Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation.

We present an in-depth clinical and neuroimaging analysis of a family carrying the MAPT K298E mutation associated with frontotemporal dementia (FTD). Initial identification of this mutation in a single clinical case led to a comprehensive investigation involving four affected siblings allowing to elucidate the mutation's phenotypic expression.A 60-year-old male presented with significant behavioral changes and progressed rapidly, exhibiting speech difficulties and cognitive decline. Neuroimaging via FDG-PET revealed asymmetrical frontotemporal hypometabolism. Three siblings subsequently showed varied but consistent clinical manifestations, including abnormal behavior, speech impairments, memory deficits, and motor symptoms correlating with asymmetric frontotemporal atrophy observed in MRI scans.Based on the genotype-phenotype correlation, we propose that the p.K298E mutation results in early-onset behavioral variant FTD, accompanied by a various constellation of speech and motor impairment.This detailed characterization expands the understanding of the p.K298E mutation's clinical and neuroimaging features, underlining its role in the pathogenesis of FTD. Further research is crucial to comprehensively delineate the clinical and epidemiological implications of the MAPT p.K298E mutation.

Gait Analysis and Magnetic Resonance Imaging Characteristics in Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Isolated rapid eye movement sleep behavioral disorder (iRBD) can precede neurodegenerative diseases. There is an urgent need for biomarkers to aid early intervention and neuroprotection. OBJECTIVE: The aim is to assess quantitative motor, cognitive, and brain magnetic resonance imaging (MRI) characteristics in iRBD patients. METHODS: Thirty-eight polysomnography-confirmed iRBD patients and 28 age- and sex-matched healthy controls underwent clinical, cognitive, and motor functional evaluations, along with brain MRI. Motor tasks included nine-hole peg test, five-times-sit-to-stand test, timed-up-and-go test, and 4-meter walking test with and without cognitive dual task. Quantitative spatiotemporal gait parameters were obtained using an optoelectronic system. Brain MRI analysis included functional connectivity (FC) of the main resting-state networks, gray matter (GM) volume using voxel-based morphometry, cortical thickness, and deep GM and brainstem volumes using FMRIB's Integrated Registration and Segmentation Tool and FreeSurfer. RESULTS: iRBD patients relative to healthy subjects exhibited a poorer performance during the nine-hole peg test and five-times-sit-to-stand test, and greater asymmetry of arm-swing amplitude and stride length variability during dual-task gait. Dual task significantly worsened the walking performance of iRBD patients more than healthy controls. iRBD patients exhibited nonmotor symptoms, and memory, abstract reasoning, and visuospatial deficits. iRBD patients exhibited decreased FC of pallidum and putamen within the basal ganglia network and occipital and temporal areas within the visuo-associative network, and a reduced volume of the supramarginal gyrus. Brain functional alterations correlated with gait changes. CONCLUSIONS: Subtle motor and nonmotor alterations were identified in iRBD patients, alongside brain structural and functional MRI changes. These findings may represent early signs of neurodegeneration and contribute to the development of predictive models for progression to parkinsonism. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Stepwise Functional Brain Architecture Correlates with Atrophy in Progressive Supranuclear Palsy.

BACKGROUND: Stepwise functional connectivity (SFC) detects whole-brain functional couplings of a selected region of interest at increasing link-step topological distances. OBJECTIVE: This study applied SFC to test the hypothesis that stepwise architecture propagating from the disease epicenter would shape patterns of brain atrophy in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). METHODS: Thirty-six patients with PSP-RS and 44 age-matched healthy control subjects underwent brain magnetic resonance imaging on a 3-T scanner. The disease epicenter was defined as the peak of atrophy observed in an independent cohort of 13 cases with postmortem confirmation of PSP pathology and used as seed region for SFC analysis. First, we explored SFC rearrangements in patients with PSP-RS, as compared with age-matched control subjects. Subsequently, we tested SFC architecture propagating from the disease epicenter as a determinant of brain atrophy distribution. RESULTS: The disease epicenter was identified in the left midbrain tegmental region. Compared with age-matched control subjects, patients with PSP-RS showed progressively widespread decreased SFC of the midbrain with striatal and cerebellar regions through direct connections and sensorimotor cortical regions through indirect connections. A correlation was found between average link-step distance from the left midbrain in healthy subjects and brain volumes in patients with PSP-RS (r = 0.38, P < 0.001). CONCLUSIONS: This study provides comprehensive insights into the topology of functional network rearrangements in PSP-RS and demonstrates that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP-RS. Our findings support the view of a network-based pathology propagation in this primary tauopathy. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

Analysis of individual alpha frequency in a large cohort from a tertiary memory center.

BACKGROUND AND PURPOSE: Precise and timely diagnosis is crucial for the optimal use of emerging disease-modifying treatments for Alzheimer disease (AD). Electroencephalography (EEG), which is noninvasive and cost-effective, can capture neural abnormalities linked to various dementias. This study explores the use of individual alpha frequency (IAF) derived from EEG as a diagnostic and prognostic tool in cognitively impaired patients. METHODS: This retrospective study included 375 patients from the tertiary Memory Clinic of IRCCS San Raffaele Hospital, Milan, Italy. Participants underwent clinical and neuropsychological assessments, brain imaging, cerebrospinal fluid biomarker analysis, and resting-state EEG. Patients were categorized by amyloid status, the AT(N) classification system, clinical diagnosis, and mild cognitive impairment (MCI) progression to AD dementia. IAF was calculated and compared among study groups. Receiver operating characteristic (ROC) analysis was used to calculate its discriminative performance. RESULTS: IAF was higher in amyloid-negative subjects and varied significantly across AT(N) groups. ROC analysis confirmed IAF's ability to distinguish A-T-N- from the A+T+N+ and A+T-N+ groups. IAF was lower in AD and Lewy body dementia patients compared to MCI and other dementia types, with moderate discriminatory capability. Among A+ MCI patients, IAF was significantly lower in those who converted to AD within 2 years compared to stable MCI patients and predicted time to conversion (p < 0.001, R = 0.38). CONCLUSIONS: IAF is a valuable tool for dementia diagnosis and prognosis, correlating with amyloid status and neurodegeneration. It effectively predicts MCI progression to AD, supporting its use in early, targeted interventions in the context of disease-modifying treatments.

Resting state functional brain networks associated with emotion processing in frontotemporal lobar degeneration.

This study investigated the relationship between emotion processing and resting-state functional connectivity (rs-FC) of the brain networks in frontotemporal lobar degeneration (FTLD). Eighty FTLD patients (including cases with behavioral variant of frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy syndrome, motor neuron disease) and 65 healthy controls underwent rs-functional MRI. Emotion processing was tested using the Comprehensive Affect Testing System (CATS). In patients and controls, correlations were investigated between each emotion construct and rs-FC changes within critical networks. Mean rs-FC of the clusters significantly associated with CATS scoring were compared among FTLD groups. FTLD patients had pathological CATS scores compared with controls. In controls, increased rs-FC of the cerebellar and visuo-associative networks correlated with better scores in emotion-matching and discrimination tasks, respectively; while decreased rs-FC of the visuo-spatial network was related with better performance in the affect-matching and naming. In FTLD, the associations between rs-FC and CATS scores involved more brain regions, such as orbitofrontal and middle frontal gyri within anterior networks (i.e., salience and default-mode), parietal and somatosensory regions within visuo-spatial and sensorimotor networks, caudate and thalamus within basal-ganglia network. Rs-FC changes associated with CATS were similar among all FTLD groups. In FTLD compared to controls, the pattern of rs-FC associated with emotional processing involves a larger number of brain regions, likely due to functional specificity loss and compensatory attempts. These associations were similar across all FTLD groups, suggesting a common physiopathological mechanism of emotion processing breakdown, regardless the clinical presentation and pattern of atrophy.

Longitudinal White Matter Damage Evolution in Parkinson's Disease.

BACKGROUND: White matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial. OBJECTIVE: To investigate the longitudinal evolution of micro- and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD. METHODS: A total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal-appearing white matter (NAWM). Using tract-based spatial statistics, diffusion tensor (DT) MRI metrics of whole-brain WM and NAWM were obtained. Linear mixed-effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression using linear regression and Cox proportional hazards models. RESULTS: At baseline, PD patients showed alterations of all DT MRI measures compared to controls. Longitudinally, DT MRI measures did not vary significantly and no association with clinical variables was found. WMH volume changed over time and was associated with impairment in global cognition, executive functions, and language. Baseline WMH volume was a moderate risk factor for progression to mild cognitive impairment. CONCLUSIONS: Our study suggests an association between WMHs and cognitive deterioration in PD, whereas WM microstructural damage is a negligible contributor to clinical deterioration. WMHs assessed by MRI can provide an important tool for monitoring the development of cognitive impairment in PD patients. © 2021 International Parkinson and Movement Disorder Society.

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family.

BACKGROUND AND PURPOSE: Q336H is a rare MAPT mutation, previously found in a single patient with behavioral variant frontotemporal dementia and tau pathology (Pick bodies). Here, we describe the clinical characteristics of two members of a new family carrying the Q336H MAPT mutation. METHODS: Clinical, genetic, and neuroradiological assessment and follow-up of the proband were made. RESULTS: At age 37 years, the proband developed naming and object recognition impairment, due to a lack of knowledge. After 3 years, he developed behavioral disorders. Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography showed the involvement of the left temporal pole. A diagnosis of semantic variant primary progressive aphasia (svPPA) was made. At follow-up after 6 and 12 months, a rapid worsening of cognitive deficits occurred. His parent presented, at age 65 years, slowly progressive memory deficits without behavioral impairment, and, on MRI, evidence of mesial temporal atrophy, consistent with a clinical diagnosis of Alzheimer disease (AD). CONCLUSIONS: This is the second family carrying the MAPT Q336H mutation reported so far. We showed that svPPA and AD-like phenotype can be associated with this mutation. A wide clinical variability exists at the intrafamilial level for Q336H MAPT mutation, pointing to genetic and/or environmental influencing factors on disease expression. We also confirmed that svPPA can be associated with MAPT mutations, suggesting that this gene should be analyzed also in patients with svPPA, especially with early onset. In addition, an AD-like phenotype may be associated with this mutation, suggesting its different effects on protein misfolding and aggregation.

Brain Structural Changes in Focal Dystonia-What About Task Specificity? A Multimodal MRI Study.

BACKGROUND: The neural basis of task specificity in dystonia is still poorly understood. This study investigated gray and white matter (WM) brain alterations in patients with task-specific dystonia (TSD) and non-task-specific dystonia (NTSD). METHODS: Thirty-six patients with TSD (spasmodic dysphonia, writer's cramp), 61 patients with NTSD (blepharospasm, cervical dystonia), and 83 healthy controls underwent 3D T1-weighted and diffusion tensor magnetic resonance imaging (MRI). Whole brain cortical thickness and voxel-based morphometry; volumes of basal ganglia, thalamus, nucleus accumbens, amygdala, and hippocampus; and WM damage were assessed. Analysis of variance models were used to compare MRI measures between groups, adjusting for age and botulinum toxin (BoNT) treatment. RESULTS: The comparison between focal dystonia patients showed cortical thickness and gray matter (GM) volume differences (ie, decreased in NTSD, increased in TSD) in frontal, parietal, temporal, and occipital cortical regions; basal ganglia; thalamus; hippocampus; and amygdala. Cerebellar atrophy was found in NTSD patients relative to controls. WM damage was more severe and widespread in task-specific relative to NTSD patients. TSD patients receiving BoNT, relative to nontreated patients, had cortical thickening and increased GM volume in frontoparietal, temporal, and occipital regions. NTSD patients experiencing pain showed cortical thickening of areas involved in pain-inhibitory mechanisms. CONCLUSIONS: TSD and NTSD are characterized by opposite alterations of the main cortical and subcortical sensorimotor and cognitive-controlling brain structures, suggesting the possible presence of different pathophysiological and/or compensatory mechanisms underlying the complexity of the two clinical phenotypes of focal dystonia. © 2020 International Parkinson and Movement Disorder Society.

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.

Changes in functional and structural brain connectome along the Alzheimer's disease continuum.

The aim of this study was two-fold: (i) to investigate structural and functional brain network architecture in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), stratified in converters (c-aMCI) and non-converters (nc-aMCI) to AD; and to assess the relationship between healthy brain network functional connectivity and the topography of brain atrophy in patients along the AD continuum. Ninety-four AD patients, 47 aMCI patients (25 c-aMCI within 36 months) and 53 age- and sex-matched healthy controls were studied. Graph analysis and connectomics assessed global and local, structural and functional topological network properties and regional connectivity. Healthy topological features of brain regions were assessed based on their connectivity with the point of maximal atrophy (epicenter) in AD and aMCI patients. Brain network graph analysis properties were severely altered in AD patients. Structural brain network was already altered in c-aMCI patients relative to healthy controls in particular in the temporal and parietal brain regions, while functional connectivity did not change. Structural connectivity alterations distinguished c-aMCI from nc-aMCI cases. In both AD and c-aMCI, the point of maximal atrophy was located in left hippocampus (disease-epicenter). Brain regions most strongly connected with the disease-epicenter in the healthy functional connectome were also the most atrophic in both AD and c-aMCI patients. Progressive degeneration in the AD continuum is associated with an early breakdown of anatomical brain connections and follows the strongest connections with the disease-epicenter. These findings support the hypothesis that the topography of brain connectional architecture can modulate the spread of AD through the brain.

Breakdown of the affective-cognitive network in functional dystonia.

Previous studies suggested that brain regions subtending affective-cognitive processes can be implicated in the pathophysiology of functional dystonia (FD). In this study, the role of the affective-cognitive network was explored in two phenotypes of FD: fixed (FixFD) and mobile dystonia (MobFD). We hypothesized that each of these phenotypes would show peculiar functional connectivity (FC) alterations in line with their divergent disease clinical expressions. Resting state fMRI (RS-fMRI) was obtained in 40 FD patients (12 FixFD; 28 MobFD) and 43 controls (14 young FixFD-age-matched [yHC]; 29 old MobFD-age-matched [oHC]). FC of brain regions of interest, known to be involved in affective-cognitive processes, and independent component analysis of RS-fMRI data to explore brain networks were employed. Compared to HC, all FD patients showed reduced FC between the majority of affective-cognitive seeds of interest and the fronto-subcortical and limbic circuits; enhanced FC between the right affective-cognitive part of the cerebellum and the bilateral associative parietal cortex; enhanced FC of the bilateral amygdala with the subcortical and posterior cortical brain regions; and altered FC between the left medial dorsal nucleus and the sensorimotor and associative brain regions (enhanced in MobFD and reduced in FixFD). Compared with yHC and MobFD patients, FixFD patients had an extensive pattern of reduced FC within the cerebellar network, and between the majority of affective-cognitive seeds of interest and the sensorimotor and high-order function ("cognitive") areas with a unique involvement of dorsal anterior cingulate cortex connectivity. Brain FC within the affective-cognitive network is altered in FD and presented specific features associated with each FD phenotype, suggesting an interaction between brain connectivity and clinical expression of the disease.

MRI of Motor and Nonmotor Therapy-Induced Complications in Parkinson's Disease.

Levodopa therapy remains the most effective drug for the treatment of Parkinson's disease, and it is associated with the greatest improvement in motor function as assessed by the Unified Parkinson's Disease Rating Scale. Dopamine agonists have also proven their efficacy as monotherapy in early Parkinson's disease but also as adjunct therapy. However, the chronic use of dopaminergic therapy is associated with disabling motor and nonmotor side effects and complications, among which levodopa-induced dyskinesias and impulse control behaviors are the most common. The underlying mechanisms of these disorders are not fully understood. In the last decade, classic neuroimaging methods and more sophisticated techniques, such as analysis of gray-matter structural imaging and functional magnetic resonance imaging, have given access to anatomical and functional abnormalities, respectively, in the brain. This review presents an overview of structural and functional brain changes associated with motor and nonmotor therapy-induced complications in Parkinson's disease. Magnetic resonance imaging may offer structural and/or functional neuroimaging biomarkers that could be used as predictive signs of development, maintenance, and progression of these complications. Neurophysiological tools, such as theta burst stimulation and transcranial magnetic stimulation, might help us to integrate neuroimaging findings and clinical features and could be used as therapeutic options, translating neuroimaging data into clinical practice. © 2020 International Parkinson and Movement Disorder Society.

Tracking Cortical Changes Throughout Cognitive Decline in Parkinson's Disease.

BACKGROUND: The objectives of this study were to investigate progressive cortical thinning and volume loss in Parkinson's disease (PD) patients with different longitudinal patterns of cognitive decline: with stable normal cognition, with stable mild cognitive impairment, with conversion to mild cognitive impairment, and with conversion to dementia. METHODS: We recruited 112 patients (37 Parkinson's disease with stable normal cognition, 20 Parkinson's disease with stable mild cognitive impairment, 36 Parkinson's disease with conversion to mild cognitive impairment, 19 Parkinson's disease with conversion to dementia) and 38 healthy controls. All patients underwent at least 2 visits within 4 years including clinical/cognitive assessments and structural MRI (total visits, 393). Baseline cortical thickness and gray matter volumetry were compared between groups. In PD, gray matter changes over time were investigated and compared between groups. RESULTS: At baseline, compared with Parkinson's disease with stable normal cognition cases, Parkinson's disease with conversion to mild cognitive impairment patients showed cortical atrophy of the parietal and occipital lobes, similar to Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia patients. The latter groups (ie, patients with cognitive impairment from the study entry) showed additional involvement of the frontotemporal cortices. No baseline volumetric differences among groups were detected. The longitudinal analysis (group-by-time interaction) showed that, versus the other patient groups, Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia cases accumulated the least cortical damage, with Parkinson's disease with conversion to dementia showing unique progression of right thalamic and hippocampal volume loss; Parkinson's disease with conversion to mild cognitive impairment patients showing specific cortical thinning accumulation in the medial and superior frontal gyri, inferior temporal, precuneus, posterior cingulum, and supramarginal gyri bilaterally; and Parkinson's disease with stable normal cognition patients showing cortical thinning progression, mainly in the occipital and parietal regions bilaterally. CONCLUSIONS: Cortical thinning progression is more prominent in the initial stages of PD cognitive decline. The involvement of frontotemporoparietal regions, the hippocampus, and the thalamus is associated with conversion to a more severe stage of cognitive impairment. In PD, gray matter alterations of critical brain regions may be an MRI signature for the identification of patients at risk of developing dementia. © 2020 International Parkinson and Movement Disorder Society.

Structural Brain Connectome and Cognitive Impairment in Parkinson Disease.

Purpose To investigate the structural brain connectome in patients with Parkinson disease (PD) and mild cognitive impairment (MCI) and in patients with PD without MCI. Materials and Methods This prospective study was approved by the local ethics committees, and written informed consent was obtained from all subjects prior to enrollment. The individual structural brain connectome of 170 patients with PD (54 with MCI, 116 without MCI) and 41 healthy control subjects was obtained by using deterministic diffusion-tensor tractography. A network-based statistic was used to assess structural connectivity differences among groups. Results Patients with PD and MCI had global network alterations when compared with both control subjects and patients with PD without MCI (range, P = .004 to P = .048). Relative to control subjects, patients with PD and MCI had a large basal ganglia and frontoparietal network with decreased fractional anisotropy (FA) in the right hemisphere and a subnetwork with increased mean diffusivity (MD) involving similar regions bilaterally (P < .01). When compared with patients with PD without MCI, those with PD and MCI had a network with decreased FA, including basal ganglia and frontotemporoparietal regions bilaterally (P < .05). Similar findings were obtained by adjusting for motor disability (P < .05, permutation-corrected P = .06). At P < .01, patients with PD and MCI did not show network alterations relative to patients with PD without MCI. Network FA and MD values were used to differentiate patients with PD and MCI from healthy control subjects and patients with PD without MCI with fair to good accuracy (cross-validated area under the receiver operating characteristic curve [principal + secondary connected components] range, 0.75-0.85). Conclusion A disruption of structural connections between brain areas forming a network contributes to determine an altered information integration and organization and thus cognitive deficits in patients with PD. These results provide novel information concerning the structural substrates of MCI in patients with PD and may offer markers that can be used to differentiate between patients with PD and MCI and patients with PD without MCI. © RSNA, 2016 Online supplemental material is available for this article.

The cumulative effect of genetic polymorphisms on depression and brain structural integrity.

In major depressive disorder (MDD), the need to study multiple-gene effect on brain structure is emerging. Our aim was to assess the effect of accumulation of specific SERT, BDNF and COMT gene functional polymorphisms on brain structure in MDD patients. Seventy-seven MDD patients and 66 controls underwent a clinical assessment, genetic testing and MRI scan. Compared with controls, patients were more BDNF-Val homozygotes, COMT-Met carriers and SERT-L' carriers. Thus, subjects were split into three groups: 1. High-frequency susceptibility polymorphism group (hfSP, subjects with all three SPs); 2. Intermediate-frequency SP group (ifSP, two SPs); and 3. Low-frequency SP group (lfSP, one/none SP). Cortical thickness, volumetry of hippocampus, amygdala and subcortical structures, and white matter (WM) tract integrity were assessed. Compared to controls, hfSP patients showed thinning of the middle frontal cortex bilaterally, left frontal pole, and right lateral occipital cortex, and smaller hippocampal volume bilaterally; and both hfSP and lfSP patient groups showed thinning of the left inferior parietal cortex and reduced WM integrity of the corpus callosum. Compared to patients, hfSP controls showed greater integrity of the fronto-occipital cortices and corpus callosum. We showed that cortical prefrontal and occipital damage of MDD patients is modulated by the SP accumulation, while damage to the parietal cortex and corpus callosum seem to be independent of genetic accumulation. HfSP controls may experience protective mechanisms leading to a preserved integrity of critical cortical and WM regions. Investigating the effect of multiple genes is promising to understand the pathological mechanisms underlying MDD. Hum Brain Mapp 37:2173-2184, 2016. © 2016 Wiley Periodicals, Inc.

Structural brain correlates of cognitive and behavioral impairment in MND.

OBJECTIVE: To assess the structural correlates of cognitive and behavioral impairment in motor neuron diseases (MND) using multimodal MRI. METHODS: One hundred one patients with sporadic MND (56 classic amyotrophic lateral sclerosis, 31 upper motor neuron phenotype, and 14 lower motor neuron phenotype) and 51 controls were enrolled. Patients were classified into MND with a pure motor syndrome (MND-motor) and with cognitive/behavioral symptoms (MND-plus). Cortical thickness measures and diffusion tensor (DT) metrics of white matter (WM) tracts were assessed. A random forest approach was used to explore the independent role of cortical and WM abnormalities in explaining major cognitive and behavioral symptoms. RESULTS: There were 48 MND-motor and 53 MND-plus patients. Relative to controls, both patient groups showed a distributed cortical thinning of the bilateral precentral gyrus, insular and cingulate cortices, and frontotemporal regions. In all regions, there was a trend toward a more severe involvement in MND-plus cases, particularly in the temporal lobes. Both patient groups showed damage to the motor callosal fibers, which was more severe in MND-plus. MND-plus patients also showed a more severe involvement of the extra-motor WM tracts. The best predictors of executive and non-executive deficits and behavioral symptoms in MND were diffusivity abnormalities of the corpus callosum and frontotemporal tracts, including the uncinate, cingulum, and superior longitudinal fasciculi. CONCLUSIONS: Cortical thinning and WM degeneration are highly associated with neuropsychological and behavioral symptoms in patients with MND. DT MRI metrics seem to be the most sensitive markers of extra-motor deficits within the MND spectrum.

Brain structural and functional connectivity in Parkinson's disease with freezing of gait.

OBJECTIVE: To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinson's disease and freezing of gait (PD-FoG). METHODS: T1-weighted, diffusion tensor (DT) MRI and RS functional MRI (fMRI) were obtained from 22 PD-FoG patients and 35 controls on a 3.0 T MR scanner. Patients underwent clinical, motor, and neuropsychological evaluations. Gray matter (GM) volumes and white matter (WM) damage were assessed using voxel based morphometry and tract-based spatial statistics, respectively. The pedunculopontine tract (PPT) was studied using tractography. RS fMRI data were analyzed using a model free approach investigating the main sensorimotor and cognitive brain networks. Multiple regression models were performed to assess the relationships between structural, functional, and clinical/cognitive variables. Analysis of GM and WM structural abnormalities was replicated in an independent sample including 28 PD-FoG patients, 25 PD patients without FoG, and 30 healthy controls who performed MRI scans on a 1.5 T scanner. RESULTS: Compared with controls, no GM atrophy was found in PD-FoG cases. PD-FoG patients showed WM damage of the PPT, corpus callosum, corticospinal tract, cingulum, superior longitudinal fasciculus, and WM underneath the primary motor, premotor, prefrontal, orbitofrontal, and inferior parietal cortices, bilaterally. In PD-FoG, right PTT damage was associated with a greater disease severity. Analysis on the independent PD sample showed similar findings in PD-FoG patients relative to controls as well as WM damage of the genu and body of the corpus callosum and right parietal WM in PD-FoG relative to PD no-FoG patients. RS fMRI analysis showed that PD-FoG is associated with a decreased functional connectivity of the primary motor cortex and supplementary motor area bilaterally in the sensorimotor network, frontoparietal regions in the default mode network, and occipital cortex in the visual associative network. CONCLUSIONS: This study suggests that FoG in PD can be the result of a poor structural and functional integration between motor and extramotor (cognitive) neural systems.

White Matter Degeneration in Atypical Alzheimer Disease.

PURPOSE: To assess white matter (WM) tract damage in patients with atypical Alzheimer disease (AD), including early-onset AD (EOAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA), by using diffusion-tensor magnetic resonance (MR) imaging and to identify similarities and differences across the AD spectrum. MATERIALS AND METHODS: This study was approved by the local ethical committees on human studies, and written informed consent from all subjects was obtained prior to enrollment. WM tract damage and cortical atrophy were assessed by using diffusion-tensor MR imaging and voxel-based morphometry, respectively, in 28 patients with EOAD, 12 patients with lvPPA, and 13 patients with PCA relative to age- and sex-matched healthy subjects. Conjunction and interaction analyses were used to define overlapping and syndrome-specific patterns of brain damage. RESULTS: Patients with EOAD, lvPPA, and PCA shared a common pattern of WM damage that involved the body of the corpus callosum, fornix, and main anterior-posterior pathways (P < .05). They also shared cortical atrophy of the left temporoparietal regions and precuneus (P < .05, family-wise error corrected). Patients with EOAD also had specific damage to the genu and splenium of the corpus callosum and parahippocampal tract bilaterally (P < .05). In all patients with AD, particularly in the two focal forms (lvPPA and PCA), WM damage was more severe and widely distributed than expected on the basis of cortical atrophy. CONCLUSION: In atypical AD clinical phenotypes, the distribution of WM damage exceeds cortical atrophy and may reflect the pathologic dissemination through structural connections from atrophic to unaffected cortical regions. WM degeneration may be an early marker of AD pathologic changes in EOAD and focal AD forms.