S1-04-05

Oral O1-01: D&CC (Molecular Pathology/Hispathological) Lewy body diseases together with Dementia with Lewy bodies (DLB), which is characterized by PD changes and widespread Lewy bodies and neurites in the cerebral isocortex and diencephalic nuclei. Mutations in the a-synuclein gene are associated with autosomal dominant PD and DLB, whereas mutations of genes the products of which are involved in the degradation of a-synuclein and proteins linked with PD, such as parkin and ubiquitin C-terminal hydrolase -1 (UCHL-1), are associated with sporadic, autosomal dominant or autosomal recessive Lewy body diseases. Cases with early PD changes restricted to the medulla oblongata, pons and olfactory bulb are considered pre-clinical PD. Recent studies have shown that lipoxidative and glycoxidative stress damage precedes a-synuclein aggregation in the frontal cortex in pre-clinical PD. Target proteins are synucleins and proteins related with mitochondria and redox homeostasis. Oxidative stress damage varies with disease progression in the frontal cortex in DLB. a-synuclein in Lewy body diseases is nitrated, phosphorylated and has an abnormal configuration. These modifications are associated with abnormal protein-protein interactions, mainly with rab proteins and phospholipases, which result in reduced transport of synaptic vesicles to pre-synaptic sites, and conduct to impaired activity of type I metabotropic glutamate receptors, respectively. Aggregates of a-synuclein and associated proteins are considered the result of impaired function of the ubiquitin-proteasome-system (UPS). Our observations in transgenic mice and modified cell lines have shown no modifications in the expression levels of the proteasome and in enzymatic proteasomal activities. However, UCHL-1 mRNA and protein levels are reduced in parallel with a-synuclein aggregates in Lewy body diseases, thus implicating down-regulation of UCHL-1 in the pathogenesis of sporadic PD and DLB. S1-04-04

DEMENTIA WITH LEWY BODIES

Ian McKeith, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. Contact e-mail: [email protected] Background: Dementia with Lewy Bodies (DLB) is a common cause of dementia in older people but is still associated by many clinicians with uncertainty about diagnosis and mangement . Accurate clinical diagnosis of DLB is justified by the specific functional disabilities, care needs and responses to pharmacological treatments of this group compared with other dementias. Objective(s): To review recent guidelines about the clinical and pathological diagnosis of DLB. Methods: The DLB International Consortium published revised methods for diagnosis and management in December 2005. No major amendments to the three core features of DLB are proposed, but better methods for measurement of symptom severity are recommended. A new category of features “suggestive” of DLB is described comprising, REM sleep behaviour disorder (RBD), severe neuroleptic sensitivity, and abnormal dopamine transporter neuro-imaging imaging. If one or more of these suggestive features is present, in addition to one or more core features, a diagnosis of probable DLB is made. Possible DLB can be diagnosed if one or more is present in a patient with dementia even in the absence of any core features. The revised criteria are also more explicit about the importance to be attached to clinical and radiological evidence of cerebrovascular disease since pathological and imaging studies suggest that white matter lesions (periventricular and deep white matter), microvascular changes and lacunes may frequently be present. For the purposes of assessing Lewy-related pathology, the latest recommendation is to use alpha-synuclein immunohistochemistry and a semi-quantitative grading of lesion density rather than the counting methods previously proposed. The pattern of regional involvement is more important than total LB count. The guidelines have also been modified to address the issue of concomitant Alzheimer type pathology to take account of the pathoplastic effect that this has upon the clinical presentation. Finally a patient management outline is offered including behavioural and pharmacological components and acknowledging that in the absence of substantial RCT evidence the recommendations are largely based upon expert opinion. Conclusions: New diagnostic criteria and management guidelines for DLB are now available for clinical use and further research and evaluation should be widely disemminated.

S1-04-05

S7

NEUROPATHOLOGY OF FRONTOTEMPORAL DEMENTIA

David G. Munoz, University of Toronto, Toronto, ON, Canada. Contact e-mail: [email protected] Background: The frontotemporal dementias (FTD) or Pick complex constitute a group of diseases characterized by focal atrophy preferentially involving the anterior lobes of the brain in a bilateral asymmetrical fashion. Some patients present with behavioral disturbances, whereas others manifest language impairments, either non-fluent primary progressive aphasia or semantic dementia. Objective(s): To determine the probability of the association of a given syndrome with a histological substrate. Methods: Study of our own 60 case series, supported by review of the literature. Conclusions: Diseases with tau cytoplasmic neuronal inclusions-Pick’s disease and corticobasal degeneration- represent nearly half of all cases, and are the most common cause of primary progressive aphasia. Cases with ubiquitin only -motor neuron disease type- cytoplasmic inclusions are the most common substrate of FTD overall, and especially in cases with behavioral or semantic dementia presentations. A subgroup with autosomal dominant disease transmission is characterized by additional intranuclear ubiquitin inclusions. S1-04-06

ALZHEIMER’S DISEASE WITH AMYGDALA LEWY BODIES: A DISTINCT FORM OF LEWY BODY DISEASE

Dennis Dickson, Hirotake Uchikado, Mayo Clinic, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: Lewy bodies (LBs) are ␣-synuclein-immunoreactive neuronal inclusions with a predilection for specific cortical and subcortical regions, including the amygdala. Objective(s): In this study the presence of LBs was assessed in 347 cases of AD. Methods: In 87 cases, LBs were frequent and associated with neuronal loss in vulnerable brainstem nuclei; these cases had diagnostic features of brainstem (N⫽3), transitional (N⫽32) or diffuse (N⫽52) Lewy body disease (LBD). The remaining 260 cases of “pure” AD were screened for amygdala LBs (AD/ALB), and 62 (24%) cases were found. If AD/LBD are included, LBs were detected in 149 (43%) cases of AD. The presence of ␣-synuclein pathology was assessed in multiple brain regions in the 62 cases of AD/ALB and in 57 randomly selected cases of AD, and only sparse ␣-synuclein pathology was detected in both. Results: The burden of ␣-synuclein pathology in brainstem nuclei, amygdala and neocortex was significantly lower in AD/ALB than in AD/LBD. In comparison to AD and AD/LBD, AD/ALB did not differ in age at death, disease duration, male-to-female ratio, brain weight, Braak neurofibrillary tangle stage, average senile plaque density or apolipoprotein E ⑀4 allele frequency. No clinical differences were detected between AD/ALB and AD. Conclusions: The results suggest that AD/ ALB is clinically similar to AD, but pathologically different from AD/ LBD, suggesting that it is a neuropathologically distinct and isolated ␣-synucleinopathy. SUNDAY, JULY 16, 2006 ORAL O1-01 D&CC (MOLECULAR PATHOLOGY/HISPATHOLOGICAL) O1-01-01

SYNAPTIC ALTERATIONS IN INFERIOR TEMPORAL LOBE IN ALZHEIMER’S DISEASE (AD) AND MILD COGNITIVE IMPAIRMENT (MCI)

Stephen W. Scheff1, Douglas A. Price1, Frederick A. Schmitt1, Julie A. Schneider2, David A. Bennett2, Steven T. DeKosky3, Elliot J. Mufson2, 1University of Kentucky, Lexington, KY, USA; 2Rush Presbyterian/St. Luke’s Medical Center, Chicago, IL, USA; 3University of Pittsburgh, Pittsburgh, PA, USA. Contact e-mail: [email protected]