Multiple sclerosis (MS) is postulated to be a cell mediated autoimmune disease directed against central nervous system myelin components. Our understanding of the disease has been enhanced by a number of factors: 1) advances in our understanding of the immune system; 2) clinical trials which are beginning to identify treatments which can affect MS; 3) a better understanding of the clinical features of MS; and 4) advances in MRI imaging of the brain. Based on the current state of knowledge, this paper proposes a 21 point unifying hypothesis on the etiology and treatment of the disease. This hypothesis makes a series of assumptions, many of which are unproven, and is presented as a framework from which to investigate and treat the disease, not as a established biology. It is hypothesized that the underlying pathogenesis of MS is related to an inappropriate class of immune response against myelin antigens favoring proinflammatory Th1 versus anti-inflammatory Th2 or Th3 type responses. Environmental and genetic factors predispose toward MS by affecting the class of response and effectiveness of treatment is also related to how it impacts on this common final pathway. Because of epitope spreading, there is not one autoantigen involved in MS and the progressive form of MS differs immunologically from the relapsing remitting form. Viruses trigger and perpetuate MS, although MS is not related to a persistent viral infection. Because MS is a multifactorial disease, there are clinical and perhaps immunological subtypes of MS and a single type of treatment is unlikely to control the disease in all patients. Thus, there will be responders and non-responders to each effective therapy and ultimately combination therapy will be required to cure the disease.

Good cognitive performance requires adherence to rules specific to the task at hand. Patients with neurological disease often make rule violation (RV) errors, but the anatomical basis for RV during cognitive testing remains debated. The present study examined the neuroanatomical correlates of RV errors made on tests of executive functioning in 166 subjects diagnosed with neurodegenerative disease or as neurologically healthy. Specifically, RV errors were voxel-wisely correlated with gray matter volume derived from high-definition magnetic resonance images using voxel-based morphometry implemented in SPM2. Latent variable analysis showed that RV errors tapped a unitary construct separate from repetition errors. This analysis was used to generate factor scores to represent what is common among RV errors across tests. The extracted RV factor scores correlated with tissue loss in the lateral middle and inferior frontal gyri and the caudate nucleus bilaterally. When a more stringent control for global cognitive functioning was applied using Mini Mental State Exam scores, only the correlations with the right lateral prefrontal cortex (PFC) remained significant. These data underscore the importance of right lateral PFC in behavioral monitoring and highlight the potential of RV error assessment for identifying patients with damage to this region. (JINS, 2009, 15, 354–364.)

The purpose of this study was to examine the relationships between lobar volumes and set shifting. We studied 101 subjects, including 36 normal controls, 16 patients with probable Alzheimer's disease, 30 patients with frontotemporal dementia (FTD), and 19 patients with semantic dementia (SD), using a shifting paradigm that carefully controlled for component abilities. Subjects were administered two conditions of the Delis–Kaplan Executive Function System (D-KEFS) Design Fluency Test. In the control condition (DF:Control), examinees generated as many unique designs as possible in 60 s by drawing lines connecting only unfilled dots. In the switching condition (DF:Switch), examinees generated designs by drawing lines alternating between filled and unfilled dots. We used BRAINS2 software to generate volumes of the right and left frontal, temporal, and parietal lobes. Partial correlations and multiple regressions showed that, after controlling for Mini-Mental State Examination and DF:Control, only the right and left frontal lobe volumes significantly correlated with the DF:Switch, most clearly in the FTD and SD groups. Follow-up analyses indicated that frontal contributions to shifting were not related to working memory. Results highlight the importance of carefully controlling for component cognitive processes when studying executive functioning. (JINS, 2007, 13, 386–392.)

This study tested the hypothesis that the hippocampus has a relatively specific role in retaining information over delays. Thirty-seven subjects with probable Alzheimer's disease were evaluated with a verbal memory task and structural MRI. Cortical gray matter but not hippocampal volume predicted immediate free recall. In contrast, hippocampal volume was the best predictor of how well information was retained over a delay, even after controlling for levels of immediate recall. Results suggest that the role of the hippocampus is relatively specific to the consolidation of new memories. (JINS, 2004, 10, 639–643.)