Alzheimer disease (AD) is the most common dementing illness in the elderly, but there is equivocal evidence regarding the frequency of other disorders such as Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD), and hippocampal sclerosis (HS). This ambiguity may be related to factors such as the age and gender of subjects with dementia. Therefore, the objective of this study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS among 382 subjects with dementia from the State of Florida Brain Bank and to study the effect of age and gender on these frequencies. AD was the most frequent pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of VaD increased with age, whereas the relative frequencies of FTD and LBD declined with age. Males were overrepresented among those with LBD, whereas females were overrepresented among AD subjects with onset age over 70 years. These estimates of the a priori probabilities of dementing disorders have implications for clinicians and researchers.

We describe four cases of a new clinicopathological entity presenting with either a frontotemporal dementia or corticobasal degeneration syndrome with a mean age of onset of 45 years (range 41-50) characterized pathologically by deposition of neurofilament proteins. All four patients had a rapidly progressive course and have become mute and non-ambulatory, and three have died after mean illness duration of only 3 years (range 2 1/2 -4). Both structural (MRI) and functional (PET and SPECT) imaging demonstrated frontal and temporal lobe and basal ganglia involvement. Gross neuropathological examination in the three deceased patients (the fourth patient, still alive, was diagnosed by brain biopsy) revealed changes affecting predominantly the frontal and temporal cortices, basal ganglia and brainstem. There was superficial linear spongiosis affecting the frontal lobes in all three autopsied patients, and severe caudate atrophy was noted in two of them and demonstrated on MRI in the living patient. On routine staining, there were numerous intracytoplasmic inclusions, which ranged from eosinophilic to basophilic. Some had a clearly defined basophilic margin, while others were granular with a hyaline core. With modified Bielschowsky silver technique, a small number of the inclusions were intensely stained. Inclusions were not labelled with other silver stains. Immuno histochemistry revealed that the inclusions were immunoreactive with antibodies to neurofilament heavy and light chain subunits and to ubiquitin, but not with antibodies to tau and alpha-synuclein. These neurofilament- and ubiquitin-positive inclusions were widespread, specific to neurons and occasionally intranuclear. The frequency and distribution of the inclusions and the silver and immunohistochemical profiles in these four cases is novel and has not been described in detail before. We propose the term neurofilament inclusion body disease for this entity.

Antiepileptic drugs (AEDs) are frequently used to treat seizures in glioma patients. AEDs may have an unrecognized impact in modulating O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that has an important role in tumor cell resistance to alkylating agents. We report that levetiracetam (LEV) is the most potent MGMT inhibitor among several AEDs with diverse MGMT regulatory actions. In vitro, when used at concentrations within the human therapeutic range for seizure prophylaxis, LEV decreases MGMT protein and mRNA expression levels. Chromatin immunoprecipitation analysis reveals that LEV enhances p53 binding on the MGMT promoter by recruiting the mSin3A/histone deacetylase 1 (HDAC1) corepressor complex. However, LEV does not exert any MGMT inhibitory activity when the expression of either p53, mSin3A, or HDAC1 is abrogated. LEV inhibits malignant glioma cell proliferation and increases glioma cell sensitivity to the monofunctional alkylating agent temozolomide. In 4 newly diagnosed patients who had 2 craniotomies 7-14 days apart, prior to the initiation of any tumor-specific treatment, samples obtained before and after LEV treatment showed the inhibition of MGMT expression. Our results suggest that the choice of AED in patients with malignant gliomas may have an unrecognized impact in clinical practice and research trial design.

This study demonstrated that additional improvements in the established criteria for DLBD are needed. Our empirically derived criteria enhanced the distinction of DLBD from AD while allowing the clinician the choice of maximizing sensitivity with acceptable specificity, and vice versa.