Cognitive Impairment In Multiple Sclerosis

Multiple Sclerosis (MS) is a common disease in Western countries of temperate/cold climate, but in tropical countries an increasing number of cases have been diagnosticated.

Moved by the lack of information about Cognitive Dysfunction of Brazilian MS patients, the present study attempted to describe features of NeuroPsychological alterations in patients with Relapsing/Remitting MS living in the city of Sao Paulo.

They were compared to healthy volunteers, matched for age and education. In the absence of global intellectual deterioration, the patients had a deficit:

1. In Learning and Verbal Long-Term Memory Tasks and
   • In Visual Long-Term Memory of complex figure
2. In timed tasks, accounted for by a slowness of mental processes
3. In tasks with a Motor component
4. Tendency to Depression was observed
   • Anxiety levels were normal

Few studies have demonstrated Language impairment in patients with Multiple Sclerosis (MS) compared to healthy controls.

The purpose of this investigation was to examine Language Functions, specifically Naming, Comprehension, and Verbal Fluency, in patients with MS and healthy controls to:

1. Determine if patients with MS demonstrate Language impairment
2. Provide clarification of MS-related Language disturbance,
   • Particularly in patients with MS of differing courses

Results showed that both Chronic/Progressive and Relapsing/Remitting patients with MS performed significantly more poorly than controls on Naming, Aural Comprehension, Letter Fluency, and Category Fluency, as well as other Language-based Cognitive measures.

Chronic/Progressive patients obtained significantly lower scores than Relapsing/Remitting patients on the latter three tests.

The language disturbance in this MS sample may be partly explained by Impairment in other Verbal Cognitive Functions. These findings highlight the importance of assessing Language abilities in patients with MS.

Objective
To explore functional CorticoCortical connections (Corpus Callosum) in Multiple Sclerosis by means of coherence of the EEG, and to evaluate their correlations with the degree of Cognitive Impairment and with Brain T₂ lesion load assessed by MRI.

Methods
EEG coherence was studied from 28 patients with Clinically Definite Multiple Sclerosis. Ten minutes of resting EEG were recorded with 20 scalp electrodes, with BinAural reference.

FFT power and coherence were calculated in artifact free epochs of 1 second and compared with values from 22 control subjects of comparable age and sex distribution.

Patients also underwent MRI (n=27) and NeuroPsychological Examination (n=21).

Results
Compared with controls, patients with Multiple Sclerosis showed increased theta power in the FrontoTemporal-Central regions (p<0.005).

theta Band coherence was decreased between homologous areas (p<0.02). alpha Band coherence was decreased both in the local and long distance connections (p<0.0005).

These findings were most striking both in patients with high MRI SubCortical lesion load and in patients with Cognitive involvement.

A significant correlation was found between InterHemispheric theta (p=0.02) and alpha (p=0.017) and AnteroPosterior alpha (p=0.013) coherence and SubCortical MRI lesion load, but not with exclusively PeriVentricular lesion load.

Conclusions
These findings support the hypothesis that Cognitive Impairment in Multiple Sclerosis is mostly dependent on involvement of CorticoCortical connections related to DeMyelination and/or Axonal Loss within the White Matter immediately underlying the Cortex.

Cognitive Dysfunction occurs in up to 65% of patients with Multiple Sclerosis (MS), but there is no effective treatment for the symptoms.

The authors conducted a 12-week, open-pilot study to assess the efficacy and tolerability of Donepezil HCl (Aricept^®) administered in patients with MS and Cognitive Impairment.

Seventeen patients at a long-term care facility with Mini-Mental State Examination scores of < or = 25 received 5 mg of Donepezil HCl for a 4-week period, followed by 8 weeks of 10 mg of Donepezil HCl.

Cognitive, Neurologic, Functional, and Behavioral assessments were conducted at baseline and at 4 and 12 weeks.

Statistically significant improvement was observed in several Cognitive domains including: Attention, Memory, and Executive functioning, as well as different aspects of behavior.

These data suggest that Donepezil HCl merits further study as a potentially viable treatment option for patients with Cognitive Impairment associated with MS.

Word list learning was studied in patients with a definite diagnosis of Multiple Sclerosis and in Normal Control subjects by means of the Selective Reminding Procedure of Buschke and Fuld in two learning conditions:

1. Using unrelated items and
2. Paired-associate items

The Multiple Sclerosis patients displayed poor learning in both conditions.

To identify the functional locus of their deficit, stochastic Markov chain analyzes were performed, which allowed individual measurements of Encoding, Automatic and Intentional Retrieval abilities.

On both tasks, encoding on the first trial and Automatic Retrieval on the subsequent trials were impaired in Multiple Sclerosis patients; whereas Intentional Retrieval, both with and without reminding by the examiner, appeared to be preserved.

As all of the impaired abilities require a normal speed of information processing, the salient learning deficit of the Multiple Sclerosis patients could be tentatively traced back to the slowing down of their mental activity.

To evaluate the underlying mechanisms of Cognitive decline in Multiple Sclerosis, two clinically and demographically matched Multiple Sclerosis groups differing in Cognitive status were assessed with Attention related tasks.

In addition to the Attention tests recommended by the Cognitive Function Study Group of the American National Multiple Sclerosis Society, a test of sustained attention was used to evaluate the role of possible fatigue on Cognitive performance.

The Cognitively mildly deteriorated group was slower than the Cognitively preserved group and the controls on all tests of Attention.

The mildly deteriorated group did not, however, consistently differ from the other groups in the error scores of the Attention tests.

The preserved group exhibited slowness at the end of the Visual vigilance test, but no deficits were found on the other Attention related tests in this group.

It is suggested that dissociable kinds of Processing slowness are the origin of the deficits found on the Attention tests in the two Multiple Sclerosis groups.

Our preserved group exhibited signs of Motor and Fatigue related slowness, whereas the mildly deteriorated group also had extensive Cognitive slowness.

As sensitive indicators of Cognitive slowness, Attentional tests should be included in evaluation of the Cognitive status of patients with Multiple Sclerosis.

The pattern of mental dysfunction in Multiple Sclerosis (MS) is characteristic of the so-called SubCortical Dementia.

Cognitive dysfunction results predominantly by the disruption of communication among Cortical and SubCortical areas, as a consequence of the White Matter damage.

As expected, studies with conventional Magnetic Resonance Imaging (MRI) demonstrated that Cognitive Impairment in MS patients is related to the lesion burden, although the strength of this correlation is weak.

This can be partially explained by the poor pathological specificity of conventional MRI techniques and by the invisible damage in the Normal-Appearing White Matter (NAWM).

Recent studies using non-conventional MRI techniques with a higher specificity for the heterogeneous substrates of MS pathology, such as the assessment of HypoIntense lesion load on T1-weighted scans.

And the measurement of the Magnetization Transfer Ratio (MTR) of whole Brain, MS lesions and NAWM, support this interpretation.

Other factors, such as the site of MS lesions and the presence of active inflammation, also seem to play an important role.

Background And Purpose
Multiple Sclerosis (MS) is a DeMyelinating Disease most often associated with progressive physical Impairment; however, its effects are noted to extend beyond physical disability.

Our purpose was to determine the relationship between T₂ lesion volume and NeuroCognitive and physical disability in Relapsing/Remitting Multiple Sclerosis.

Methods
We studied a cohort of 19 patients with Relapsing/Remitting MS. Of this group, there were 15 women and four men from varying SocioEconomic backgrounds.

This volunteer sample was selected from a larger group of 53 patients with MS in our longitudinal MS study.

Because they had been untreated with any Interferon-ß medications, had been followed for at least 12 months, and had a clinical status of Relapsing/Remitting MS.

Results
Of 12 NeuroCognitive parameters tested, two correlated significantly with lesion loads. The correlation of the Symbol-Digit Modalities Test, which analyzes Information-Processing Speed, was significant (P = .0204).

The correlation of the fifth trial of the Rey Auditory Verbal Learning test, which tests Verbal Long-Term Memory, was also significant (P = .0348).

None of the other 10 NeuroCognitive Examinations, however, showed a significant correlation with total lesion volume

1. Paced Auditory Serial Addition Test-1.6, P = .7381
2. Paced Auditory Serial Addition Test-2.0, P = .4180
3. Controlled Oral Word Association Test, P = .8906
4. Category Fluency Test, P = .4423
5. Bells test, P = .9097
6. Rey Auditory Verbal Learning Test-Delay, P = .9843
7. Rey Auditory Verbal Learning Test-Recognition, P = .7467
8. Word Span Test, P = .4939
9. Road Map test, P = 0.4939

The Lesion Load also did not correlate with the physical disability scales as rated according to the Expanded Disability Status Scale (P = .68) or Ambulation Index (P = .95).

Conclusion
Our results indicate that T₂ lesion volume does not seem to be a robust surrogate marker of NeuroPsychological Impairment in patients with MS.

We think that global measurements of parameters that are more specific to the disease process may offer more precise correlation with Cognitive Dysfunction and other Disability parameters.

Background And Purpose
MR imaging is a sensitive diagnostic tool and ParaClinical marker of disease activity and prognosis in Multiple Sclerosis (MS), yet the role of MR imaging of MS is controversial.

The aim of this study was to describe the relationship between Cognitive function and MS lesion size and position.

As shown on comparative images from Conventional Spin-Echo (CSE) and fast Fluid-Attenuated Inversion-Recovery (fast FLAIR) MR studies.

Methods
CSE and fast FLAIR sequences consisted of 40 noncontiguous, 3-mm-thick axial sections matched for geometric position in 18 patients with Relapsing/Remitting MS.

Lesions were scored for size, anatomic position, and their comparative appearance on CSE and fast FLAIR images.

The NeuroPsychological assessment tested general Psychological performance, Memory, and Frontal Lobe Executive Function.

Results
Fast FLAIR images showed significantly more small (146 versus six) and medium-sized (18 versus four) JuxtaCortical lesions than did CSE sequences.

Small JuxtaCortical lesions displayed only on fast FLAIR images had a distinctive appearance, suggestive of small areas of PeriVascular inflammation.

The number of these lesions corresponded to reduced performance on the fifth and delayed trials of the Rey Auditory Verbal Learning Memory function test.

Conclusion
fast FLAIR images show small lesions at the JuxtaCortical boundary that are not seen on CSE studies.

The presence of such lesions correlates with impaired retention of information in Memory tasks, which is characteristic of Cognitive problems in patients with MS.

A previous study by Scarrabelotti and Carrollwas the first to use Jacoby's Process Dissociation Procedure with an MS group to investigate Memory function, and the first to obtain MetaMemory judgments about recall under inclusion and exclusion instructions.

Twelve months later using different words, 49 MS and 39 matched controls were readministered a Word Stem Completion Task, and made MetaMemory judgments about their performance.

The California Verbal Learning Test (CVLT), Stroop, and Reitan's Word Finding Test (WFT), tests considered to particularly rely on Conscious processing, were also readministered.

At year one testing no group differences were identified in Word Stem Completion under Indirect, Inclusion, or Exclusion instructions, nor in Conscious and Automatic estimates.

By contrast in year two, MS subjects remembered significantly fewer words under Inclusion, and employed significantly less Conscious processing than the control group to achieve remembering.

However, estimates of Automatic Memory Processing were the same for both groups. MS subjects equalled controls in the Prospective and Retrospective monitoring of words they Consciously recalled under Inclusion instructions, in both years.

By contrast, each group was poor at monitoring words completed Automatically under Exclusion instructions; and by year two, MS subjects were even less able to monitor such material than controls.

Finally by the second year, reduced Conscious Processing was also related to reduced performance on the Stroop, WFT, and CVLT recall and use of Semantic clustering.

Taken together, these findings indicate that Automatic Memory Processing is intact in MS, but Impairment in Memory, MetaMemory, and other Cognitive tasks becomes evident over time when they rely on Conscious Processes.

To investigate the status of Attention in Multiple Sclerosis (MS) we administered tests of Focused and Divided Attention to 39 MS patients and 18 age- and education-matched control subjects.

In addition, a test of vigilance and a test of Automatic Information Processing was administered.

MS patients performed as well as controls on the Automatic Processing Task and on most measures of Focused and Divided Attention when accuracy but not speed was the dependent variable.

By contrast, the MS patients performed significantly worse than controls on the more effortful measures of Attention, especially those that engaged Working Memory or emphasized speeded responding.

These results indicate that deficits of Attention in MS patients are most likely to be evident on tasks which require Concentrated Cognitive effort.

MS patients and age- and education-matched normal controls were administered several laboratory tests of MetaMemory and a questionnaire designed to measure subjects' capability to appraise their ability to remember events that might occur in everyday life.

On laboratory tasks involving newly acquired information, MS patients with poor Recognition Memory abilities or poor performance on the Wisconsin Card Sorting Test (WCST) exhibited impairments on one test of MetaMemory;

Patients with deficits in both Recognition and on the WCST showed more extensive impairments in MetaMemory.

In contrast to their performance on tests involving Newly Acquired Information, all groups of MS patients predicted their ability to recognize answers to general information questions that they could not recall as accurately as controls.

And, like controls, they also searched their memories longer for answers to items that they believed they would recognize.

In general, the results support the hypothesis that both Trace-Access and Inferential mechanisms, which are thought to involve the PreFrontal Cortex, contribute to MetaMemory, but the nature of the Memory task importantly influences the accuracy of MetaMemory, as well.

Results from the questionnaire indicated that many MS patients with demonstrable Memory Deficits do not acknowledge their Memory difficulties.

Hence, patient self-reports about Memory are likely to be unreliable sources of information for clinical purposes.