Early metabolic alterations in the normal­appearing grey and white matter of patients with clinically isolated syndrome suggestive of multiple sclerosis: A proton MR spectroscopic study.

Proton magnetic resonance spectroscopy (1H-MRS) is an advanced method of examining metabolic profiles. The present study aimed to assess in vivo metabolite levels in areas of normal-appearing grey (thalamus) and white matter (centrum semiovale) using 1H-MRS in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis and compare them to healthy controls (HCs). Data from 35 patients with CIS (CIS group), of which 23 were untreated (CIS-untreated group) and 12 were treated (CIS-treated group) with disease-modifying-therapies (DMTs) at the time of 1H-MRS, and from 28 age- and sex-matched HCs were collected using a 3.0 T MRI and single-voxel 1H-MRS (point resolved spectroscopy sequence; repetition time, 2,000 msec; time to echo, 35 msec). Concentrations and ratios of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline (tCho), myoinositol, glutamate (Glu), glutamine (Gln), Glu + Gln (Glx) and glutathione (Glth) were estimated in the thalamic-voxel (th) and centrum semiovale-voxel (cs). For the CIS group, the median duration from the first clinical attack to 1H-MRS was 102 days (interquartile range, 89.5.-131.5). Compared with HCs, significantly lower Glx(cs) (P=0.014) and ratios of tCho/tCr(th) (P=0.026), Glu/tCr(cs) (P=0.040), Glx/tCr(cs) (P=0.004), Glx/tNAA(th) (P=0.043) and Glx/tNAA(cs) (P=0.015) were observed in the CIS group. No differences in tNAA levels were observed between the CIS and the HC groups; however, tNAA(cs) was higher in the CIS-treated than in the CIS-untreated group (P=0.028). Compared with those in HC group, decreased Glu(cs) (P=0.019) and Glx(cs) levels (P=0.014) and lower ratios for tCho/tCr(th) (P=0.015), Gln/tCr(th) (P=0.004), Glu/tCr(cs) (P=0.021), Glx/tCr(th) (P=0.041), Glx/tCr(cs) (P=0.003), Glx/tNAA(th) (P=0.030) and Glx/tNAA(cs) (P=0.015) were found in the CIS-untreated group. The present findings showed alterations in the normal-appearing grey and white matter of patients with CIS; moreover, the present results suggested an early indirect treatment effect of DMTs on the brain metabolic profile of these patients.

Hippocampal Metabolic Alterations in Amyotrophic Lateral Sclerosis: A Magnetic Resonance Spectroscopy Study.

BACKGROUND: Magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) has been overwhelmingly applied to motor regions to date and our understanding of frontotemporal metabolic signatures is relatively limited. The association between metabolic alterations and cognitive performance in also poorly characterised. MATERIAL AND METHODS: In a multimodal, prospective pilot study, the structural, metabolic, and diffusivity profile of the hippocampus was systematically evaluated in patients with ALS. Patients underwent careful clinical and neurocognitive assessments. All patients were non-demented and exhibited normal memory performance. 1H-MRS spectra of the right and left hippocampi were acquired at 3.0T to determine the concentration of a panel of metabolites. The imaging protocol also included high-resolution T1-weighted structural imaging for subsequent hippocampal grey matter (GM) analyses and diffusion tensor imaging (DTI) for the tractographic evaluation of the integrity of the hippocampal perforant pathway zone (PPZ). RESULTS: ALS patients exhibited higher hippocampal tNAA, tNAA/tCr and tCho bilaterally, despite the absence of volumetric and PPZ diffusivity differences between the two groups. Furthermore, superior memory performance was associated with higher hippocampal tNAA/tCr bilaterally. Both longer symptom duration and greater functional disability correlated with higher tCho levels. CONCLUSION: Hippocampal 1H-MRS may not only contribute to a better academic understanding of extra-motor disease burden in ALS, but given its sensitive correlations with validated clinical metrics, it may serve as practical biomarker for future clinical and clinical trial applications. Neuroimaging protocols in ALS should incorporate MRS in addition to standard structural, functional, and diffusion sequences.

Binding objects to their spatiotemporal context: Age gradient and neuropsychological correlates of What-Where-When task performance.

A number of recent studies have shown that the ability to accurately recall bound object and spatiotemporal aspects of an experienced event develops gradually in children and is greatly impaired in the elderly, reflecting developmental discontinuities in the integrity of the underlying medial temporal lobe network. Using a novel What-Where-When (WWW) visuospatial reconstruction task, the experiential memory performance of a group of healthy older adults (aged 60-80) was compared to that of a group of younger adults (aged 20-40). Both groups were equated on their general cognitive ability, their executive functioning, and on the presence of depression, anxiety, and stress symptomatology. As hypothesized, the performance of the older adults in the binding task was significantly lower, with younger participants recalling three times the amount of bound object and spatiotemporal triads than their older counterparts. Psychomotor speed was found to be lower in older adults and was the only neuropsychological index to significantly affect success on the WWW binding task. Based on this and other relevant studies, the selective associative memory impairment obtained using a non-verbal What-Where-When paradigm emerges as a marker for the detection of early pre-clinical signs of experiential memory pathology.

Specific disruption of the ventral anterior temporo-frontal network reveals key implications for language comprehension and cognition.

Recent investigations have raised the question of the role of the anterior lateral temporal cortex in language processing (ventral language network). Here we present the language and overall cognitive performance of a rare male patient with chronic middle cerebral artery cerebrovascular accident with a well-documented lesion restricted to the anterior temporal cortex and its connections via the extreme capsule with the pars triangularis of the inferior frontal gyrus (i.e. Broca's region). The performance of this unique patient is compared with that of two chronic middle cerebral artery cerebrovascular accident male patients with damage to the classic dorsal posterior temporo-parietal language system. Diffusion tensor imaging is used to reconstruct the relevant white matter tracts of the three patients, which are also compared with those of 10 healthy individuals. The patient with the anterior temporo-frontal lesion presents with flawless and fluent speech, but selective impairment in accessing lexico-semantic information, in sharp contrast to the impairments in speech, sentence comprehension and repetition observed after lesions to the classic dorsal language system. The present results underline the contribution of the ventral language stream in lexico-semantic processing and higher cognitive functions, such as active selective controlled retrieval.

Neurometabolic Alterations in Motor Neuron Disease: Insights from Magnetic Resonance Spectroscopy.

Magnetic resonance spectroscopy (MRS) has contributed important academic insights in motor neuron diseases (MNDs), particularly in amyotrophic lateral sclerosis (ALS). Over the past three decades momentous methodological advances took place, including the emergence of high-field magnetic resonance imaging (MRI) platforms, multi-voxel techniques, whole-brain protocols, novel head-coil designs, and a multitude of open-source imaging suites. Technological advances in MRS are complemented by important conceptual developments in MND, such as the recognition of the importance of extra-motor brain regions, multi-timepoint longitudinal study designs, assessment of asymptomatic mutation carriers, description of genotype-associated signatures, and the gradual characterisation of non-ALS MND phenotypes. We have conducted a systematic review of published MRS studies in MND to identify important emerging research trends, key lessons from pioneering studies, and stereotyped shortcomings. We also sought to highlight notable gaps in the current literature so that research priorities for future studies can be outlined. While MRS remains relatively underutilised in MND compared to other structural, diffusivity and functional imaging modalities, our review suggests that MRS can not only advance our academic understanding of MND biology, but has a multitude of practical benefits for clinical and pharmaceutical trial applications.

The association of theory of mind with language and visuospatial abilities in amyotrophic lateral sclerosis: a pilot study.

Objective: Dysfunction of social cognition is well-recognized as one of amyotrophic lateral sclerosis (ALS) cognitive impairments. Previous studies have mostly associated social cognition subcomponents, including Theory of Mind (ToM), with executive dysfunction using highly-demanding tasks. In the present study, we investigate dysfunction of affective ToM in a sample of ALS patients without dementia and evaluate any possible associations both with executive and non-executive dysfunction.Methods: We included 42 ALS patients and 30 healthy controls (HC) and administered the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS). Affective ToM was examined based on the ECAS judgment of preference task; total score and type of errors ("favourite", "unclassified") were recorded for all participants.Results: A significant proportion of ALS patients (31%) were impaired on ToM task, scoring significantly lower compared to HC. Impairments in ToM task were more frequent (45%) in patients with cognitive impairment compared to those with intact cognition (15%). ALS patients showed significantly more errors on ToM task compared to HC. A significant association was found between ToM score and ECAS language and visuospatial abilities but not fluency, executive or memory function.Conclusion: Dysfunction of affective ToM appears prevalent in ALS patients without dementia, and associates with language and visuospatial abilities. These associations align with motor and extra-motor symptoms due to the degeneration across corresponding networks. Impaired ToM should be considered in clinical settings, since it might contribute to patients' social life, as well as the burden of their caregivers and relatives.

The severity of executive dysfunction among different PD-MCI subtypes.

Aim to examine the severity of executive dysfunction among different Parkinson's disease (PD)-mild cognitive impairment (MCI) subtypes in the early stages of the disease. The final sample consisted of 65 patients with mild PD progression. Based on neuropsychological measures, our sample was categorized into three PD-MCI subtypes: (1) PD-MCI executive group (n = 24), (2) PD-MCI executive plus memory group (n = 22), and (3) PD-MCI executive plus visuospatial group (n = 19). Patients' executive functions were evaluated with the Trail Making Test-Part B (TMT-B) and Stroop Neuropsychological Screening Test (SNST) for mental flexibility and inhibitory control, respectively. One-way ANOVA results indicated significant differences among the three subgroups on TMT-B and SNST performance. Post hoc Tukey honestly significant different (HSD) tests revealed that the PD-MCI executive plus visuospatial group had lower performances on both executive measures than the other two groups. Contrastingly, no significant differences were observed between the PD-MCI executive group and PD-MCI executive plus memory group. Our results indicated that the severity of executive dysfunction varies across different PD-MCI subtypes. These findings are discussed within the framework of the dual syndrome hypothesis and highlight the utility of determination of executive impairment severity for effective clinical management of patients with PD.

The Role of the Right Hemisphere White Matter Tracts in Chronic Aphasic Patients After Damage of the Language Tracts in the Left Hemisphere.

The involvement of the right hemisphere (RH) in language, and especially after aphasia resulting from left hemisphere (LH) lesions, has been recently highlighted. The present study investigates white matter structure in the right hemisphere of 25 chronic post-stroke aphasic patients after LH lesions in comparison with 24 healthy controls, focusing on the four cortico-cortical tracts that link posterior parietal and temporal language-related areas with Broca's region in the inferior frontal gyrus of the LH: the Superior Longitudinal Fasciculi II and III (SLF II and SLF III), the Arcuate Fasciculus (AF), and the Temporo-Frontal extreme capsule Fasciculus (TFexcF). Additionally, the relationship of these RH white matter tracts to language performance was examined. The patients with post-stroke aphasia in the chronic phase and the healthy control participants underwent diffusion tensor imaging (DTI) examination. The aphasic patients were assessed with standard aphasia tests. The results demonstrated increased axial diffusivity in the RH tracts of the aphasic patients. Patients were then divided according to the extent of the left hemisphere white matter loss. Correlations of language performance with radial diffusivity (RD) in the right hemisphere homologs of the tracts examined were demonstrated for the TFexcF, SLF III, and AF in the subgroup with limited damage to the LH language networks and only with the TFexcF in the subgroup with extensive damage. The results argue in favor of compensatory roles of the right hemisphere tracts in language functions when the LH networks are disrupted.

Neuroimaging data indicate divergent mesial temporal lobe profiles in amyotrophic lateral sclerosis, Alzheimer's disease and healthy aging.

A prospective, standardised neuroimaging protocol was implemented to characterise mesial temporal lobe pathology in amyotrophic lateral sclerosis, Alzheimer's disease and healthy controls focusing on the evaluation of interconnected white and grey matter structures. "Hippocampal pathology in Amyotrophic Lateral Sclerosis: selective vulnerability of subfields and their associated projections" [1]. High-resolution diffusion tensor and structural imaging data were acquired on a 3 T MRI platform using standardised sequence parameters. The integrity of the fornix and the perforant pathway was assessed by tractography, to provide fractional anisotropy, axial diffusivity and radial diffusivity measures. Quantitative structural imaging was used to estimate the total intracranial volume, total hippocampal volumes and hippocampal subfield volumes for each participant. Raw white- and grey-matter measures, demographic and clinical data are available online at 'Mendeley Data'. Amyotrophic lateral sclerosis and Alzheimer's disease exhibit divergent hippocampal profiles.

The Edinburgh cognitive and behavioral amyotrophic lateral sclerosis screen (ECAS): sensitivity in differentiating between ALS and Alzheimer's disease in a Greek population.

Objectives: (1) Adapt the ECAS into Greek, validate it in ALS patients and compare with the ALS-CBS. (2) Determine the sensitivity and specificity of ECAS in the differentiation between AD and non-demented ALS patients as compared with the ACE-III and mini-ACE. Methods: ALS patients (n = 28) were recruited and AD patients (n = 26) were matched in age, sex, and education with ALS patients (n = 24). The normative data were derived from a random sample of controls (n = 52). Bayes correlation analysis was conducted to examine convergent validity. Bayes t-test was performed to assess between groups' differences. Receiver operating characteristics (ROC) curve analyses and area under the curve (AUC) were implemented to appraise the sensitivity and specificity in the differentiation between the AD and non-demented ALS patients. Results: The ECAS and its sub-scores in addition to the behavior interview demonstrated robust correlations with the ALS-CBS. Impairment in language and verbal fluency were the most prominent deficits in the ALS patients. The most frequently reported change was apathy. The ROC analysis demonstrated that the ECAS-ALS nonspecific score (comprising memory and visuospatial domains) is the most sensitive and specific in differentiating the AD from ALS patients. The other measures expressed high sensitivity, yet a poor specificity. Conclusions: The ECAS is a multi-purpose screening tool. The ECAS-ALS specific appraises the whole spectrum of the highly prevalent cognitive impairments in ALS. The ECAS-ALS nonspecific (memory and visuospatial) is a sensitive score to detect AD related deficits and is able to differentiate the AD from the non-demented ALS patients better than the ACE-III and mini-ACE.

Hippocampal pathology in amyotrophic lateral sclerosis: selective vulnerability of subfields and their associated projections.

Although hippocampal involvement in amyotrophic lateral sclerosis (ALS) has been consistently highlighted by postmortem studies, memory impairment remains under-recognized and the involvement of specific hippocampal subfields and their connectivity patterns are poorly characterized in vivo. A prospective multimodal neuroimaging study has been undertaken with 50 well-characterized ALS patients, 18 patients with Alzheimer's disease, and 40 healthy controls to evaluate their mesial temporal lobe profile. Patients with ALS and Alzheimer's disease have divergent hippocampal signatures. The cornu ammonis 2/3 subfield and the hippocampus-amygdala transition area are the most affected regions in ALS in contrast to Alzheimer's disease, where the presubiculum and subiculum are the most vulnerable regions. Tractography reveals considerable fornix and perforant pathway pathology in both patient groups. Mesial temporal lobe structures in ALS have a selective and disease-specific vulnerability profiles, and their white matter projections exhibit concomitant degeneration. Our combined gray and white matter analyses indicate a connectivity-based, network-defined involvement of interconnected temporal lobe structures as opposed to contiguous involvement of adjacent structures. Our findings underline the importance of screening for memory deficits and personalized management strategies in ALS.

The Modality Effect on Delayed Free Recall in Non-demented Patients With Mild Parkinson's Disease Progression.

Background: The modality effect plays the central role in learning and memory functions. Retrieval failure constitutes a common memory impairment that occurs among patients with Parkinson's disease (PD). However, little knowledge exists about the relation between modality effect and delayed recall impairment in PD. The primary goal of this study was to compare delayed free recall performance between three different memory modalities (verbal, visual, and cross visual-verbal) in a sample of non-demented patients with mild PD progression. The secondary goal was to explore the frequency of deficient performance on the basis of normative comparisons on each of the three delayed free-recall measures. Method: A total of 71 non-demented patients with mild PD progression were recruited for the administration of the Montreal Cognitive Assessment (MoCA), the Rey Auditory Verbal Learning Test (RAVLT), the Rey Osterrieth Complex Figure Test (ROCFT), and the Greek Version of Face-Name Associative Memory Examination (GR-FNAME12). Results: The percentages of deficient-performances for the three delayed free recall measures were 45.1% (32/71), 39.4% (28/71) and 31% (22/71) for the GR-FNAME12, ROFCT and RAVLT, respectively. The results indicated no significant difference between performances of the GR-FNAME12 and ROCFT, both of which were significantly lower than performance on the RAVLT. Conclusions: In conclusion, delayed free recall appears to be more severely affected in the cross visual-verbal and visual memory modalities than in verbal-memory modalities in the early phase of PD progression.

Verbal memory and sentence comprehension in aphasia: A case series.

This case series explores the relationship between verbal memory capacity and sentence comprehension in four patients with aphasia. Two sentence comprehension tasks showed that two patients, P1 and P2, had impaired syntactic comprehension, whereas P3 and P4's sentence comprehension was intact. The memory assessment tasks showed that P1 and P2 had severely impaired short-term memory, whereas P3 and P4 performed within the normal range in the short-term memory tasks. This finding suggests an association between short-term memory deficit and sentence comprehension difficulties. P1 and P3 exhibited impaired comparable working memory deficits, suggesting a dissociation between working memory and sentence comprehension.

The performance of patients with Parkinson's disease on the Face-Name Associative Memory Examination.

In this study, we examined the performance of patients with Parkinson's disease (PD) with different cognitive profiles on the Face-Name Associative Memory Examination (FNAME). We evaluated 71 patients with a comprehensive neuropsychological battery. The results revealed that the group with executive and additional visuospatial deficits demonstrated significantly lower scores on FNAME. This finding indicates the possible clinical utility of FNAME for screening patients with PD with distinct cognitive profiles. Further longitudinal studies are needed to consider the prognostic adequacy of FNAME in detecting high-risk Parkinson's disease dementia (PDD).

Ipsilateral and contralateral cerebro-cerebellar white matter connections: A diffusion tensor imaging study in healthy adults.

BACKGROUND AND PURPOSE: The cerebellum has a pivotal role in regulating human behavior; yet whether this function is mediated only through contralateral cerebro-cerebellar pathways is under-investigated. Thus, we examined feed-backward and feed-forward ipsilateral and contralateral cerebro-cerebellar connections using a detereministic diffusion tensor imaging (DTI) algorithm, the robustness of which was also estimated using phantom DTI data. MATERIALS AND METHODS: Fifty-one healthy controls (22-60 years old; 15 males/36 females) were scanned in a 3T MRI scanner with a 30-direction DTI sequence. Multiple region-of-interest (ROI) method was applied for the reconstruction of the ipsilateral and contralateral (based on cerebellar seed ROI) fronto-ponto-cerebellar (FPC), parieto-ponto-cerebellar (PPC), temporo-ponto-cerebellar (TPC), occipito-ponto-cerebellar (OPC) and dentate-rubro-thalamo-cortical (DRTC) tract bilaterally using the Brainance DTI Suite. A realistic diffusion MR phantom was used to evaluate the fiber tracking methodology for 16 fibers containing crossing, kissing, splitting and bending configurations. RESULTS: Both contralateral and ipsilateral FPC, PPC, OPC and ipsilateral DRTC tracts were successfully reconstructed; the contralateral DRTC tract was not reconstructed in all subjects. Also, the TPC tract was not reproduced in several subjects mostly regarding the contralateral connection. Descriptive DTI measures (number of fibers, fractional anisotropy, radial and axial diffusivity) are presented for each tract. Regarding phantom data, Brainance DTI Suite returned a dataset of 16 fibers that almost perfectly matched the 16 ground truth fibers. CONCLUSIONS: We identified ipsilateral and contralateral connections using a clinically applicable DTI sequence, a robust deterministic algorithm and an unbiased methodology, which can be applied in daily practice in different brain pathologies.

Hippocampal structural and functional integrity in multiple sclerosis patients with or without memory impairment: a multimodal neuroimaging study.

The increasing evidence for a pure amnestic-like profile in multiple sclerosis (MS) introduces the role of hippocampal formation in MS episodic memory function. The aim of the present study was to investigate structural and functional hippocampal changes in mildly-disabled MS patients with and without memory impairment. Thirty-one MS patients with or without memory impairment and 16 healthy controls (HC) underwent MRI in a 3.0 T MRI scanner. Patients were categorized as memory preserved (MP) and memory impaired (MI) based on verbal and visual memory scores extracted from the Brief Repeatable Neuropsychological Battery. The acquisition protocol included high-resolution 3D-T1-weighted, diffusion weighted imaging and echo-planar imaging sequences for the analysis of hippocampal gray matter (GM) density, perforant pathway area (PPA) tractography, and hippocampal functional connectivity (FC), respectively. Compared to HC, we found decreased left and bilateral hippocampal GM density in MP and MI patients, respectively, decreased fractional anisotropy and increased radial diffusivity on left PPA in MI patients, and reduced FC in MI between left hippocampus and left superior frontal gyrus, precuneus/posterior cingulated cortex and lateral occipital gyrus/angular gyrus. The only differences between MP and MI were found in FC. Specifically, MP patients showed FC changes between left hippocampus and right temporo-occipital fusiform/lingual gyrus (increased FC) as well as supramarginal gyrus (decreased FC). In conclusion, we highlight the early detection of structural hippocampal changes in MS without neuropsychologically-detected memory deficits and decreased hippocampal FC in MS patients with impaired memory performance, when both GM density and PPA integrity are affected.

Clinical and Radiological Markers of Extra-Motor Deficits in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is now universally recognized as a complex multisystem disorder with considerable extra-motor involvement. The neuropsychological manifestations of frontotemporal, parietal, and basal ganglia involvement in ALS have important implications for compliance with assistive devices, survival, participation in clinical trials, caregiver burden, and the management of individual care needs. Recent advances in neuroimaging have been instrumental in characterizing the biological substrate of heterogeneous cognitive and behavioral deficits in ALS. In this review we discuss the clinical and radiological aspects of cognitive and behavioral impairment in ALS focusing on the recognition, assessment, and monitoring of these symptoms.

The Clinical and Radiological Spectrum of Hippocampal Pathology in Amyotrophic Lateral Sclerosis.

Hippocampal pathology in Amyotrophic Lateral Sclerosis (ALS) remains surprisingly under recognized despite compelling evidence from neuropsychology, neuroimaging and neuropathology studies. Hippocampal dysfunction contributes significantly to the clinical heterogeneity of ALS and requires structure-specific cognitive and neuroimaging tools for accurate in vivo evaluation. Recent imaging studies have generated unprecedented insights into the presymptomatic and longitudinal processes affecting this structure and have contributed to the characterisation of both focal and network-level changes. Emerging neuropsychology data suggest that memory deficits in ALS may be independent from executive dysfunction. In the era of precision medicine, where the development of individualized care strategies and patient stratification for clinical trials are key priorities, the comprehensive review of hippocampal dysfunction in ALS is particularly timely.