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Abstract Bradykinesia is defined as a “complex” of motor alterations including decreased movement amplitude and/or speed and tendency to reduce them with movement repetition (sequence effect). This study aimed at investigating the neural and kinematic correlates of bradykinesia during hand-tapping in people with Parkinson’s disease (pwPD) relative to healthy controls. Twenty-five pwPD and 25 age- and sex-matched healthy controls underwent brain functional MRI (fMRI) during a hand-tapping task: subjects alternatively opened and closed their right hand as fully and quickly as possible. Hand-tapping kinematic parameters were objectively measured during the fMRI task using an optical fibre glove. During the fMRI task, pwPD showed reduced hand-tapping amplitude (hypokinesia) and a greater sequence effect. PwPD relative to healthy controls showed a reduced activity of fronto-parietal areas, middle cingulum/supplementary motor area (SMA), parahippocampus, pallidum/thalamus and motor cerebellar areas. Moreover, pwPD showed an increased activity of brain cognitive areas such as superior temporal gyrus, posterior cingulum, and cerebellum crus I. The decreased activity of cerebellum IV–V–VI, vermis IV–V, inferior frontal gyrus, and cingulum/SMA correlated with hypokinesia and with the sequence effect. Interestingly, a reduced activity of areas involved in motor planning and timing correlated both with hypokinesia and with the sequence effect in pwPD. This study has the major strength of collecting objective motor parameters and brain activity simultaneously, providing a unique opportunity to investigate the neural correlates of the “bradykinesia complex”.

Abstract Background The identification and staging of Alzheimer’s Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD. Methods One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses. Results Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI. Conclusions Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

Abstract Background Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer’s disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue. Methods Following the initiative of the University of Washington’s National Alzheimer’s Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms. Results Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward. Conclusions The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings.

ObjectivesWe report the clinical presentation and evolution of a case with a novel Progranulin gene (GRN) mutation and non-fluent language disturbances at onset.Materials and methodsA 60 year-old, white patient was followed due to a history of language disturbances. Eighteen months after onset, the patient underwent FDG positron emission tomography (PET), and at month 24 was hospitalized to perform neuropsychological evaluation, brain 3 T MRI, lumbar puncture for cerebrospinal fluid (CSF) analysis, and genotyping. At month 31, the patient repeated the neuropsychological evaluation and brain MRI.ResultsAt onset the patient complained prominent language production difficulties, such as effortful speech and anomia. At month 18, FDG-PET showed left fronto-temporal and striatal hypometabolism. At month 24, the neuropsychological evaluation reported prevalent speech and comprehension deficits. Brain MRI reported left fronto-opercular and striatal atrophy, and left frontal periventricular white matter hyperintensities (WMHs). Increased CSF total tau level was observed. Genotyping revealed a new GRN c.1018delC (p.H340TfsX21) mutation. The patient received a diagnosis of non-fluent variant of primary progressive aphasia (nfvPPA). At month 31, language deficits worsened, together with attention and executive functions. The patient presented also with behavioral disturbances, and a progressive atrophy in the left frontal-opercular and temporo-mesial region.Discussion and conclusionThe new GRN p.H340TfsX21 mutation resulted in a case of nfvPPA characterized by fronto-temporal and striatal alterations, typical frontal asymmetric WMHs, and a fast progression toward a widespread cognitive and behavioral impairment, which reflects a frontotemporal lobar degeneration. Our findings extend the current knowledge of the phenotypic heterogeneity among GRN mutation carriers.

Amyotrophic lateral sclerosis (ALS) has traditionally been associated with brain damage involving the primary motor cortices and corticospinal tracts. In the recent decades, most of the research studies in ALS have focused on extra-motor and subcortical brain regions. The aim of these studies was to detect additional biomarkers able to support the diagnosis and to predict disease progression. The involvement of the frontal cortices, mainly in ALS cases who develop cognitive and/or behavioral impairment, is amply recognized in the field. A potential involvement of fronto-temporal and fronto-striatal connectivity changes in the disease evolution has also been reported. On this latter regard, there is still a shortage of studies which investigated basal ganglia (BG) alterations and their role in ALS clinical manifestation and progression. The present review aims to provide an overview on the magnetic resonance imaging studies reporting structural and/or functional BG alterations in patients with ALS, to clarify the role of BG damage in the disease clinical evolution and to propose potential future developments in this field.

Abstract The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype–phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD.

ObjectiveMutations in the TARDBP gene are a rare cause of genetic motor neuron disease (MND). Morphologic MRI characteristics of MND patients carrying this mutation have been poorly described. Our objective was to investigate distinctive clinical and MRI features of a relatively large sample of MND patients carrying TARDBP mutations.MethodsEleven MND patients carrying a TARDBP mutation were enrolled. Eleven patients with sporadic MND (sMND) and no genetic mutations were also selected and individually matched by age, sex, clinical presentation and disease severity, along with 22 healthy controls. Patients underwent clinical and cognitive evaluations, as well as 3D T1-weighted and diffusion tensor (DT) MRI on a 3 Tesla scanner. Gray matter (GM) atrophy was first investigated at a whole-brain level using voxel-based morphometry (VBM). GM volumes and DT MRI metrics of the main white matter (WM) tracts were also obtained. Clinical, cognitive and MRI features were compared between groups.ResultsMND with TARDBP mutations was associated with all possible clinical phenotypes, including isolated upper/lower motor neuron involvement, with no predilection for bulbar or limb involvement at presentation. Greater impairment at naming tasks was found in TARDBP mutation carriers compared with sMND. VBM analysis showed significant atrophy of the right lateral parietal cortex in TARDBP patients, compared with controls. A distinctive reduction of GM volumes was found in the left precuneus and right angular gyrus of TARDBP patients compared to controls. WM microstructural damage of the corticospinal tract (CST) and inferior longitudinal fasciculi (ILF) was found in both sMND and TARDBP patients, compared with controls, although decreased fractional anisotropy of the right CST and increased axial diffusivity of the left ILF (p = 0.017) was detected only in TARDBP mutation carriers.ConclusionsTARDBP patients showed a distinctive parietal pattern of cortical atrophy and greater damage of motor and extra-motor WM tracts compared with controls, which sMND patients matched for disease severity and clinical presentation were lacking. Our findings suggest that TDP-43 pathology due to TARDBP mutations may cause deeper morphologic alterations in both GM and WM.

In the present study, we aimed to investigate the resting-state functional connectivity (RS-FC) of the globus pallidus (GP) in patients with amyotrophic lateral sclerosis (ALS) compared to healthy controls, and the relationship between RS-FC changes and disgust recognition. Twenty-six pure-motor ALS patients and 52 healthy controls underwent RS functional MRI and a neuropsychological assessment including the Comprehensive Affect Testing System. A seed-based RS-FC analysis was performed between the left and right GP and the rest of the brain and compared between groups. Correlations between RS-FC significant changes and subjects’ performance in recognizing disgust were tested. Compared to controls, patients were significantly less able to recognize disgust. In ALS compared to controls, the seed-based analysis showed: reduced RS-FC between bilateral GP and bilateral middle and superior frontal and middle cingulate gyri, and increased RS-FC between bilateral GP and bilateral postcentral, supramarginal and superior temporal gyri and Rolandic operculum. Decreased RS-FC was further observed between left GP and left middle and inferior temporal gyri and bilateral caudate; and increased RS-FC was also shown between right GP and left lingual and fusiform gyri. In patients and controls, lower performance in recognizing disgust correlated with reduced RS-FC between left GP and left middle and inferior temporal gyri. In pure-motor ALS patients, we demonstrated altered RS-FC between GP and the rest of the brain. The reduced left pallidum-temporo-striatal RS-FC may have a role in the lower ability of patients in recognizing disgust.

Objective: Emotional processes might influence freezing of gait (FoG) in Parkinson’s disease (PD) patients. We assessed brain functional MRI (fMRI) activity during a “FoG-observation-task” in PD-FoG patients relative to healthy controls. Methods: Twenty-four PD-FoG patients and 18 age- and sex-matched healthy controls performed clinical and neuropsychological evaluations, and fMRI experiments including: i) “FoG-observation-task” consisting of watching a patient experiencing FoG during a walking task (usually evoking FoG); ii) “gait-observation-task” consisting of watching a healthy subject performing similar walking tasks without experiencing FoG. Results: During both tasks, PD-FoG patients showed reduced activity of the fronto-parietal mirror neuron system (MNS) relative to controls. In the “FoG-observation-task” relative to the “gait-observation-task”, PD-FoG patients revealed an increased recruitment of the anterior medial prefrontal cortex and a reduced recruitment of the dorsomedial prefrontal cortex and hippocampus relative to controls. Healthy controls in the “FoG-observation-task” relative to the “gait-observation-task” showed increased recruitment of cognitive empathy areas and decreased activity of the fronto-parietal MNS. Conclusion: Our results suggest that when PD-FoG patients observe a subject experiencing FoG, there is an increased activity of brain areas involved in self-reflection emotional processes and a reduced activity of areas related to motor programming, executive functions and cognitive empathy. These findings support previous evidence on the critical role of the emotional circuit in the mechanisms underlying FoG.

In the present study we investigated emotion recognition in pure motor amyotrophic lateral sclerosis (ALS) patients and its relationship with the integrity of basal ganglia, hippocampus and amygdala. Twenty ALS patients without either cognitive or behavioural impairment, and 52 matched healthy controls performed a neuropsychological assessment including the Comprehensive Affect Testing System (CATS) investigating emotion recognition. All participants underwent also a 3T brain MRI. Volumes of basal ganglia, hippocampus and amygdala bilaterally were measured using FIRST in FSL. Sociodemographic, cognitive and MRI data were compared between groups. In ALS patients, correlations between CATS significant findings, brain volumes, cognition, mood and behaviour were explored. ALS patients showed altered performances at the CATS total score and, among the investigated emotions, patients were significantly less able to recognize disgust compared with controls. No brain volumetric differences were observed between groups. In ALS patients, a lower performance in disgust recognition was related with a reduced volume of the left pallidum and a lower performance on the Edinburgh Cognitive and Behavioural ALS Screen. Cognitively/behaviourally unimpaired ALS patients showed impaired disgust recognition, which was associated with pallidum volume. The association with cognitive alterations may suggest impaired disgust recognition as an early marker of cognitive decline.

The purpose of the present review is to provide an update of the available recent scientific literature on the use of magnetic resonance imaging (MRI) in Alzheimer’s disease (AD). MRI is playing an increasingly important role in the characterization of the AD signatures, which can be useful in both the diagnostic process and monitoring of disease progression. Furthermore, this technique is unique in assessing brain structure and function and provides a deep understanding of in vivo evolution of cerebral pathology. In the reviewing process, we established a priori criteria and we thoroughly searched the very recent scientific literature (January 2018–March 2020) for relevant articles on this topic. In summary, we selected 73 articles out of 1654 publications retrieved from PubMed. Based on this selection, this review summarizes the recent application of MRI in clinical trials, defining the predementia stages of AD, the clinical utility of MRI, proposal of novel biomarkers and brain regions of interest, and assessing the relationship between MRI and cognitive features, risk and protective factors of AD. Finally, the value of a multiparametric approach in clinical and preclinical stages of AD is discussed.

Objective: To investigate the progression of resting-state functional connectivity (rs-FC) changes in patients with amyotrophic lateral sclerosis (ALS) and their relationship with frontal cognitive alterations. Methods: This is a multicentre, observational and longitudinal study. At baseline and after six months, 25 ALS patients underwent 3D T1-weighted MRI, resting-state functional MRI (rs-fMRI), and the computerized Test of Attentional Performance (TAP). Using independent component analysis, rs-FC changes of brain networks involving connections to frontal lobes and their relationship with baseline cognitive scores and cognitive changes over time were assessed. With a seed-based approach, rs-FC longitudinal changes of the middle frontal gyrus (MFG) were also explored. Results: After six months, ALS patients showed an increased rs-FC of the left anterior cingulate, left middle frontal gyrus (MFG) and left superior frontal gyrus within the frontostriatal network, and of the left MFG, left supramarginal gyrus and right angular gyrus within the left frontoparietal network. Within the frontostriatal network, a worse baseline performance at TAP divided attention task was associated with an increased rs-FC over time in the left MFG and a worse baseline performance at the category fluency index was related with increased rs-FC over time in the left frontal superior gyrus. After six months, the seed-based rs-FC analysis of the MFG with the whole brain showed decreased rs-FC of the right MFG with frontoparietal regions in patients compared to controls. Conclusions: Rs-FC changes in ALS patients progressed over time within the frontostriatal and the frontoparietal networks and are related to frontal-executive dysfunction. The MFG seems a potential core region in the framework of a frontoparietal functional breakdown, which is typical of frontotemporal lobar degeneration. These findings offer new potential markers for monitoring extra-motor progression in ALS.

Abstract Background A growing number of pharmacological and nonpharmacological trials have been performed to test the efficacy of approved or experimental treatments in Alzheimer disease (AD) and mild cognitive impairment (MCI). In this context, functional magnetic resonance imaging (fMRI) may be a good candidate to detect brain changes after a short period of treatment. Main body This critical review aimed to identify and discuss the available studies that have tested the efficacy of pharmacological and nonpharmacological treatments in AD and MCI cases using task-based or resting-state fMRI measures as primary outcomes. A PubMed-based literature search was performed with the use of the three macro-areas: ‘disease’, ‘type of MRI’, and ‘type of treatment’. Each contribution was individually reviewed according to the Cochrane Collaboration’s tool for assessing risk of bias. Study limitations were systematically detected and critically discussed. We selected 34 pharmacological and 13 nonpharmacological articles. According to the Cochrane Collaboration’s tool for assessing risk of bias, 40% of these studies were randomized but only a few described clearly the randomization procedure, 36% declared the blindness of participants and personnel, and only 21% reported the blindness of outcome assessment. In addition, 28% of the studies presented more than 20% drop-outs at short- and/or long-term assessments. Additional common shortcomings of the reviewed works were related to study design, patient selection, sample size, choice of outcome measures, management of drop-out cases, and fMRI methods. Conclusion There is an urgent need to obtain efficient treatments for AD and MCI. fMRI is powerful enough to detect even subtle changes over a short period of treatment; however, the soundness of methods should be improved to enable meaningful data interpretation.

This study identified structural and functional brain connectivity alterations in two independent samples of patients along the posterior cortical atrophy (PCA) disease course. Twenty-one PCA patients and 44 controls were recruited from two expert centres. Microstructural damage of white matter (WM) tracts was assessed using probabilistic tractography; resting state (RS) functional connectivity of brain networks was explored using a model free approach; grey matter (GM) atrophy was investigated using voxel-based morphometry. Compared with controls, common patterns of damage across PCA patients included: GM atrophy in the occipital-temporal-parietal regions; diffusion tensor (DT) MRI alterations of the corpus callosum and superior (SLF) and inferior longitudinal fasciculi (ILF) bilaterally; and decreased functional connectivity of the occipital gyri within the visual network and the precuneus and posterior cingulum within the default mode network (DMN). In PCA patients with longer disease duration and greater disease severity, WM damage extended to the cingulum and RS functional connectivity alterations spread within the frontal, dorsal attentive and salience networks. In PCA, reduced DMN functional connectivity was associated with SLF and ILF structural alterations. PCA patients showed distributed WM damage. Altered RS functional connectivity extends with disease worsening from occipital to temporo-parietal and frontostriatal regions, and this is likely to occur through WM connections. Future longitudinal studies are needed to establish trajectories of damage spreading in PCA and whether a combined DT MRI/RS functional MRI approach is promising in monitoring the disease progression. Keywords: Posterior cortical atrophy, White matter, Diffusion tensor MRI, Resting state functional connectivity, Default mode network, Visual network

This prospective study explored whether an approach combining structural [cortical thickness and white matter (WM) microstructure] and resting state functional MRI can aid differentiation between 62 early onset Alzheimer's disease (EOAD) and 27 behavioural variant of frontotemporal dementia (bvFTD) patients. Random forest and receiver operator characteristic curve analyses assessed the ability of MRI in classifying the two clinical syndromes. All patients showed a distributed pattern of brain alterations relative to controls. Compared to bvFTD, EOAD patients showed bilateral inferior parietal cortical thinning and decreased default mode network functional connectivity. Compared to EOAD, bvFTD patients showed bilateral orbitofrontal and temporal cortical thinning, and WM damage of the corpus callosum, bilateral uncinate fasciculus, and left superior longitudinal fasciculus. Random forest analysis revealed that left inferior parietal cortical thickness (accuracy 0.78, specificity 0.76, sensitivity 0.83) and WM integrity of the right uncinate fasciculus (accuracy 0.81, specificity 0.96, sensitivity 0.43) were the best predictors of clinical diagnosis. The combination of cortical thickness and DT MRI measures was able to distinguish patients with EOAD and bvFTD with accuracy 0.82, specificity 0.76, and sensitivity 0.96. The diagnostic ability of MRI models was confirmed in a subsample of patients with biomarker-based clinical diagnosis. Multiparametric MRI is useful to identify brain alterations which are specific to EOAD and bvFTD. A severe cortical involvement is suggestive of EOAD, while a prominent WM damage is indicative of bvFTD. Keywords: Early onset Alzheimer's disease, Behavioural variant of frontotemporal dementia, Diagnosis, Cortical thickness, White matter (WM) damage, Resting state functional MRI

We built and validated a deep learning algorithm predicting the individual diagnosis of Alzheimer's disease (AD) and mild cognitive impairment who will convert to AD (c-MCI) based on a single cross-sectional brain structural MRI scan. Convolutional neural networks (CNNs) were applied on 3D T1-weighted images from ADNI and subjects recruited at our Institute (407 healthy controls [HC], 418 AD, 280 c-MCI, 533 stable MCI [s-MCI]). CNN performance was tested in distinguishing AD, c-MCI and s-MCI. High levels of accuracy were achieved in all the classifications, with the highest rates achieved in the AD vs HC classification tests using both the ADNI dataset only (99%) and the combined ADNI + non-ADNI dataset (98%). CNNs discriminated c-MCI from s-MCI patients with an accuracy up to 75% and no difference between ADNI and non-ADNI images. CNNs provide a powerful tool for the automatic individual patient diagnosis along the AD continuum. Our method performed well without any prior feature engineering and regardless the variability of imaging protocols and scanners, demonstrating that it is exploitable by not-trained operators and likely to be generalizable to unseen patient data. CNNs may accelerate the adoption of structural MRI in routine practice to help assessment and management of patients. Keywords: Alzheimer's disease, Mild cognitive impairment, Diagnosis, Prediction, Deep learning, Convolutional neural networks

ObjectivesThis is a cross-sectional study aimed at investigating cognitive performances in patients with primary lateral sclerosis (PLS) and using diffusion tensor (DT) magnetic resonance imaging (MRI) to determine the topographical distribution of microstructural white matter (WM) damage in patients with or without cognitive deficits.MethodsDT MRI scans were obtained from 21 PLS patients and 35 age- and sex-matched healthy controls. All PLS patients underwent a comprehensive neuropsychological battery. Tract-based-spatial-statistics (TBSS) was used to perform a whole-brain voxel-wise analysis of fractional anisotropy (FA), axial, radial (radD) and mean diffusivity (MD).ResultsTen PLS patients had abnormal scores in at least one neuropsychological test (PLS with cognitive deficits, PLS-cd). Compared with healthy controls and cognitively unimpaired PLS patients (PLS-cu), PLS-cd cases showed decreased FA and increased MD and radD in the corticospinal tract (CST), corpus callosum, brainstem, anterior limb of internal capsule, superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes, bilaterally. Compared with healthy controls, PLS-cd patients showed further decreased FA and increased radD in the cerebellar WM, bilaterally. Compared with controls, PLS-cu patients showed decreased FA in the mid-body of corpus callosum. In PLS, executive and language test scores correlated with WM damage.ConclusionsThis is the first study evaluating the relationship between cognitive performance and WM tract damage in PLS patients. PLS can be associated with a multi-domain cognitive impairment. WM damage to interhemispheric, limbic and major associative WM tracts seem to be the structural correlate of cognitive abnormalities in these patients.