Hippocampal connectivity in Amyotrophic Lateral Sclerosis (ALS): more than Papez circuit impairment

Abstract Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p < .05, family-wise error corrected). Interestingly, changes of Digit Span forward performance were inversely related to RS-fMRI signal fluctuations in the cerebellum, while changes of both episodic and visual memory scores were inversely related to mean and radial diffusivity abnormalities in several WM fiber tracts, including middle cerebellar peduncles. Our findings revealed that ALS patients showed significant functional and structural connectivity changes across the regions comprising the Papez circuit, as well as more extended areas including cerebellum and frontal, temporal and parietal areas, supporting the theory of a multi-system pathology in ALS that spreads from cortical to subcortical structures.

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Usefulness of diffusion tensor imaging in amyotrophic lateral sclerosis: potential biomarker and association with the cognitive profile

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20170032 ◽

2017 ◽

Vol 75 (5) ◽

pp. 272-276 ◽

Cited By ~ 2

Author(s):

Marcelo Chaves ◽

Mariela Bettini ◽

Maria Cecilia Fernandez ◽

Maria Jose Garcia Basalo ◽

Juan Ignacio Rojas ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Diffusion Tensor Imaging ◽

White Matter ◽

Diffusion Tensor ◽

Cognitive Profile ◽

Healthy Controls ◽

Potential Biomarker ◽

Preliminary Study ◽

Als Patients ◽

Lateral Sclerosis

ABSTRACT The objective of this preliminary study was to correlate diffusion tensor imaging (DTI) alterations with the cognitive profile of patients with amyotrophic lateral sclerosis (ALS). Methods This was a case-control study conducted from December 1, 2012 to December 1, 2014. Clinical and demographic data were recorded. A neuropsychological test battery adapted to ALS patients was used. An MRI with DTI was performed in all patients and fractional anisotropy (FA) was analyzed in the white matter using the tract based spatial statistics program. Results Twenty-four patients with ALS (15 females, mean age 66.9 + -2.3) and 13 healthy controls (four females, average age 66.9 + - 2) were included. The DTI showed white matter damage in ALS patients vs. healthy controls (p < 0.001). Discussion In our preliminary study the alterations of white matter in DTI were significantly associated with cognitive impairment in patients with ALS.

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Brainstem Involvement in Amyotrophic Lateral Sclerosis: A Combined Structural and Diffusion Tensor MRI Analysis

Frontiers in Neuroscience ◽

10.3389/fnins.2021.675444 ◽

2021 ◽

Vol 15 ◽

Author(s):

Haining Li ◽

Qiuli Zhang ◽

Qianqian Duan ◽

Jiaoting Jin ◽

Fangfang Hu ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Correlation Analysis ◽

Disease Severity ◽

Structural Changes ◽

Diffusion Tensor ◽

Healthy Controls ◽

Significant Difference ◽

Als Patients ◽

And Diffusion ◽

Lateral Sclerosis

IntroductionThe brainstem is an important component in the pathology of amyotrophic lateral sclerosis (ALS). Although neuroimaging studies have shown multiple structural changes in ALS patients, few studies have investigated structural alterations in the brainstem. Herein, we compared the brainstem structure between patients with ALS and healthy controls.MethodsA total of 33 patients with ALS and 33 healthy controls were recruited in this study. T1-weighted and diffusion tensor imaging (DTI) were acquired on a 3 Tesla magnetic resonance imaging (3T MRI) scanner. Volumetric and vertex-wised approaches were implemented to assess the differences in the brainstem’s morphological features between the two groups. An atlas-based region of interest (ROI) analysis was performed to compare the white matter integrity of the brainstem between the two groups. Additionally, a correlation analysis was used to evaluate the relationship between ALS clinical characteristics and structural features.ResultsVolumetric analyses showed no significant difference in the subregion volume of the brainstem between ALS patients and healthy controls. In the shape analyses, ALS patients had a local abnormal surface contraction in the ventral medulla oblongata and ventral pons. Compared with healthy controls, ALS patients showed significantly lower fractional anisotropy (FA) in the left corticospinal tract (CST) and bilateral frontopontine tracts (FPT) at the brainstem level, and higher radial diffusivity (RD) in bilateral CST and left FPT at the brainstem level by ROI analysis in DTI. Correlation analysis showed that disease severity was positively associated with FA in left CST and left FPT.ConclusionThese findings suggest that the brainstem in ALS suffers atrophy, and degenerative processes in the brainstem may reflect disease severity in ALS. These findings may be helpful for further understanding of potential neural mechanisms in ALS.

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White matter changes in the perforant path in patients with amyotrophic lateral sclerosis

10.1101/547588 ◽

2019 ◽

Author(s):

J. Mollink ◽

M. Hiemstra ◽

K.L. Miller ◽

I.N. Huszar ◽

M. Jenkinson ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

White Matter ◽

Dentate Gyrus ◽

Fractional Anisotropy ◽

Granule Cells ◽

Mean Diffusivity ◽

Perforant Path ◽

Papez Circuit ◽

Als Patients ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive and incurable motor neuron disease. Some ALS patients are affected by a level of cognitive or behavioural decline that meets the criteria for frontotemporal dementia (FTD). ALS and FTD share genetic and pathological features; for example, the deposition of phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) in the brain. Spreading of pTDP-43 pathology in ALS towards brain areas that connect via the Papez circuit is a possible indicator of progression towards FTD. For example, pTDP-43 aggregates in the granule cells of the hippocampus correlate well with clinically manifest FTD. Here, we test the hypothesis that white matter degeneration of the perforant path – as part of the Papez circuit – in the hippocampus is a feature of ALS, even in the absence of fully developed FTD or deposition of pTDP-43 inclusions in hippocampal granule cells. We used diffusion MRI (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of hippocampus sections from controls (n=5) and ALS patients (n=14) to perform an in-depth study of white matter in the perforant path.The dMRI results show a significant decrease in fractional anisotropy (p=0.01) and an increase in mean diffusivity (p=0.01), axial diffusivity (p=0.03) and radial diffusivity (p=0.03) in the perforant path in ALS patients compared to controls, possibly indicating a loss of white matter fibres. Myelin density (measured with PLI retardance) was lower in ALS patients compared to controls (p=0.05) and correlated with dMRI fractional anisotropy (r=0.52, p=0.03). The dMRI and PLI results were confirmed by the immunohistochemistry; both myelin (proteolipid protein, p=0.03) and neurofilaments (SMI-312, p=0.02) were lower in ALS patients. The activated microglial (CD68) density was similar in ALS and controls. Only two out of the fourteen ALS cases showed pTDP-43 pathology in the dentate gyrus; however, while these two ALS-FTD cases showed reduced myelination in the perforant path, the values were comparable to other ALS cases.We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP-43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of clinically observed cognitive decline to the amount of white matter atrophy in the perforant path.

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Advanced magnetic resonance neuroimaging in bulbar and limb onset early amyotrophic lateral sclerosis

Journal of Neurosciences in Rural Practice ◽

10.4103/0976-3147.165423 ◽

2016 ◽

Vol 7 (01) ◽

pp. 102-108 ◽

Cited By ~ 5

Author(s):

Maulik Vora ◽

Suresh Kumar ◽

Sanjiv Sharma ◽

Sudhir Sharma ◽

Sushma Makhaik ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Magnetic Resonance ◽

Early Diagnosis ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Consistent Finding ◽

Bulbar Onset ◽

Als Patients ◽

Lateral Sclerosis ◽

Limb Onset

ABSTRACT Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal and most common motor neuron disease, caused by progressive loss of motor neurons. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) studies detect pathological changes in neuronal fibers in vivo. We evaluated the role of DTI and MRS in early course of the disease, which may prove beneficial in the early diagnosis and better management. Materials and Methods: Twenty-one patients with ALS and 13 age-matched controls received 1.5T DTI and three-dimensional multi-voxel MRS. Fractional anisotropy (FA), apparent diffusion coefficient, N-acetyl aspartate (NAA)/Creatine (Cr), and NAA/Choline (Ch) ratios were analyzed in various regions of the brain and compared with healthy controls. ALS patients were classified as definite, possible, and probable category, and patients were also studied in limb versus bulbar onset. Results: Decreased FA and increase mean diffusivity values in regions of corticospinal tract (CST) and corpus callosum (CC) was consistent finding in definite and probable disease category (P < 0.05). In possible disease, CC involvement was not significant. NAA/Cr and NAA/Ch ratios were lower in CC and regions of CST. However, in possible disease, CC involvement was not significant, while regions of CST were showing significant reduction in NAA/Cr and NAA/Ch ratios (P < 0.05). Conclusion: DTI and MRS detect changes associated with ALS even in the early phase of the disease. Bulbar onset and limb onset ALS patients show different pattern of involvement. Extramotor involvement suggested by CC involvement is a feature seen in bulbar onset patient and can suggest poor outcome in such patients. The present findings may be helpful for designing further studies in the direction of more early diagnosis of disease and its management.

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Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement

Diagnostics ◽

10.3390/diagnostics11040624 ◽

2021 ◽

Vol 11 (4) ◽

pp. 624

Author(s):

Robert Rusina ◽

Rik Vandenberghe ◽

Rose Bruffaerts

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cognitive Impairment ◽

Frontotemporal Dementia ◽

Clinical Manifestations ◽

Executive Dysfunction ◽

Motor Disorder ◽

Behavioral Impairment ◽

Caregiver Support ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) has long been considered to be a purely motor disorder. However, it has become apparent that many ALS patients develop cognitive and behavioral manifestations similar to frontotemporal dementia and the term amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is now used in these circumstances. This review is intended to be an overview of the cognitive and behavioral manifestations commonly encountered in ALS patients with the goal of improving case-oriented management in clinical practice. We introduce the principal ALS-FTSD subtypes and comment on their principal clinical manifestations, neuroimaging findings, neuropathological and genetic background, and summarize available therapeutic options. Diagnostic criteria for ALS-FTSD create distinct categories based on the type of neuropsychological manifestations, i.e., changes in behavior, impaired social cognition, executive dysfunction, and language or memory impairment. Cognitive impairment is found in up to 65%, while frank dementia affects about 15% of ALS patients. ALS motor and cognitive manifestations can worsen in parallel, becoming more pronounced when bulbar functions (affecting speech, swallowing, and salivation) are involved. Dementia can precede or develop after the appearance of motor symptoms. ALS-FTSD patients have a worse prognosis and shorter survival rates than patients with ALS or frontotemporal dementia alone. Important negative prognostic factors are behavioral and personality changes. From the clinician’s perspective, there are five major distinguishable ALS-FTSD subtypes: ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, fully developed frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer’s disease. Although the most consistent ALS and ALS-FTSD pathology is a disturbance in transactive response DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein metabolism have also been observed in ALS-FTSD. Early detection and careful monitoring of cognitive deficits in ALS are crucial for patient and caregiver support and enable personalized management of individual patient needs.

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Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis

Behavioural Neurology ◽

10.1155/2018/2635202 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Cinzia Femiano ◽

Francesca Trojsi ◽

Giuseppina Caiazzo ◽

Mattia Siciliano ◽

Carla Passaniti ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Diffusion Tensor Imaging ◽

Diffusion Tensor ◽

Anterior Cingulate ◽

Behavioral Impairment ◽

Brain Areas ◽

Significant Difference ◽

Als Patients ◽

Lateral Sclerosis ◽

Diffusion Tensor Imaging Dti

Apathy is recognized as the most common behavioral change in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder. Particularly, apathy has been reported to be associated with poor ALS prognosis. However, the brain microstructural correlates of this behavioral symptom, reported as the most common in ALS, have not been completely elucidated. Using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS), here we aimed to quantify the correlation between brain microstructural damage and apathy scores in the early stages of ALS. Twenty-one consecutive ALS patients, in King’s clinical stage 1 or 2, and 19 age- and sex-matched healthy controls (HCs) underwent magnetic resonance imaging and neuropsychological examination. Between-group comparisons did not show any significant difference on cognitive and behavioral variables. When compared to HCs, ALS patients exhibited a decreased fractional anisotropy (FA) [p<.05, threshold-free cluster enhancement (TFCE) corrected] in the corpus callosum and in bilateral anterior cingulate cortices. Self-rated Apathy Evaluation Scale (AES) scores and self-rated apathy T-scores of the Frontal Systems Behavior (FrSBe) scale were found inversely correlated to FA measures (p<.05, TFCE corrected) in widespread white matter (WM) areas, including several associative fiber tracts in the frontal, temporal, and parietal lobes. These results point towards an early microstructural degeneration of brain areas biologically involved in cognition and behavior regulation in ALS. Moreover, the significant correlations between apathy and DTI measures in several brain areas may suggest that subtle WM changes may be associated with mild behavioral symptoms in ALS even in the absence of overt cognitive and behavioral impairment.

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A Computational Study of Executive Dysfunction in Amyotrophic Lateral Sclerosis

Journal of Clinical Medicine ◽

10.3390/jcm9082605 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2605 ◽

Cited By ~ 2

Author(s):

Alexander Steinke ◽

Florian Lange ◽

Caroline Seer ◽

Susanne Petri ◽

Bruno Kopp

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Computational Study ◽

Executive Dysfunction ◽

Wisconsin Card Sorting Test ◽

Card Sorting ◽

Cognitive Neuropsychology ◽

Cognitive Symptom ◽

Als Patients ◽

Lateral Sclerosis ◽

Disease Specific

Executive dysfunction is a well-documented, yet nonspecific corollary of various neurological diseases and psychiatric disorders. Here, we applied computational modeling of latent cognition for executive control in amyotrophic lateral sclerosis (ALS) patients. We utilized a parallel reinforcement learning model of trial-by-trial Wisconsin Card Sorting Test (WCST) behavior. Eighteen ALS patients and 21 matched healthy control participants were assessed on a computerized variant of the WCST (cWCST). ALS patients showed latent cognitive symptoms, which can be characterized as bradyphrenia and haphazard responding. A comparison with results from a recent computational Parkinson’s disease (PD) study (Steinke et al., 2020, J Clin Med) suggests that bradyphrenia represents a disease-nonspecific latent cognitive symptom of ALS and PD patients alike. Haphazard responding seems to be a disease-specific latent cognitive symptom of ALS, whereas impaired stimulus-response learning seems to be a disease-specific latent cognitive symptom of PD. These data were obtained from the careful modeling of trial-by-trial behavior on the cWCST, and they suggest that computational cognitive neuropsychology provides nosologically specific indicators of latent facets of executive dysfunction in ALS (and PD) patients, which remain undiscoverable for traditional behavioral cognitive neuropsychology. We discuss implications for neuropsychological assessment, and we discuss opportunities for confirmatory computational brain imaging studies.

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Amyotrophic Lateral Sclerosis–Frontotemporal Dementia: Shared and Divergent Neural Correlates Across the Clinical Spectrum

Neurology ◽

10.1212/wnl.0000000000013123 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013123

Author(s):

Camilla Cividini ◽

Silvia Basaia ◽

Edoardo G. Spinelli ◽

Elisa Canu ◽

Veronica Castelnovo ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Functional Connectivity ◽

Frontotemporal Dementia ◽

Structural Damage ◽

Structural Connectivity ◽

Neural Correlates ◽

The Other ◽

Single Subject ◽

Als Patients ◽

Lateral Sclerosis

Objectives.A significant overlap between amyotrophic lateral sclerosis (ALS) and behavioral variant of frontotemporal dementia (bvFTD) has been observed at clinical, genetic and pathological levels. Within this continuum of presentations, the presence of mild cognitive and/or behavioral symptoms in ALS patients has been consistently reported, although it is unclear whether this is to be considered a distinct phenotype or, rather, a natural evolution of ALS. Here, we used mathematical modeling of MRI connectomic data to decipher common and divergent neural correlates across the ALS-FTD spectrum.Methods.We included 83 ALS patients, 35 bvFTD patients and 61 healthy controls, who underwent clinical, cognitive and MRI assessments. ALS patients were classified according to the revised Strong criteria into 54 ALS with only motor deficits (ALS-cn), 21 ALS with cognitive and/or behavioral involvement (ALS-ci/bi), and 8 ALS with bvFTD (ALS-FTD). First, we assessed the functional and structural connectivity patterns across the ALS-FTD spectrum. Second, we investigated whether and where MRI connectivity alterations of ALS patients with any degree of cognitive impairment (i.e., ALS-ci/bi and ALS-FTD) resembled more the pattern of damage of one (ALS-cn) or the other end (bvFTD) of the spectrum, moving from group-level to single-subject analysis.Results.As compared with controls, extensive structural and functional disruption of the frontotemporal and parietal networks characterized bvFTD (bvFTD-like pattern), while a more focal structural damage within the sensorimotor-basal ganglia areas characterized ALS-cn (ALS-cn-like pattern). ALS-ci/bi patients demonstrated an “ALS-cn-like” pattern of structural damage, diverging from ALS-cn with similar motor impairment for the presence of enhanced functional connectivity within sensorimotor areas and decreased functional connectivity within the “bvFTD-like” pattern. On the other hand, ALS-FTD patients resembled both structurally and functionally the bvFTD-like pattern of damage with, in addition, the structural ALS-cn-like damage in the motor areas.Conclusions.Our findings suggest a maladaptive role of functional rearrangements in ALS-ci/bi concomitantly with similar structural alterations compared to ALS-cn, supporting the hypothesis that ALS-ci/bi might be considered as a phenotypic variant of ALS, rather than a consequence of disease worsening.

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Neuropsychological deficits in amyotrophic lateral sclerosis (ALS): a South India experience

Neuropsychological Trends ◽

10.7358/neur-2013-013-raje ◽

2013 ◽

Author(s):

Jamuna Rajeswaran ◽

Atchayaram Nalini

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cognitive Deficits ◽

Neuropsychological Test ◽

Executive Dysfunction ◽

Planning Problem ◽

Perceptual Skills ◽

Neuropsychological Profile ◽

Indian Setting ◽

Als Patients ◽

Lateral Sclerosis

ALS is a terminal progressive degenerative neurological disorder studies suggest that approximately 35% to 52% of ALS patients experience cognitive deficits which may be identified early in the course of the disease. Cognitive deficits being the integral part of the disease has not been studied in the Indian setting. This is one of the first studies assessing the pattern of cognitive impairment in ALS in the Indian condition. The objective is to examine the neuropsychological profile of amyotrophic lateral sclerosis. Cognitive function was studied in 20 ALS patients: mean age 45.85 13.9 years (22- 65). Neuropsychological test battery was administered. In all 21 test were administered individually in 4-5 sessions which lasted for 7-8 hours. The results show that the majority of patients were from lower/middle socio-economic background. Scores were compared with gender, age and education specific norms, wherein scores falling below 15th percentile of the normative data were treated as deficits. ALS-associated cognitive impairments include deficiencies in visual attention, working memory, fluency, cognitive flexibility, response inhibition, planning, problem solving, and visual-perceptual skills. These impairments indicate executive dysfunction. In conclusion ALS is a disease that affects higher cognitive frontal functions, especially the EF.

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The Cognitive and Behavioural Profile of Amyotrophic Lateral Sclerosis: Application of the Consensus Criteria

Behavioural Neurology ◽

10.1155/2013/126010 ◽

2013 ◽

Vol 27 (2) ◽

pp. 143-153 ◽

Cited By ~ 35

Author(s):

Monica Consonni ◽

Sandro Iannaccone ◽

Chiara Cerami ◽

Paola Frasson ◽

Marco Lacerenza ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Short Term Memory ◽

Executive Dysfunction ◽

Cognitively Impaired ◽

Action Naming ◽

Cognitive Behavioural ◽

Behavioural Profile ◽

Als Patients ◽

The Impact ◽

Lateral Sclerosis

Objective:The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteria [9]. The study also intends to assess the impact of physical disability on cognitive and behavioural abnormalities.Methods:Detailed neurological, neuropsychological and neurobehavioral evaluations were administered to 23 ALS patients, 11 Lower Motor Neuron Disease (LMND) patients and 39 healthy controls. Strong et al.’s criteria [9] were applied to diagnose the presence of cognitive/behavioural impairment. Clinical and neuropsychological scores were used for group comparisons and correlation analyses.Results:In comparison with LMND and controls, a subgroup of ALS patients (∼30%) manifested executive dysfunction, which was severe enough to classify them as cognitively impaired. Action naming difficulties and short-term memory deficits were also observed. Aspontaneity, disorganization and mental rigidity reached clinical relevance in 20% of ALS patients. A small percentage of ALS patients (13%) also had comorbid dementia. The cognitive or behavioural status was not related to the clinical features of ALS.Conclusion:The use of consensus criteria for cognitive and behavioural impairment and the comparison with the LMND group proved useful in defining the spectrum of non-motor manifestations of ALS.

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