takes advantage on the availability of early scans which are becoming common practice while imposing a negligible added patient discomfort.

Clinical and MRI Predictors of Conversion From Mild Behavioural Impairment to Dementia.

OBJECTIVE: As an analogy with mild cognitive impairment (MCI), the mild behavioral impairment (MBI) construct has been proposed as a diagnostic label for those presenting late-onset behavioral symptoms. To date, however, the clinical, cognitive, and structural imaging features associated with an increased risk of conversion from MBI to dementia are poorly understood. METHODS: We retrospectively analyzed the cognitive performance and structural brain MRI of 113 subjects, with a clinical follow-up of at least 4 years available. Subjects were randomly assigned to a Group A (56 subjects; age: 65.4 ± 7.9 years, 15 females, MMSE score: 28.4 ± 2.3)) or to a Group B (57 subjects, age: 66.6 ± 6.4, 17 females, MMSE score: 28.0 ± 1.4). In the Group A, cognitive and structural variables were compared between converters (at 4 years) and nonconverters and then verified in the Group B group. RESULTS: In the Group A, 14 patients converted to behavioral-variant of frontotemporal dementia (bv-FTD) and 4 to Alzheimer's Disease (AD). Converters presented at baseline lower executive function scores and total Theory of Mind (ToM scores), as well as more severe focal frontal atrophy. In the Group B, 13 subjects converted to bv-FTD and none to AD. The combination of the variables identified in the Group A significantly (p <0.001) discriminated between converters and nonconverters in the Group B with a sensitivity of 0.615 and a specificity of 1 (total accuracy 91.22%). CONCLUSION: The combined presence of executive deficit, impaired ToM, and presence of isolated frontal atrophy was associated with risk of progression from MBI to a clinically evident neurodegenerative condition, mainly bv-FTD, over a 4-year period.

Comparative Study of MRI Biomarkers in the Substantia Nigra to Discriminate Idiopathic Parkinson Disease.

BACKGROUND AND PURPOSE: Several new MR imaging techniques have shown promising results in patients with Parkinson disease; however, the comparative diagnostic values of these measures at the individual level remain unclear. Our aim was to compare the diagnostic value of MR imaging biomarkers of substantia nigra damage for distinguishing patients with Parkinson disease from healthy volunteers. MATERIALS AND METHODS: Thirty-six patients and 20 healthy volunteers were prospectively included. The MR imaging protocol at 3T included 3D T2-weighted and T1-weighted neuromelanin-sensitive images, diffusion tensor images, and R2* mapping. T2* high-resolution images were also acquired at 7T to evaluate the dorsal nigral hyperintensity sign. Quantitative analysis was performed using ROIs in the substantia nigra drawn manually around the area of high signal intensity on neuromelanin-sensitive images and T2-weighted images. Visual analysis of the substantia nigra neuromelanin-sensitive signal intensity and the dorsolateral nigral hyperintensity on T2* images was performed. RESULTS: There was a significant decrease in the neuromelanin-sensitive volume and signal intensity in patients with Parkinson disease. There was also a significant decrease in fractional anisotropy and an increase in mean, axial, and radial diffusivity in the neuromelanin-sensitive substantia nigra at 3T and a decrease in substantia nigra volume on T2* images. The combination of substantia nigra volume, signal intensity, and fractional anisotropy in the neuromelanin-sensitive substantia nigra allowed excellent diagnostic accuracy (0.93). Visual assessment of both substantia nigra dorsolateral hyperintensity and neuromelanin-sensitive images had good diagnostic accuracy (0.91 and 0.86, respectively). CONCLUSIONS: The combination of neuromelanin signal and volume changes with fractional anisotropy measurements in the substantia nigra showed excellent diagnostic accuracy. Moreover, the high diagnostic accuracy of visual assessment of substantia nigra changes using dorsolateral hyperintensity analysis or neuromelanin-sensitive signal changes indicates that these techniques are promising for clinical practice.

A normative study of the Italian printed word version of the free and cued selective reminding test.

According to the new research criteria for the diagnosis of Alzheimer's disease, episodic memory impairment, not significantly improved by cueing, is the core neuropsychological marker, even at a pre-dementia stage. The FCSRT assesses verbal learning and memory using semantic cues and is widely used in Europe. Standardization values for the Italian population are available for the colored picture version, but not for the 16-item printed word version. In this study, we present age- and education-adjusted normative data for FCSRT-16 obtained using linear regression techniques and generalized linear model, and critical values for classifying sub-test performance into equivalent scores. Six scores were derived from the performance of 194 normal subjects (MMSE score, range 27-30, mean 29.5 ± 0.5) divided per decade (from 20 to 90), per gender and per level of education (4 levels: 3-5, 6-8, 9-13, >13 years): immediate free recall (IFR), immediate total recall (ITR), recognition phase (RP), delayed free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. This study confirms the effect of age and education, but not of gender on immediate and delayed free and cued recall. The Italian version of the FCSRT-16 can be useful for both clinical and research purposes.

Volume of interest-based [18F]fluorodeoxyglucose PET discriminates MCI converting to Alzheimer's disease from healthy controls. A European Alzheimer's Disease Consortium (EADC) study.

An emerging issue in neuroimaging is to assess the diagnostic reliability of PET and its application in clinical practice. We aimed at assessing the accuracy of brain FDG-PET in discriminating patients with MCI due to Alzheimer's disease and healthy controls. Sixty-two patients with amnestic MCI and 109 healthy subjects recruited in five centers of the European AD Consortium were enrolled. Group analysis was performed by SPM8 to confirm metabolic differences. Discriminant analyses were then carried out using the mean FDG uptake values normalized to the cerebellum computed in 45 anatomical volumes of interest (VOIs) in each hemisphere (90 VOIs) as defined in the Automated Anatomical Labeling (AAL) Atlas and on 12 meta-VOIs, bilaterally, obtained merging VOIs with similar anatomo-functional characteristics. Further, asymmetry indexes were calculated for both datasets. Accuracy of discrimination by a Support Vector Machine and the AAL VOIs was tested against a validated method (PALZ). At the voxel level SMP8 showed a relative hypometabolism in the bilateral precuneus, and posterior cingulate, temporo-parietal and frontal cortices. Discriminant analysis classified subjects with an accuracy ranging between .91 and .83 as a function of data organization. The best values were obtained from a subset of 6 meta-VOIs plus 6 asymmetry values reaching an area under the ROC curve of .947, significantly larger than the one obtained by the PALZ score. High accuracy in discriminating MCI converters from healthy controls was reached by a non-linear classifier based on SVM applied on predefined anatomo-functional regions and inter-hemispheric asymmetries. Data pre-processing was automated and simplified by an in-house created Matlab-based script encouraging its routine clinical use. Further validation toward nonconverter MCI patients with adequately long follow-up is needed.

Functional imaging in pre-motor Parkinson's disease.

Several non motor symptoms (NMS) can precede the onset of the classical motor Parkinson's disease (PD) syndrome. The existence of pre-motor and even pre-clinical PD stages has been proposed but the best target population to be screened to disclose PD patients in a pre-clinical, thus asymptomatic, stage is still matter of debate. The REM sleep behavior disorder (RBD) often affects PD patients at different stages of the disease and could precede the onset of motor symptoms by several years. However, RBD could also precede other synucleinopathies (namely, dementia with Lewy bodies and multisystem atrophy), and less frequently could be related to other neurological conditions or remain idiopathic. Moreover, not all PD patients exhibit RBD. Despite these caveats, RBD probably represents the best feature to disclose pre-motor PD patients given its high-risk of developing a full motor syndrome. Other clinical clues in the premotor stages of PD undergoing active investigation include hyposmia, depression, and autonomic dysfunction. Effective biomarkers are needed in order to improve the diagnostic accuracy in the pre-motor stage of PD, to monitor disease progression and to plan both pharmacological and non-pharmacological intervention. Functional imaging, in particular radionuclide methodologies, has been often used to investigate dopaminergic and non-dopaminergic features as well as cortical functioning in patients with RBD in its idiopathic form (iRBD) and/or associated with PD. Recently, new tracers to image α-synuclein pathologies are under development. Functional imaging in pre-motor PD, and in particular in iRBD, could improve our knowledge about the underlying mechanisms and the neurodegenerative progress of PD.

Recommendations of the Sleep Study Group of the Italian Dementia Research Association (SINDem) on clinical assessment and management of sleep disorders in individuals with mild cognitive impairment and dementia: a clinical review.

Clinical assessment and management of sleep disturbances in patients with mild cognitive impairment and dementia has important clinical and social implications. Poor sleep results in an increased risk of morbidities and mortality in demented patients and is a source of stress for caregivers. Sleep disturbances show high prevalence in mild cognitive impairment and dementia patients and they are often associated one to another in the same patient. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of individuals with cognitive decline. The Sleep Study Group of the Italian Dementia Research Association (SINDem) reviewed evidence from original research articles, meta-analyses and systematic reviews published up to December 2013. The evidence was classified in quality levels (I, II, III) and strength of recommendations (A, B, C, D, E). Where there was a lack of evidence, but clear consensus, good practice points were provided. These recommendations may not be appropriate for all circumstances and should therefore be adopted only after a patient's individual characteristics have been carefully evaluated.

Cognitive impairment in degenerative parkinsonisms: role of radionuclide brain imaging.

Cognitive impairment in Parkinson's disease (PD) and atypical parkinsonian syndromes is gaining increased clinical significance. The neurochemical and neuropathological basis in the various parkinsonian forms and even in an individual patient are not fully elucidated yet and could be heterogeneous. Loss of dopaminergic, cholinergic and noradrenergic innervation has been suggested to be the underlying neurochemical deficits for cognitive impairment and dementia in PD, but the onset of cognitive impairment and the progression to dementia may not share the same underlying neurochemical basis. Similarly, pathological evidence is also heterogeneous, ranging from subcortical pathology, limbic or cortical Lewy body type degeneration, and Alzheimer's type pathology that can be found even in the same patient with PD dementia (PDD). Typically, the prototype of early cognitive deficit in PD is a dysexecutive syndrome, but other cognitive domains are more involved when dementia develops, mainly including visuospatial, language and memory dysfunction. Functional radionuclide neuroimaging, by means of single-photon emission computed tomography and positron emission tomography, are contributing to characterize the topographic cortical pattern of cognitive impairment, as well as to define the underlying neurochemical deficit. Lastly, the advent of amyloid PET may help clarifying the meaning of amyloid load in diffuse Lewy body disease and PDD. Knowing the neurochemical and pathophysiological substrate of cognitive deficit in patients with PD or other degenerative Parkinsonisms may help the clinician in understanding the clinical condition of an individual patient in order to plan pharmacological and non-pharmacological intervention. The introduction of acetylcholinesterase inhibitors for therapy of PDD is an example of information integration between clinical-neuropsychological and pathophysiological-neurochemical aspects obtained also with the key contribution of functional neuroimaging.

A retrospective study of audiological function in a group of congenital hypothyroid patients.

A retrospective survey has been carried out on audiological function in 46 congenital hypothyroid cases; mental and physical development were also assessed, as well as the adequacy of substitutive therapy. Using traditional audiometry it was found that 50% of the congenital hypothyroid patients were hypocusic. Severe and profound hearing loss (5 cases) was found in the group of hypothyroid patients with dyshormonogenesis, whereas only one-third of patients with thyroid agenesis presented a mild or moderate hearing loss not related to the time of diagnosis and treatment. The hearing loss was twice as frequent in the patients with clinical hypothyroidism. Using electrophysiological techniques, the early or slow potentials were comparable between hypocusic or normocusic patients; however a longer latency of the slow vertex responses was observed in the hypothyroid group as compared to the normal population. The mean estimated I.Q. was about 2 standard deviations below the average; however 30% of subjects had normal or above normal intellectual level, this percentage rises to 55% if only patients below 16 years are considered. The height was significantly shorter only in the late treated patients (1 year). No correlations were found among audiological and psychological variables, nor between these variables and height. All patients were on desiccated thyroid, but therapy was inadequate in 26% of cases and subclinical hypothyroidism was found in 33% of cases.