Treponema denticola Has the Potential to Cause Neurodegeneration in the Midbrain via the Periodontal Route of Infection-Narrative Review.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common example of dementia. The neuropathological features of AD are the abnormal deposition of extracellular amyloid-ß (Aß) and intraneuronal neurofibrillary tangles with hyperphosphorylated tau protein. It is recognized that AD starts in the frontal cerebral cortex, and then it progresses to the entorhinal cortex, the hippocampus, and the rest of the brain. However, some studies on animals suggest that AD could also progress in the reverse order starting from the midbrain and then spreading to the frontal cortex. Spirochetes are neurotrophic: From a peripheral route of infection, they can reach the brain via the midbrain. Their direct and indirect effect via the interaction of their virulence factors and the microglia potentially leads to the host peripheral nerve, the midbrain (especially the locus coeruleus), and cortical damage. On this basis, this review aims to discuss the hypothesis of the ability of Treponema denticola to damage the peripheral axons in the periodontal ligament, to evade the complemental pathway and microglial immune response, to determine the cytoskeletal impairment and therefore causing the axonal transport disruption, an altered mitochondrial migration and the consequent neuronal apoptosis. Further insights about the central neurodegeneration mechanism and Treponema denticola's resistance to the immune response when aggregated in biofilm and its quorum sensing are suggested as a pathogenetic model for the advanced stages of AD.

Locus Coeruleus Dysfunction and Trigeminal Mesencephalic Nucleus Degeneration: A Cue for Periodontal Infection Mediated Damage in Alzheimer's Disease?

Alzheimer's disease (AD) is a leading neurodegenerative disease with deteriorating cognition as its main clinical sign. In addition to the clinical history, it is characterized by the presence of two neuropathological hallmark lesions; amyloid-beta (Aß) and neurofibrillary tangles (NFTs), identified in the brain at post-mortem in specific anatomical areas. Recently, it was discovered that NFTs occur initially in the subcortical nuclei, such as the locus coeruleus in the pons, and are said to spread from there to the cerebral cortices and the hippocampus. This contrasts with the prior acceptance of their neuropathology in the enthorinal cortex and the hippocampus. The Braak staging system places the accumulation of phosphorylated tau (p-tau) binding to NFTs in the locus coeruleus and other subcortical nuclei to precede stages I-IV. The locus coeruleus plays diverse psychological and physiological roles within the human body including rapid eye movement sleep disorder, schizophrenia, anxiety, and depression, regulation of sleep-wake cycles, attention, memory, mood, and behavior, which correlates with AD clinical behavior. In addition, the locus coeruleus regulates cardiovascular, respiratory, and gastrointestinal activities, which have only recently been associated with AD by modern day research enabling the wider understanding of AD development via comorbidities and microbial dysbiosis. The focus of this narrative review is to explore the modes of neurodegeneration taking place in the locus coeruleus during the natural aging process of the trigeminal nerve connections from the teeth and microbial dysbiosis, and to postulate a pathogenetic mechanism due to periodontal damage and/or infection focused on Treponema denticola.

The Mechanistic Pathways of Periodontal Pathogens Entering the Brain: The Potential Role of Treponema denticola in Tracing Alzheimer's Disease Pathology.

Alzheimer's Disease (AD) is a complex neurodegenerative disease and remains the most common form of dementia. The pathological features include amyloid (Aß) accumulation, neurofibrillary tangles (NFTs), neural and synaptic loss, microglial cell activation, and an increased blood-brain barrier permeability. One longstanding hypothesis suggests that a microbial etiology is key to AD initiation. Among the various periodontal microorganisms, Porphyromonas gingivalis has been considered the keystone agent to potentially correlate with AD, due to its influence on systemic inflammation. P. gingivalis together with Treponema denticola and Tannerella forsythia belong to the red complex consortium of bacteria advocated to sustain periodontitis within a local dysbiosis and a host response alteration. Since the implication of P. gingivalis in the pathogenesis of AD, evidence has emerged of T. denticola clusters in some AD brain tissue sections. This narrative review explored the potential mode of spirochetes entry into the AD brain for tracing pathology. Spirochetes are slow-growing bacteria, which can hide within ganglia for many years. It is this feature in combination with the ability of these bacteria to evade the hosts' immune responses that may account for a long lag phase between infection and plausible AD disease symptoms. As the locus coeruleus has direct connection between the trigeminal nuclei to periodontal free nerve endings and proprioceptors with the central nervous system, it is plausible that they could initiate AD pathology from this anatomical region.

Relapsing-remitting and secondary-progressive multiple sclerosis patients differ in decoding others' emotions by their eyes.

BACKGROUND AND PURPOSE: Difficulties in emotion processing and social cognition identified in multiple sclerosis (MS) patients have a potential impact on their adaptation to the social environment. We aimed to explore the neural correlates of emotion recognition in MS and possible differences between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) patients by the Reading the Mind in the Eyes test (RMEt). METHODS: A total of 43 MS patients (27 RRMS, 16 SPMS) and 25 matched healthy controls (HC) underwent clinical assessments, RMEt, and a high-resolution T1-weighted 3-T magnetic resonance imaging (MRI) scan. The number of correct answers on the RMEt was compared between groups. T1-weighted volumes were processed according to an optimized voxel-based morphometry (VBM) protocol to obtain gray matter (GM) maps. Voxelwise analyses were run to assess potential associations between RMEt performance and regional GM volumes. RESULTS: Taken altogether, MS patients reported significantly lower performance on the RMEt compared to HC. When dividing the patients into those with RRMS and those with SPMS, only the latter group was found to perform significantly worse than HC on the RMEt. VBM analysis revealed significant association between RMEt scores and GM volumes in several cortical (temporoparieto-occipital cortex) and subcortical (hippocampus, parahippocampus, and basal ganglia) brain regions, and in the cerebellum in SPMS patients only. CONCLUSIONS: Results suggest that, in addition to other clinical differences between RRMS and SPMS, the ability to recognize others' emotional states may be affected in SPMS more significantly than RRMS patients. This is supported by both behavioral and MRI data.

Dual-Task Performance in Multiple Sclerosis' Patients: Cerebellum Matters?

OBJECTIVE: Gait, cognitive impairments, and their mutual influence in dual tasking (cognitive-motor dual tasking, CM-DT) are important to address therapeutic approaches in patients with multiple sclerosis (PMS). CM-DT correlates have been widely investigated with variable and dissimilar results, due to differences in methods. However, although the cerebellum has recently shown to be involved in both motor and cognitive functions, few studies have explored its role in the integration of the concurrent execution of gait and cognition. This case-control study aims to explore the effects of adding a cognitive task to walking in PMS and to investigate the role of the cerebellum in the interfering process. METHODS: In total, 20 patients and 18 healthy controls (HC) underwent clinical assessments, dual task (DT), and 3 T magnetic resonance imaging (MRI). DT was composed by three 2-min trials requiring fast walking. In 2 of them 2 different cognitive tasks were added. RESULTS: Both groups evidenced the presence of cognitive-motor interference (CMI) for both cognitive conditions with a greater effect of word list generation task in PMS. Analysis of variance between HC and patients with high or low performances showed a significantly increased volume in Vermis lobules VIIIa and IX of high performers compared with HC. CONCLUSION: Our results show that CMI is also present in healthy individuals but is significantly more disabling in PMS. Furthermore, MRI data point to the existence of an initial mechanism of cerebellar reorganization in PMS with lower interference. Subsequently, the failure of this mechanism due to the progression of disability leads to a more evident expression of symptoms.

Can personality traits influence occupational stress in multiple sclerosis patients? A one-year longitudinal study.

Recent studies suggest that patients with Multiple Sclerosis (MS) might be at risk of unemployment due to physical and psychological symptoms. Furthermore, MS patients appear to be more exposed to a higher level of occupational stress, which might be linked to some personality characteristics. Our aim was to ascertain, by means of a longitudinal study, whether changes in occupational stress can be predicted by some personality traits, which could thereby become potential targets of therapeutic interventions. This study describes the longitudinal results of a previous work on occupational stress and personality traits in MS patients. Twenty MS patients were reevaluated one year after the baseline assessment. The statistical comparison between the baseline and follow-up visits showed a significant change in the scores on some Occupational Stress Inventory (OSI) subscales-Locus of control total (LOC-tot) and Involvement coping strategies (CI). While Neuroticism and Openness might predict changes in LOC-tot, Conscientiousness appeared to be important in the development of CI at one year. The findings indicate that certain personality traits can influence some longitudinal changes in occupational stress, thus making them useful in predicting stress at workplace.

Long-term treatment with rotigotine in drug-naïve PSP patients.

Progressive supranuclear palsy (PSP) is a severe neurodegenerative disease still lacking of alleviating treatments for either cognitive or motor disturbances. Aimed at widening the spectrum of therapeutic options, here, we describe efficacy and safety of a long-term treatment with Rotigotine, a non-ergolinic dopamine agonist, in PSP. Seven PSP drug-naïve patients, presenting with Richardson's syndrome, received up to 6 mg/24 h transdermal patch for 42 weeks as unique therapy. Adverse effects were recorded; efficacy was measured by comparing baseline and final treatment scores of Montreal Cognitive Assessment (MoCA), Unified Parkinson Disease Rating Scale part3, and PSP rating scale (PSP-RS). At the end of our observation, no significant adverse events occurred; the cognitive item of PSP-RS was improved and MoCA score was similar at baseline. Contrariwise, motor disturbances worsened according to disease progression. Our observation thus suggests that long-term treatment with low doses of rotigotine is well tolerated and may support cognitive functions of PSP patients.

Disruption of neurite morphology parallels MS progression.

OBJECTIVES: To apply advanced diffusion MRI methods to the study of normal-appearing brain tissue in MS and examine their correlation with measures of clinical disability. METHODS: A multi-compartment model of diffusion MRI called neurite orientation dispersion and density imaging (NODDI) was used to study 20 patients with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS), and 20 healthy controls. Maps of NODDI were analyzed voxel-wise to assess the presence of abnormalities within the normal-appearing brain tissue and the association with disease severity. Standard diffusion tensor imaging (DTI) parameters were also computed for comparing the 2 techniques. RESULTS: Patients with MS showed reduced neurite density index (NDI) and increased orientation dispersion index (ODI) compared with controls in several brain areas (p < 0.05), with patients with SPMS having more widespread abnormalities. DTI indices were also sensitive to some changes. In addition, patients with SPMS showed reduced ODI in the thalamus and caudate nucleus. These abnormalities were associated with scores of disease severity (p < 0.05). The association with the MS functional composite score was higher in patients with SPMS compared with patients with RRMS. CONCLUSIONS: NODDI and DTI findings are largely overlapping. Nevertheless, NODDI helps interpret previous findings of increased anisotropy in the thalamus of patients with MS and are consistent with the degeneration of selective axon populations.

The Italian validation of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) and the application of the Cognitive Impairment Index scoring procedure in MS patients.

Cognitive dysfunction occurs in almost 50-60% of patients with multiple sclerosis (MS) even in early stages of the disease and affects different aspects of patient's life. Aims of the present study were (1) to introduce and validate an Italian version of the minimal assessment of cognitive functions in MS (MACFIMS) battery and (2) to propose the use of the Cognitive Impairment Index (CII) as a scoring procedure to define the degree of impairment in relapsing-remitting (RRMS) and secondary-progressive (SPMS) patients. A total of 240 HC and 123 MS patients performed the Italian version of the MACFIMS composed by the same tests as the original except for the Paced Auditory Serial Addition Test. The CII was derived for each score of the 11 scales for participants of both groups. The results of the study show that cognitive impairment affects around 50% of our sample of MS patients. In RRMS group, only the 15.7% of patients reported a severe impairment, while in the group of SPMS, the 51.4% of patients felt in the "severely impaired" group. Results are in line with previously reported percentages of impairment in MS patients, showing that the calculation of the CII applied to the Italian version of the MACFIMS is sensitive and reliable in detecting different degrees of impairment in MS patients.

A more in-depth interpretation of MMPI-2 in MS patients by using Harris and Lingoes subscales.

Multiple Sclerosis (MS) is frequently associated with neuropsychiatric abnormalities. The aim of our study was to discriminate between psychosomatic disturbances and MS physically-related symptoms using the Harris-Lingoes subscales of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Forty-six MS out-patients (35 females; mean age = 44.5); and 82 healthy volunteers (62 females; mean age = 46.5) were evaluated with MMPI-2 questionnaire. The frequency distribution of MMPI-2 clinical scales with high scores (> = 65) and the related Harris-Lingoes subscales were analyzed for both MS patients and healthy control subjects. Data analysis showed elevated scores in 47.8% of the patients mainly on MMPI-2 clinical scales 1, 2, and 3. The Harris-Lingoes subscales analysis allowed us to isolate and identify physical symptoms contributing to elevation of MMPI-2 clinical scales, reduce the occurrence of false positives (MMPI-2 clinical scales elevations mainly due to MS physical disability) and provide a more detailed description of psycho-emotional symptoms of MS patients. In conclusion, our study shows the utility of Harris-Lingoes subscales analysis when MMPI-2 is used for psychological assessment of MS patients.

[Domestic accidents in patients with multiple sclerosis: proposal and application of questionnaires for their detection]. / Gli incidenti domestici nei pazienti con Sclerosi Multipla: proposta e applicazione di questionari per la loro rilevazione.

OBJECTIVES: Domestic accidents are an important topic as for different viewpoints: for the people that could be victim of them, for the health and economic systems. It could be imagined that people affected by neurological diseases, such as Multiple Sclerosis (MS), could incur into domestic accidents more frequently than people in the general population. Aim of the present work is to introduce a survey's questionnaire for registering occurrence and characteristics of domestic accidents in a population with particular features such as MS patients. METHODS: In 2011, a first edition of this survey questionnaire was already proposed and then applied with a sample of MS patients (QuID). RESULTS: A subsequent newest version of the test (QuID-II) has then been proposed, based on the information collected and on the limits showed by that first edition. CONCLUSIONS: With this new version deepen information can be collected on the characteristics, the biological, environmental and behavioural risk factors for the occurrence of domestic accidents, and this could be useful in planning prevention programs.

Adverse working events in patients with multiple sclerosis.

Multiple sclerosis (MS) and working status have recently arisen great interest. Fatigue, physical disability, cognition, and psychological disturbances have been linked to unemployment, as well to accidents during daily activities. The aim of our study was to determine frequency of different types of accidents at workplace (AWE) and possible clinical differences among employed (MSe) and unemployed (MSu) MS patients. Sixty MS patients (31 employed, 29 unemployed) and twenty healthy control subjects were recruited. All employed participants were requested to complete an ad-hoc questionnaire to collect AWE and related risks occurring at workplace in the past 2 months. Physical, cognitive, mood, and fatigue evaluations were also assessed. Illness and bumps along with risk of bumps and near falls resulted the most frequent AWE and risks occurring in MSe. Interestingly, those AWE were mostly observed among subjects with anxiety, depression, and cognitive fatigue rather than depending on severity of physical impairment. Moreover, psychological aspects, like anxiety and anger, seemed to play a crucial role in determining AWE. This study provides data on AWE occurrence and suggests possible mechanisms underlying negative events at workplace in MS. This might be important for planning strategies of AWE prevention in MS patients.

Regression-Based Norms for the Brief Visuospatial Memory Test-Revised in Italian population and application in MS patients.

OBJECTIVE: The Brief Visuospatial Memory Test-Revised (BVMT-R) is one of the most widely used tests for the assessment of learning and memory in the visual/spatial domain. The aim of this study was to use multiple regression to derive normative data for the use of BVMT-R in an Italian population. METHOD: We employed a regression-based norms procedure to maximally utilize a relatively small sample while controlling for a variety of demographic factors in addition to age. Additionally, we used these norms to compare the performance of Italian healthy controls with patients diagnosed with multiple sclerosis (MS), thereby providing evidence of the method's validity. RESULTS: A total of 200 healthy volunteers and 70 MS patients participated in this study and completed the BVMT-R according to the published procedures. Regression-based norms were generated for the Italian sample and are presented herein. CONCLUSIONS: Using these norms, the performance of the MS patients was found to be significantly worse than that of the controls.

Role of inflammation and apoptosis in multiple sclerosis: Comparative analysis between the periphery and the central nervous system.

Multiple sclerosis (MS) is a complex, multifactorial disease associated with damage to the axonal myelin sheaths and neuronal degeneration. The pathognomonic event in MS is oligodendrocyte loss accompanied by axonal damage, blood-brain barrier leakage, inflammation and infiltration of immune cells. The etiopathogenesis of MS is far from being elucidated. However, increasing evidence suggests that the inflammatory and apoptotic responses, occurring in patients either at the peripheral level or the central nervous system (CNS), can play a role. In this review, we give a comprehensive picture of general aspects of inflammation and apoptosis in MS, with special emphasis on the until now not well highlighted possible links between phenomena relevant to these aspects occurring in either the periphery or in the CNS during MS.

Autonomic Function Tests and MIBG in Parkinson's Disease: Correlation to Disease Duration and Motor Symptoms.

AIMS: Disorders of the autonomic nervous system (ANS) have a variable degree of clinical relevance in patients with Parkinson's disease (PD). Here, we assessed whether subclinical autonomic dysfunction, as evaluated by a complete battery of autonomic function tests (AFTs), correlates with PD progression. METHODS: A series of 27 consecutive patients with PD underwent extensive ANS investigations including the head-up tilt test (HUTT), Valsalva maneuver, deep-breathing test, and handgrip test (HG); further, they performed 123I-meta-iodobenzylguanidine (MIBG) scintigraphy. RESULTS: Seven of the 27 patients showed orthostatic hypotension (OH) at HUTT and pathological responses to the deep-breathing and HG test and Valsalva maneuver. The majority of the remaining 20 patients with PD showed pathological responses to deep-breathing (n = 13) and/or HG (n = 11). Only 3 of 27 suffered relevant OH. MIBG uptake of myocardium was decreased in 19 patients with PD (H/M ratio 1.3 ± 0.2). Prolonged clinical observation (>3 years), persistent response to levodopa, and MIBG repetition allowed us to exclude negative MIBG as attributable to atypical Parkinsonism. MIBG uptake did not correlate with OH and other AFTs. Both HG test response and MIBG did correlate with the Unified Parkinson's Disease Rating Scale (UPDRS) motor score and disease duration. A positive correlation emerged between diastolic blood pressure (DBP) response to HG test and MIBG and with systolic blood pressure (SBP) response at tilt test. CONCLUSIONS: Our investigation suggests that ANS impairment affects the majority of patients with PD, even those PD patients showing negative MIBG, irrespective of clinical neurovegetative symptoms. The strict correlation that has been revealed with disease progression supports the routine utilization of AFTs as a reliable and inexpensive tool for monitoring peripheral sympathetic dysfunction in PD and optimizing therapy.

Occupational stress and personality traits in multiple sclerosis: A preliminary study.

Multiple Sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system, causing a wide range of neurological and psychological symptoms. Impairment of ambulation and cognition in particular are associated with work difficulties and unemployment. Although many aspects of work status have been investigated in MS, there are no reports on factors that predict the development of occupational stress, prior to job loss. The aim of this preliminary study was to ascertain if personality traits predispose MS patients to occupational stress. We evaluated 26 MS patients using physical disability scales and self-report questionnaires focused on mood, fatigue, and personality [measured with the NEO Five Factor Inventory]. The primary outcome measure was the Occupational Stress Indicator [OSI]. Results showed significant positive correlations (p<.05) between high neuroticism, and occupational stress. Conversely, low extraversion and conscientiousness were also associated with job stress. The direction of these correlations was consistent with prior research showing that high neuroticism, and low extraversion and conscientiousness, are risk factors for MS disease severity as evidenced by brain atrophy, cognitive impairment and adaptation in MS. We are developing interventions to help patients cope with these maladaptive personality dispositions in the hope that employment may be maintained.

An investigation of hearing impairment in de-novo Parkinson's disease patients: A preliminary study.

OBJECTIVE: To investigate the peripheral auditory pathway in Parkinson's disease (PD) by using objective, quantitative and non-invasive audiological techniques, transient-evoked (TEOAE) and distortion product (DPOAE) otoacoustic emissions, in order to detect subclinical alterations of cochlear functioning and possible changes after dopaminergic stimulation. METHODS: We enrolled 11 untreated de-novo PD patients and 11 age and sex-matched healthy controls. Subjects underwent a routine audiological evaluation and otoacoustic emission recordings. The patients were then slowly-titrated to a stable dose of 100 mg levodopa four times in a day. A post-treatment assessment was made in order to detect significant changes in audiological responses. Finally, possible associations between clinical data and hearing results were also evaluated. RESULTS: At pure-tone audiometry, higher auditory threshold levels were observed in PD when compared to the controls. Moreover, DPOAE responses in PD patients were found low at almost all tested frequencies, suggesting subclinical cochlear damage. Interestingly, after dopaminergic treatment, a significant increase in DPOAE responses was detected. Notably, DPOAE dysfunction correlated with clinical severity, whereas high hearing thresholds appeared positively related with more prolonged disease duration. CONCLUSIONS: Our findings demonstrate that otoacoustic emission recording and pure-tone audiometry reveal levodopa-sensitive cochlear dysfunction and hearing loss in PD. A parallel improvement in subjective motor symptoms and DPOAE objective responses could help clinicians in monitoring therapeutic responses and dynamic changes during the course of the disease.

A Preliminary Investigation of Abnormal Personality Traits in MS Using the MCMI-III.

Neuropsychiatric abnormalities are frequently reported in patients with multiple sclerosis (MS). Previous studies have investigated the neurotic aspects of psychopathology, and the importance of the personality structure underlying neurotic symptoms has only recently been reconsidered. The aim of our study was to investigate the frequency and type of personality profiles in MS using the Millon Clinical Multiaxial Inventory-III (MCMI-III). We evaluated 77 nondemented patients with MS using physical disability scales and self-report questionnaires focused on mood, fatigue, and personality. In our cohort study, we found a personality scale score greater than 85 in 62.3% of enrolled participants. In particular, high scores on the Histrionic and Narcissistic scales emerged, respectively, in 20.8% and 15.6% of the sample. The presence of moderate abnormal elevation scores in MCMI personality scales in MS does not seem to be influenced by age, the Expanded Disability Status Scale score, disease course, or disease duration. Our research study focused on the importance of identifying personality maladaptation in patients with MS.

A survey of the nature of trauma of post-traumatic benign paroxysmal positional vertigo.

OBJECTIVE: A clinical description of post-traumatic benign paroxysmal positional vertigo (t-BPPV) in a large cohort is reported, sometimes caused by apparently insignificant minor head traumas. The aim of the study was to carefully assess the prevalence of t-BPPV and the main outcomes belonging to specific traumatic events. DESIGN: Retrospective analysis of medical records of t-BPPV cases among patients suffering from BPPV. STUDY SAMPLE: Among 3060 patients with a clinical diagnosis of BPPV, we reviewed 716 clinical cases in which a clear association to a traumatic event was present. RESULTS: A traumatic event was identified in 23.4% of total enrolled BPPV patients. Some minor head traumas could be more prone to determine BPPV in females. We confirmed that t-BPPV appeared significantly more difficult to treat than idiopathic form. Posterior canal t-BPPV cases required more treatment sessions before obtaining therapeutic success, while horizontal ones recovered at most after two repositioning maneuvers. CONCLUSION: Post-traumatic BPPV is considered one of the most common known etiologies. An accurate understanding of trauma mechanism, gender prevalence, and therapeutic success rates of each event, could be useful in adequately treating and planning follow-up examinations.

Assessing clinical correlates of self-rated disability in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is associated with significant impairment. OBJECTIVE: The objective of this article is to identify and compare clinical measures that can predict self-rated disability in patients with MS using the World Health Organization Disability Assessment Schedule II (WHODAS-II). METHODS: Patients with MS and healthy controls were consecutively recruited at one center. Patients were evaluated for cognitive function assessment, neurological status, perceived disability, mood, fatigue and disease duration. Controls underwent neuropsychological evaluation only. Data were analyzed using multivariate regression. RESULTS: WHODAS-II total score was predicted by fatigue (p < 0.001) and neurological status (p < 0.05). Student's t test comparisons between published WHODAS-II normative data and the enrolled cohort of patients with MS showed significantly worse (p < 0.05) scores for patients on mobility, self-care, life activities, participation and total score domains, but not in cognition. Group differences between patients with MS (n = 61) and controls (n = 61) were significant in all cognitive measures except one verbal memory test subscale. Memory function correlated best with the social participation domain of the WHODAS-II. CONCLUSIONS: Self-reported disability in patients with MS was most strongly influenced by fatigue and to a lesser extent by physical disability. Although cognitive function does affect self-assessment of disability, this is not captured by patients on the WHODAS-II cognitive domain.