Dual-task gait training improves cognition and resting-state functional connectivity in Parkinson's disease with postural instability and gait disorders.

OBJECTIVES: To assess whether dual-task gait/balance training with action observation training (AOT) and motor imagery (MI) ameliorates cognitive performance and resting-state (RS) brain functional connectivity (FC) in Parkinson's disease (PD) patients with postural instability and gait disorders (PIGD). METHODS: 21 PD-PIGD patients were randomized into 2 groups: (1) DUAL-TASK + AOT-MI group performed a 6-week training consisting of AOT-MI combined with practicing observed-imagined gait and balance exercises; and (2) DUAL-TASK group performed the same exercises combined with landscape-videos observation. At baseline and after training, all patients underwent a computerized cognitive assessment, while 17 patients had also RS-fMRI scans. Cognitive and RS-FC changes (and their relationships) over time within and between groups were assessed. RESULTS: After training, all PD-PIGD patients improved accuracy in a test assessing executive-attentive (mainly dual-task) skills. DUAL-TASK + AOT-MI patients showed increased RS-FC within the anterior salience network (aSAL), and reduced RS-FC within the anterior default mode network (aDMN), right executive control network and precuneus network. DUAL-TASK patients showed increased RS-FC within the visuospatial network, only. Group × Time interaction showed that, compared to DUAL-TASK group, DUAL-TASK + AOT-MI cases had reduced RS-FC within the aDMN, which correlated with higher accuracy in a dual-task executive-attentive test. CONCLUSIONS: In PD-PIGD patients, both trainings promote cognitive improvement and brain functional reorganization. DUAL-TASK + AOT-MI training induced specific functional reorganization changes of extra-motor brain networks, which were related with improvement in dual-task performance.

Age-related vulnerability of the human brain connectome.

Multifactorial models integrating brain variables at multiple scales are warranted to investigate aging and its relationship with neurodegeneration. Our aim was to evaluate how aging affects functional connectivity of pivotal regions of the human brain connectome (i.e., hubs), which represent potential vulnerability 'stations' to aging, and whether such effects influence the functional and structural changes of the whole brain. We combined the information of the functional connectome vulnerability, studied through an innovative graph-analysis approach (stepwise functional connectivity), with brain cortical thinning in aging. Using data from 128 cognitively normal participants (aged 20-85 years), we firstly investigated the topological functional network organization in the optimal healthy condition (i.e., young adults) and observed that fronto-temporo-parietal hubs showed a highly direct functional connectivity with themselves and among each other, while occipital hubs showed a direct functional connectivity within occipital regions and sensorimotor areas. Subsequently, we modeled cortical thickness changes over lifespan, revealing that fronto-temporo-parietal hubs were among the brain regions that changed the most, whereas occipital hubs showed a quite spared cortical thickness across ages. Finally, we found that cortical regions highly functionally linked to the fronto-temporo-parietal hubs in healthy adults were characterized by the greatest cortical thinning along the lifespan, demonstrating that the topology and geometry of hub functional connectome govern the region-specific structural alterations of the brain regions.

Italian reference values and brain correlates of verbal fluency index - vs standard verbal fluency test - to assess executive dysfunction in ALS.

Objectives: In amyotrophic lateral sclerosis (ALS), verbal fluency index (Vfi) is used to investigate fluency accounting for motor impairment. This study has three aims: (1) to provide Vfi reference values from a cohort of Italian healthy subjects; (2) to assess the ability of Vfi reference values (vs standard verbal fluency test [VFT]) in distinguishing ALS patients with and without executive dysfunction; and (3) to investigate the association between Vfi and brain structural features of ALS patients. Methods: We included 180 healthy subjects and 157 ALS patients who underwent neuropsychological assessment, including VFT and Vfi, and brain MRI. Healthy subjects were split into four subgroups according to sex and education. For each subgroup, we defined the 95th percentile of Vfi as the cutoff. In ALS, the distributions of "abnormal" cases based on Vfi and standard VFT cutoffs were compared using Fisher's exact test. Using quantile regressions in patients, we assessed the association between Vfi and VFT scores, separately, with gray matter volumes and white matter (WM) tract integrity. Results: Applying Vfi and VFT cutoffs, 9 and 13% of ALS cases, respectively, had abnormal scores (p < 0.001). In ALS, while higher Vfi scores were associated with WM changes of callosal fibers linking supplementary motor area, lower VFT performances related to corticospinal tract alterations. Discussion: We provided Italian reference values for the spoken Vfi. Compared to VFT, Vfis are critical to disentangle motor and cognitive deficits in ALS. In patients, abnormal Vfis were associated with damage to WM tracts specifically involved in ideational information processing.

Cerebellar alterations in Parkinson's disease with postural instability and gait disorders.

BACKGROUND: Few studies interrogated the involvement of cerebellum in modulating gait in Parkinson's disease (PD) patients with postural instability and gait disorders (PD-PIGD). This study aimed at assessing cerebellar atrophy and activity alterations during functional MRI (fMRI) gait-simulating motor- and dual-tasks in PD-PIGD. METHODS: Twenty-one PD-PIGD and 23 healthy controls underwent clinical assessment, structural MRI, and fMRI including a motor-task (foot anti-phase movements) and a dual-task (foot anti-phase movements while counting backwards by threes). Grey matter cerebellar volumes were assessed using SUIT atlas. FMRI activations were extracted from each cerebellar lobule, and we correlated cerebellar and basal ganglia activity. RESULTS: PD-PIGD patients had reduced volumes of cerebellar motor and non-motor areas relative to controls. During fMRI motor-task, patients showed greater activation of cognitive cerebellar areas (VI and Crus I-II) vs controls. During fMRI dual-task, PD-PIGD patients showed increased activity of cognitive areas (Crus II) and reduced activity of motor areas (I-IV). Cerebellar structural alterations correlated with increased fMRI activity of cerebellar cognitive areas and with lower executive-attentive performance. The increased activity of Crus I during the motor-task correlated with a better motor performance in PD-PIGD. Moreover, the increased activity of cerebellum correlated with a reduced activity of putamen. CONCLUSIONS: In PD-PIGD, the increased activity of non-motor cerebellar areas during gait-simulating tasks may be a consequence of grey matter atrophy or an attempt to compensate the functional failure of cerebellar motor areas and basal ganglia. Cerebellar MRI metrics are useful to characterize brain correlates of motor and dual-task abilities in PD-PIGD patients.

Awareness impairment in Alzheimer's disease and frontotemporal dementia: a systematic MRI review.

This review aims to define awareness impairment and related disturbances in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) spectrum of disorders. An update of the available scientific literature on the use of magnetic resonance imaging (MRI) in the study of awareness in these disorders is also offered. MRI plays an important role in the characterization of neurodegenerative signatures and can increase our knowledge on brain structural and functional correlates of awareness. In the reviewing process, we established a-priori criteria and we searched the scientific literature for relevant articles on this topic. In summary, we selected 36 articles out of 1340 publications retrieved from PubMed. Based on this selection, this review discusses the multiple terms used to define different or overlapping aspects of awareness impairment, and specifically summarizes recent application of MRI for investigating anosognosia, social cognition, including theory of mind and emotional processing, free will, and autonoetic awareness alterations in different neurodegenerative disorders, with most of these studies focused on AD and FTLD. This systematic review highlights the importance of awareness impairment and related domains in neurodegenerative disorders, especially in AD and FTLD, and it outlines MRI structural and functional correlates in these populations.

Brain structural abnormalities and cognitive changes in a patient with 17q21.31 microduplication and early onset dementia: a case report.

OBJECTIVES: We describe brain structural damage and cognitive profile evolution of an adult patient with 17q21.31 microduplication, a rare condition associated with psychomotor delay, behavioural disturbances and poor social interaction. METHODS: A.B., 57 years old, male, displayed obsessive and repetitive behaviours, irritability, scarce hygiene and memory loss at disease onset. He had strong familiarity for adult-onset behavioural alterations (his father and sister) and neuropsychiatric conditions (his son). Blood and cerebrospinal fluid (CSF) samples revealed 17q21.31 microduplication, shared also by his son and sister, and raised CSF tau, respectively. He was hospitalized 1 year after disease onset and underwent an MRI scan and a neuropsychological assessment, the latter being repeated 7 months later. To quantitatively investigate patient's grey matter (GM) volume, 16 age- and education-matched male controls were selected and voxel-based morphometry analysis was performed. RESULTS: During hospitalization, his behavioural profile was characterized by anosognosia, impulsivity, apathy and aggressiveness. Cognitive testing revealed main attentive-executive disturbances and difficulties in understanding non-literal language. Compared to controls, A.B. had greater GM atrophy mainly in the right hemisphere, involving amygdala, hippocampus, inferior/superior temporal gyri and temporal pole. He received a diagnosis of early onset dementia. After 7 months, he developed empathy loss, perseverative behaviour, changes in eating habits and worsening in executive-attentive abilities. CONCLUSIONS: In A.B., 17q21.31 microduplication caused a neurodegenerative condition with prevalent right temporal damage, raised CSF tau level, behavioural disturbances, memory impairment, attentive-executive and abstract language dysfunctions and fast disease progression, thus reflecting the complex interaction between such genetic substrate and clinical phenotypes.

Longitudinal clinical, cognitive, and neuroanatomical changes over 5 years in GBA-positive Parkinson's disease patients.

OBJECTIVE: To study the longitudinal disease course of Parkinson's disease (PD) patients with glucocerebrosidase (GBA) mutation (GBA-positive) compared to PD non-carriers (GBA-negative) along a 5-year follow-up, evaluating changes in clinical and cognitive outcomes, cortical thickness, and gray-matter (GM) volumes. METHODS: Ten GBA-positive and 20 GBA-negative PD patients underwent clinical, neuropsychological, and MRI assessments (cortical thickness and subcortical, hippocampal, and amygdala volumes) at study entry and once a year for 5 years. At baseline and at the last visit, each group of patients was compared with 22 age-matched healthy controls. Clinical, cognitive, and MRI features were compared between groups at baseline and over time. RESULTS: At baseline, GBA-positive and GBA-negative PD patients had similar clinical and cognitive profiles. Compared to GBA-negative and controls, GBA-positive patients showed cortical thinning of left temporal, parietal, and occipital gyri. Over time, compared to GBA-negative, GBA-positive PD patients progressed significantly in motor and cognitive symptoms, and showed a greater pattern of cortical thinning of posterior regions, and frontal and orbito-frontal cortices. After 5 years, compared to controls, GBA-negative PD patients showed a pattern of cortical thinning similar to that showed by GBA-positive cases at baseline. The two groups of patients showed similar patterns of subcortical, hippocampal, and amygdala volume loss over time. CONCLUSIONS: Compared to GBA-negative PD, GBA-positive patients experienced a more rapid motor and cognitive decline together with a greater, earlier and faster cortical thinning. Cortical thickness measures may be a useful tool for monitoring and predicting PD progression in accordance with the genetic background.

Action Observation and Motor Imagery Improve Dual Task in Parkinson's Disease: A Clinical/fMRI Study.

BACKGROUND: Action observation training and motor imagery may improve motor learning in Parkinson's disease (PD). OBJECTIVES: The objectives of this study were to assess mobility and balance (performing motor and dual tasks) and brain functional reorganization following 6 weeks of action observation training and motor imagery associated with dual-task gait/balance exercises in PD patients with postural instability and gait disorders relative to dual-task training alone. METHODS: Twenty-five PD-postural instability and gait disorder patients were randomized into 2 groups: the DUAL-TASK+AOT-MI group performed a 6-week gait/balance training consisting of action observation training-motor imagery combined with practicing the observed-imagined exercises; the DUAL-TASK group performed the same exercises combined with watching landscape videos. Exercises were increasingly difficult to include the dual task. At baseline and at 6 weeks, patients underwent: mobility, gait, and balance evaluations (also repeated 2 months after training), cognitive assessment, and functional MRI, including motor and dual tasks. RESULTS: Dual-task gait/balance training enhanced mobility, during both single- and dual-task conditions, and executive functions in PD-postural instability and gait disorders, with a long-lasting effect at 14 weeks. When exercises were preceded by action observation training-motor imagery, PD-postural instability and gait disorders showed greater improvement of balance and gait velocity both with and without the dual task, particularly during the turning phase. After training, the DUAL-TASK+AOT-MI group showed reduced recruitment of frontal areas and increased activity of cerebellum during functional-MRI motor and dual task, correlating with balance/turning velocity and executive improvements, respectively. The DUAL-TASK group showed reduced activity of supplementary motor area and increased recruitment of temporo-parietal areas during the dual task and decreased cerebellar activity during the motor task correlating with faster turning velocity. Functional MRI results were not corrected for multiple comparisons and should be interpreted carefully. CONCLUSIONS: Adding action observation training-motor imagery to dual-task gait/balance training promotes specific functional reorganization of brain areas involved in motor control and executive-attentive abilities and more long-lasting effects on dual-task mobility and balance in PD-postural instability and gait disorders. © 2021 International Parkinson and Movement Disorder Society.

The art gallery maze: a novel tool to assess human navigational abilities.

Humans differ widely in their ability to navigate effectively through the environment and in spatial memory skills. Navigation in the environment requires the analysis of many spatial cues, the construction of internal representations, and the use of various strategies. We present a novel tool to assess individual differences in human navigation, consisting of a virtual radial-arm maze presented as an art gallery to explore whether different sets of instructions (intentional or incidental) affect subjects' navigation performance. We furthermore tested the effect of the instructions on exploration strategies during both place learning and recall. We evaluated way-finding ability in 42 subjects, and individual differences in navigation were assessed through the analysis of navigational paths, which permitted the isolation and definition of a few strategies adopted by the incidental and intentional instructions groups. Our results showed that the intentional instruction group performed better than the other group: these subjects correctly paired each central statue and the two paintings in the adjacent arms, and they made less working and reference memory errors. Our analysis of path lengths showed that the intentional instruction group spent more time in the maze (thus being slower), specifically in the central hall, and covered more distance; the time spent in the main hall was, therefore, indicative of the quality of the following performance. Studying how environmental representations and the relative navigational strategies vary among "intentional" and "incidental" groups provides a new window into the acknowledgment of possible strategies to help subjects construct more efficient approaches in human navigation.

Early functional MRI changes in a prodromal semantic variant of primary progressive aphasia: a longitudinal case report.

OBJECTIVE: To assess longitudinal patterns of brain functional MRI (fMRI) activity in a case of prodromal semantic variant of a primary progressive aphasia (svPPA). METHODS: Clinical, cognitive and neuroimaging data (T1-weighted and task-based fMRI during silent naming [SN] and object knowledge [OK]) were obtained at baseline, month 8 and month 16 from a 49-year-old lady presenting with anomias and evolving to overt svPPA in 8 months. RESULTS: At baseline, the patient showed isolated anomias and mild left anterior temporal pole atrophy. During SN-fMRI, she showed bilateral temporal and left inferior frontal gyri (iFG) activations. During OK-fMRI, we observed normal performance and the recruitment of bilateral posterior hippocampi, iFG and left middle orbitofrontal gyrus (mOFG). At month 8, the patient received a diagnosis of svPPA and showed isolated right iFG activity during SN-fMRI, and a borderline performance during OK-fMRI together with a disappearance of mOFG recruitment. At the last visit (after 7-month language therapy), the patient showed a stabilization of naming disturbances, and, compared to previous visits, an increased left iFG recruitment during SN-fMRI. During OK-fMRI, she performed abnormally and did not show the activity of mOFG and iFG. Across all visits, brain atrophy remained stable. CONCLUSIONS: This case report showed longitudinal fMRI patterns during semantic-related tasks from prodromal to overt svPPA. Frontal brain recruitment may represent a compensatory mechanism in patients with early svPPA, which is likely to be reinforced by language-therapy. Brain fMRI is more sensitive compared with structural MRI to detect progressive brain changes associated with disease and treatment.

An update on magnetic resonance imaging markers in AD.

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.

Crossed aphasia confirmed by fMRI in a case with nonfluent variant of primary progressive aphasia carrying a GRN mutation.

OBJECTIVES: To characterize patterns of language lateralization in a right-handed woman with nonfluent/agrammatic primary progressive aphasia (nfvPPA) clinical picture despite showing a prevalent right-sided brain damage. METHODS: We report a case of a 58-year-old woman with nfvPPA diagnosis (age at onset = 55) previously described as a crossed aphasia case with progranulin mutation. At 2 years from the first visit, patient underwent 3DT1-weighted and a task-based functional MRI (fMRI). During the fMRI task, she was asked to perform a letter fluency test as the task of interest and to count forward as the control condition. Image processing and data analysis were performed using SPM12 and the effect of each task was tested at p < 0.05 FWE corrected. RESULTS: The structural MRI confirmed a widespread right fronto-temporal atrophy mainly involving the right inferior frontal gyrus. During the letter fluency task, we observed an increased activation centered at the right inferior orbitofrontal gyrus and right middle frontal gyrus. By reducing the threshold, the pattern of functional activation was still dramatically prevalent at the right side. CONCLUSIONS: We provided evidence of the right language lateralization in a previously suspected crossed nfvPPA. Despite the long disease duration and the large amount of atrophy at the right side, there was no fMRI evidence of a left-hemisphere contribution to language function. We might speculate that compensatory effects do not appear when the premorbid language lateralization is purely right. The investigation of the underlying functional brain substrates in crossed nfvPPA cases may help understanding disease vulnerability in these neurodegenerative conditions.