CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease.

BACKGROUND: Cholinergic neuronal loss is one of the hallmarks of AD related neurodegeneration; however, preclinical promise of α7 nAChR drugs failed to translate into humans. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of α7 nAChR and was unaccounted for in preclinical models. METHODS: Molecular methods: Function of CHRFAM7A alleles was studied in vitro in two disease relevant phenotypic readouts: electrophysiology and Aß uptake. Genome edited human induced pluripotent stem cells (iPSC) were used as a model system with the human context. Double blind pharmacogenetic study: We performed double-blind pharmacogenetic analysis on the effect of AChEI therapy based on CHRFAM7A carrier status in two paradigms: response to drug initiation and DMT effect. Mini Mental Status Examination (MMSE) was used as outcome measure. Change in MMSE score from baseline was compared by 2-tailed T-test. Longitudinal analysis of clinical outcome (MMSE) was performed using a fitted general linear model, based on an assumed autoregressive covariance structure. Model independent variables included age, sex, and medication regimen at the time of the first utilized outcome measure (AChEI alone or AChEI plus memantine), APOE4 carrier status (0, 1 or 2 alleles as categorical variables) and CHRFAM7A genotype. FINDINGS: The direct and inverted alleles have distinct phenotypes. Functional CHRFAM7A allele classifies the population as 25% non-carriers and 75% carriers. Induced pluripotent stem cell (iPSC) models α7 nAChR mediated Aß neurotoxicity. Pharmacological readout translates into both first exposure (p = 0.037) and disease modifying effect (p = 0.0048) in two double blind pharmacogenetic studies. INTERPRETATION: CHRFAM7A accounts for the translational gap in cholinergic strategies in AD. Clinical trials not accounting for this uniquely human genetic factor may have rejected drug candidates that would benefit 25% of AD. Reanalyses of the completed trials using this pharmacogenetic paradigm may identify effective therapy.

Long-standing multiple sclerosis neurodegeneration: volumetric magnetic resonance imaging comparison to Parkinson's disease, mild cognitive impairment, Alzheimer's disease, and elderly healthy controls.

Multiple sclerosis (MS) exhibits neurodegeneration driven disability progression. We compared the extent of neurodegeneration among 112 long-standing MS patients, 37 Parkinson's disease (PD) patients, 34 amnestic mild cognitive impairment (aMCI) patients, 37 Alzheimer's disease (AD) patients, and 184 healthy controls. 3T MRI volumes of whole brain (WBV), white matter (WMV), gray matter (GMV), cortical (CV), deep gray matter (DGM), and nuclei-specific volumes of thalamus, caudate, putamen, globus pallidus, and hippocampus were derived with SIENAX and FIRST software. Аge and sex-adjusted analysis of covariance was used. WBV was not significantly different between diseases. MS had significantly lower WMV compared to other disease groups (p < 0.021). Only AD had smaller GMV and CV when compared to MS (both p < 0.001). MS had smaller DGM volume than PD and aMCI (p < 0.001 and p = 0.026, respectively) and lower thalamic volume when compared to all other neurodegenerative diseases (p < 0.008). Long-standing MS exhibits comparable global atrophy with lower WMV and thalamic volume when compared to other classical neurodegenerative diseases.

Thalamic white matter in multiple sclerosis: A combined diffusion-tensor imaging and quantitative susceptibility mapping study.

Thalamic white matter (WM) injury in multiple sclerosis (MS) remains relatively poorly understood. Combining multiple imaging modalities, sensitive to different tissue properties, may aid in further characterizing thalamic damage. Forty-five MS patients and 17 demographically-matched healthy controls (HC) were scanned with 3T MRI to obtain quantitative measures of diffusivity and magnetic susceptibility. Participants underwent cognitive evaluation with the Brief International Cognitive Assessment for Multiple Sclerosis battery. Tract-based spatial statistics identified thalamic WM. Non-parametric combination (NPC) analysis was used to perform joint inference on fractional anisotropy (FA), mean diffusivity (MD) and magnetic susceptibility measures. The association of surrounding WM lesions and thalamic WM pathology was investigated with lesion probability mapping. Compared to HCs, the greatest extent of thalamic WM damage was reflected by the combination of increased MD and decreased magnetic susceptibility (63.0% of thalamic WM, peak p = .001). Controlling for thalamic volume resulted in decreased FA and magnetic susceptibility (34.1%, peak p = .004) as showing the greatest extent. In MS patients, the most widespread association with information processing speed was found with the combination of MD and magnetic susceptibility (67.6%, peak p = .0005), although this was not evident after controlling for thalamic volume. For memory measures, MD alone yielded the most widespread associations (45.9%, peak p = .012 or 76.7%, peak p = .001), even after considering thalamic volume, albeit with smaller percentages. White matter lesions were related to decreased FA (peak p = .0063) and increased MD (peak p = .007), but not magnetic susceptibility, of thalamic WM. Our study highlights the complex nature of thalamic pathology in MS.

Thalamus volume and ambulation in multiple sclerosis: a cross-sectional study.

AIM: This cross-sectional study examined if subcortical gray matter (SGM) structures accounted for differences in timed 25-foot walk (T25FW) speed between multiple sclerosis (MS) patients and controls. METHODS: Subjects underwent brain MRI and completed the T25FW. Volumes of the thalamus, caudate, putamen and pallidum were calculated from 3D T1-weighted structural brain images. T2 lesion volume (T2LV) was determined by using a semiautomated edge detection contouring-thresholding technique. RESULTS: There were differences in T25FW speed, SGM volumes and T2LV between MS and controls. T25FW speed was associated with SGM volumes and T2LV in MS and controls. Thalamic volume partially accounted for the difference in T25FW speed between the MS and controls. CONCLUSION: The reduction of thalamus volume is associated with compromised ambulation in MS patients.

Acute effects of walking, cycling, and yoga exercise on cognition in persons with relapsing-remitting multiple sclerosis without impaired cognitive processing speed.

INTRODUCTION: Cognitive impairment is a highly prevalent, disabling, and poorly managed consequence of multiple sclerosis (MS). Exercise training represents a promising approach for managing cognitive impairment in this population. However, there is limited evidence supporting an optimal exercise stimulus for improving cognition in MS. The current study compared the acute effects of moderate-intensity treadmill walking, moderate-intensity cycle ergometry, and guided yoga with those of quiet rest on executive control in 24 persons with relapsing-remitting MS without impaired cognitive processing speed using a within-subjects, repeated measures design. METHOD: Participants completed four experimental conditions that consisted of 20 minutes of moderate-intensity treadmill walking exercise, moderate-intensity cycle ergometer exercise, guided yoga, and quiet rest in a randomized, counterbalanced order. Participants underwent a modified-flanker task as a measure of executive control immediately prior to and following each condition. RESULTS: Repeated measures analyses of variance (ANOVAs) indicated general pre-to-post improvements in reaction time, but not accuracy, on the modified-flanker task for all three exercise modalities compared with quiet rest. However, there were additional, selective pre-to-post reductions in the cost of interfering stimuli on reaction time on the modified-flanker task for treadmill walking, F(1, 23) = 4.67, p = .04, η(p)2 = .17, but not cycle ergometry, F(1, 23) = 0.12, p = .73, η(p)2 < .01, or guided yoga, F(1, 23) = 0.73, p = .40, η(p)2 = .03, compared with quiet rest. CONCLUSIONS: The present results support treadmill walking as the modality of exercise that might exert the largest beneficial effects on executive control in persons with relapsing-remitting MS without impaired cognitive processing speed. This represents an exciting starting point for delineating the appropriate exercise stimulus (i.e., modality and intensity) for inclusion in a subsequent longitudinal exercise training intervention for improving cognitive performance in this population.

Reliability of a cognitive endpoint for use in a multiple sclerosis pharmaceutical trial.

OBJECTIVE: Determine reliability and basic psychometric properties of a composite cognitive endpoint, MS-COG, for monitoring change in cognitive function in MS drug trials. BACKGROUND: 50% of MS patients have cognitive impairment that impacts ability to work and quality of life. We selected neuropsychological tests based on sensitivity to MS cognitive impairment, availability of alternate forms, cross-cultural utility, and feasibility for multicenter trials, and assessed the reliability and validity of a composite endpoint, MS-COG. DESIGN/METHODS: Administered SRT, BVMT-R, PASAT, and SDMT to 60 MS patients at 4 US centers twice over 45days, along with symptom inventories by patients and informants. RESULTS: The MS-COG had test-retest reliability of 0.91. Processing Speed and Memory indices had reliabilities of 0.89 and 0.86, with modest practice effects. Reliability was high for the RR MS and SP MS subgroups as well, with correlations of .90 and .93, respectively for MS-COG. Overall, 42% of subjects obtained MS-COG scores in the impaired range, with SP MS subjects performing 0.8 SD below RR MS subjects. Impairment correlated well (r=0.37 to 0.40) with informant reports but was inconsistent with patient report, with the least reliable assessments by those with greater symptom severity. CONCLUSIONS: The MS-COG is a reliable, repeatable measure of MS cognitive functioning that is sensitive to cognitive impairment in SP MS and RR MS patients and feasible for multicenter clinical trials. Further development is warranted.

Active cognitive reserve influences the regional atrophy to cognition link in multiple sclerosis.

Recent research indicates that cognitive reserve mitigates the clinical expression of neuropsychological impairment in multiple sclerosis (MS). This literature primarily uses premorbid intelligence and lifetime experiences as indicators. However, changes in current recreational activities may also contribute to the maintenance of neural function despite brain atrophy. We examined the moderation effects of current changes in recreational activity on the relationship between brain atrophy and information processing speed in 57 relapsing-remitting MS patients. Current enrichment was assessed using the Recreation and Pastimes subscale from the Sickness Impact Profile. In patients reporting current declines in recreational activities, brain atrophy was negatively associated with cognition, but there was no such association in participants reporting stable participation. The MRI metric-by-recreational activity interaction was significant in separate hierarchical regression analyses conducted using third ventricle width, neocortical volume, T2 lesion volume, and thalamic volume as brain measures. Results suggest that recreational activities protect against brain atrophy's detrimental influence on cognition.

The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects.

The paired thalamic nuclei are gray matter (GM) structures on both sides of the third ventricle that play major roles in cortical activation, relaying sensory information to the higher cortical centers that influence cognition. Multiple sclerosis (MS) is an immune-mediated disease of the human CNS that affects both the white matter (WM) and GM. A number of clinical observations as well as recent neuropathologic and neuroimaging studies have clearly demonstrated extensive involvement of the thalamus, basal ganglia, and neocortex in patients with MS. Modern MRI techniques permit visualization of GM lesions and measurement of atrophy. These contemporary methods have fundamentally altered our understanding of the pathophysiologic nature of MS. Evidence confirms the contention that GM injury can be detected in the earliest phases of MS, and that iron deposition and atrophy of deep gray nuclei are closely related to the magnitude of inflammation. Extensive involvement of GM, and particularly of the thalamus, is associated with a wide range of clinical manifestations including cognitive decline, motor deficits, fatigue, painful syndromes, and ocular motility disturbances in patients with MS. In this review, we characterize the neuropathologic, neuroimaging, and clinical features of thalamic involvement in MS. Further, we underscore the contention that neuropathologic and neuroimaging correlative investigations of thalamic derangements in MS may elucidate not heretofore considered pathobiological underpinnings germane to understanding the ontogeny, magnitude, and progression of the disease process.

Influence of cognitive function on speech and articulation rate in multiple sclerosis.

We examined cognitive predictors of speech and articulation rate in 50 individuals with multiple sclerosis (MS) and 23 healthy controls. We measured speech and articulation rate from audio-recordings of participants reading aloud and talking extemporaneously on a topic of their choice (i.e., self-generated speech). Articulation rate was calculated for each speech sample by removing lexically irrelevant vocalizations and pauses of >200 ms. Speech rate was similarly calculated including pauses. Concurrently, the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery, as well as standardized tests of sentence intelligibility and syllable repetition were administered. Analysis of variance showed that MS patients were slower on three of the four rate measures. Greater variance in rate measures was accounted for by cognitive variables for the MS group than controls. An information processing speed composite, as measured by the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT), was the strongest predictor among cognitive tests. A composite of memory tests related to self-generated speech, above and beyond information processing speed, but not to oral reading. Self-generated speech, in this study, was not found to relate more strongly to cognitive tests than simple reading. Implications for further research are discussed.

Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis.

Information-processing speed (IPS) slowing is a primary cognitive deficit in multiple sclerosis (MS). Basal ganglia, thalamus and neocortex are thought to have a key role for efficient information-processing, yet the specific relative contribution of these structures for MS-related IPS impairment is poorly understood. To determine if basal ganglia and thalamus atrophy independently contribute to visual and auditory IPS impairment in MS, after controlling for the influence of neocortical volume, we enrolled 86 consecutive MS patients and 25 normal controls undergoing 3T brain MRI and neuropsychological testing. Using Sienax and FIRST software, neocortical and deep gray matter (DGM) volumes were calculated. Neuropsychological testing contributed measures of auditory and visual IPS using the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), respectively. MS patients exhibited significantly slower IPS relative to controls and showed reduction in neocortex, caudate, putamen, globus pallidus, thalamus and nucleus accumbens volume. SDMT and PASAT were significantly correlated with all DGM regions. These effects were mitigated by controlling for the effects of neocortical volume, but all DGM volumes remained significantly correlated with SDMT, putamen (r = 0.409, p < 0.001) and thalamus (r = 0.362, p < 0.001) having the strongest effects, whereas for PASAT, the correlation was significant for putamen (r = 0.313, p < 0.01) but not for thalamus. We confirm the significant role of thalamus atrophy in MS-related IPS slowing and find that putamen atrophy is also a significant contributor to this disorder. These DGM structures have independent, significant roles, after controlling for the influence of neocortex atrophy.

Oralmotor slowing in multiple sclerosis: relationship to neuropsychological tasks requiring an oral response.

Although most neuropsychological batteries used with multiple sclerosis (MS) patients now exclude tests that require significant motor writing or manual manipulation speed, many of the most sensitive commonly used cognitive tests nonetheless require some type of rapid oral motor response. The aim of this study is to examine the extent to which primary oral motor articulation speed problems of individuals with MS contribute to performance and group differences on neuropsychological tasks requiring a rapid spoken response. Fifty MS patients and 50 healthy controls were administered the PASAT, COWAT, Animal Naming, and SDMT tests, in addition to a measure of rudimentary oral motor speed known as the maximum repetition rate of syllables and multisyllabic combinations (MRR) task. Regression analyses revealed that the amount of variance accounted for by the group (MS-Control) variable was reduced the following amounts for the tasks when the MRR was entered before the group variable: SDMT, 10% to 6%; PASAT, 4% to 2%; COWAT, 5% to 2%; Animal Naming, 11% to 7%. Our data suggest that rudimentary oral motor speed is slowed in MS patients and makes an important contribution to group differences in performance on commonly used neuropsychological tasks requiring a rapid spoken response.

Multi-site phasic neural activity mediates the execution of an auditory continuous performance task: a PET and electrophysiological study.

BACKGROUND AND PURPOSE: We studied an auditory continuous performance task with positron emission tomography (PET) and EEG-derived current density reconstructions (CDRs) to define the spatial and temporal aspects of auditory attention. METHODS: The CDRs were employed to segregate responses to targets and non-targets at sites identified by PET. We then studied the time course of brain activity using statistical parametric mapping (SPM) of the CDR data. RESULTS: In contrast to target EEG activity, non-targets did not produce significant peaks after 300 ms. Pre-300 ms biphasic activation of auditory, left posterior frontal, left supplemental, and primary motor cortices and the anterior cingulate (AC) and biphasic suppression of posterior cingulate and occipital cortex were identical for targets and non-targets and may mediate the target non-target decision. SPM analysis of post-300 ms CDRs showed cingulate cortices were the first to be reactivated, remained active through 672 ms, and were accompanied by reactivation and deactivation of the same sites observed in the pre-P300 responses. CONCLUSIONS: The cingulate may play an important role in post-decisional activity and control activity at other sites involved in post-decisional cognitive processing.

Functional imaging during covert auditory attention in multiple sclerosis.

Recent literature suggests that the brain in multiple sclerosis (MS) undergoes reorganization that subserves the performance of visual and motor tasks. We identified sites of cerebral activity in 16 MS patients while performing a covert attention (CA) task, presented in the auditory modality. Positron emission tomography (PET) revealed activation of rostral/dorsal anterior cingulate cortex (ACC) in normal subjects studied previously. Activity in this region was not significant in MS patients, but there was a large region of activity in superior temporal cortex. Decreased activation of frontal attentional networks and greater activity in sensory/perceptual cortical areas (auditory association cortex) suggests a reduction of transmission along white matter tracts connecting these regions. This study demonstrates cingulate hypoactivity and cerebral reorganization during auditory attention in MS.

Working memory and processing speed deficits in systemic lupus erythematosus as measured by the paced auditory serial addition test.

As many as 66% of systemic lupus erythematosus (SLE) patients have been reported to have cognitive deficits. These deficits are often associated with information processing speed and working memory. Similarly, processing speed and working memory impairments are the hallmark of cognitive dysfunction in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT) places high demands on processing speed and working memory. Fisk and Archibald, however, demonstrated that the total score of the PASAT does not accurately reflect impairments in these cognitive processes. They found that MS patients used a chunking strategy to obtain correct responses and reduce the cognitive demands of the task. In the present study, PASAT performance was examined for 45 SLE patients and 27 controls using alternative scoring procedures. Although the total number of correct responses did not differ between SLE and controls at the 2.4 or 2.0 s presentation rates, SLE patients had fewer dyads (correct consecutive responses) than controls at the faster rate, and more chunking responses than controls at both rates. Disease activity, disease duration, depression, fatigue, and corticosteroids could not account for these differences. The findings suggest that SLE patients, like MS patients, chunk responses more often than controls, and that this scoring procedure may better reflect the working memory and processing speed deficits present in SLE.

T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study.

CONTEXT: While gray matter T2 hypointensity in multiple sclerosis (MS) has been associated with physical disability and clinical course, previous studies have relied on visual magnetic resonance imaging (MRI) assessments. OBJECTIVE: To quantitatively determine if T2 hypointensity is associated with conventional MRI and clinical findings in MS. DESIGN: Case-control study. SETTING: University-affiliated community-based hospital. SUBJECTS: Sixty patients with MS and 50 controls. MAIN OUTCOME MEASURES: T2 intensities of the substantia nigra, red nucleus, thalamus, putamen, globus pallidus, and caudate; third ventricular width; total brain T1 (hypointense) and T2 (hyperintense) lesion volumes; Expanded Disability Status Scale (physical disability) score; and disease course. RESULTS: Deep gray matter T2 hypointensity was present in patients with MS in all structures (P<.005) except for the substantia nigra. T2 hypointensity was associated with third ventricle enlargement and higher T2 but not T1 plaque load. The regression model predicting third ventricle width included caudate T2 hypointensity (P =.006). The model predicting T2 lesion load included globus pallidus T2 hypointensity (P =.001). Caudate T2 hypointensity was the only variable associated with disability score in regression modeling (P =.03). All T2 hypointensities differentiated the secondary progressive from the relapsing-remitting clinical courses. The final model (P<.001) predicting clinical course retained T2 hypointensity of the thalamus, caudate, and putamen but not MRI plaques or atrophy. CONCLUSIONS: Gray matter T2 hypointensity in MS is associated with brain atrophy and is a stronger predictor of disability and clinical course than are conventional MRI findings. While longitudinal studies are warranted, these results suggest that pathologic iron deposition is a surrogate marker of the destructive disease process.