Recent findings in Lewy body dementia

sao

Poster Presentation:

pi%iJ PROTEIN JosefOrpiszewski, Beckerman,

AGING

Aprot

Juris

HYPOTHESIS

Carp,

J Liepnieks,

Cannel.

Merrill

IN;

OF ALZHEIMER Norbert

D Benson,

Schormann,

Indiana

Univ.

DISEASE Barbara

Indianapolis.

KluveIN

Alzheimer disease (AD), the most common form of aging-related neumdegenerative disorders, is associated with formation of fibrillar deposits of amyloid P-protein (AP). While the direct involvement of AP in AD has been well documented, the relations between AP production, amyloid formation, and neurodegeneration remain unknown. We propose that AD is initiated by a protein-aging-related structural transformation in soluble AP. We hypothesize that spontaneous chemical modification of aspartyl residues in AP to transient succinimide induces a non-native conformation in a fraction of soluble A!3 rendering it amyloidogenic and neurotoxic. Conformationally altered AP is characterized by increased stability in solution and the presence of a non-native p-turn that determines folding of AP in solution and the structure of AP subunits incorporated into amyloid tibrils. While the soluble non-native AP is both the factor triggering the neurodegenerative cascade and the precursor of amyloid plaques, these two events result from interaction of A!3 with different sets of cellular components and need not coincide in space and time. Extensive literature data and experimental evidence are provided in support of this hypothesis. In addition to AD, protein aging and succinimide formation may also underlie other disorders associated with conformational changes in protein including prion diseases.

NON-PHARMACOLOGICAL FOR ALZHEIMER’S DISEASE John R Zeisel, Assoc,

Hearthstone

Cambridjie,

Alzheimer

Care,

COORDINATED

Lexington,

MA;

Paul

TREATMENT

Ruia. Aizheimer’s

MA

The research presented here analyzes and relates the literature on the neuroscience of Alzheimer’b disease as well as non-pharmacological Alzheimer’s treatment practices. We propose that linking brain dysfunction to environmental and communication supports, together with medications and health maintenance constitutes “treatment” for Alzheimer’s disease. This presentation links information on the parts of the brain affected by Alzheimer’s dtsease and the associated functional losses, with a structured ‘Ltreatment” model for the disease based on environmental design and specific care and communication approaches. Affected brain areas include par&al and occipital lobe damage, hippocampal complex damage, frontal lobe damage, and anterior and medial temporal lobe damage. The model takes into account the remaining brain abilities offered by the amygdala and other brain areas that appear to remain more functional well into the disease. Non-pharmacological “treatment” is defined as the coordination of ?lix approaches: 1. Naturally mapped environments that communicate to residents without taxing their brains. 2. Caregiver acceptance of patients definition of their situation. 3. Activities of Daily Living assistance that supports patients feeling of success. 4. Structured activities that develop patient? rense of self and awareness of being in a social setting. 5. Sensory approaches to memory cueing that avoid lost language skills, but rather reflect how patients actually perceive, feel, and process information 6 Self-control caregiver strategies to avoid excess patient agitation and confusion.

ALZHEIMER’S 13621ING VETERAN Brenda L Plassman, Tiffany

N Newman,

Millrnniunt Univ.

David Deborah

Pharmaceuticals,

Baltimore.

IN THE

DISEASE

NAS-NRC

REGISTRY

OF AG-

TWINS C Stejfens,

Kathleen

L Drosdick, Combridge,

Duke

A Welsh-Bohmer, ZJniL,, Durham,

Michurl

J Helms,

NC: Joanne M Meyer,

MA; John C S Breitner,

Johns

Hopkins

MD

We will report findmgs from an ongoing longitudinal study of Alzheimer’s disease (AD) in the NAS-NRC Twin Registry of male WWII veterans. We evaluated these twms for dementia using a multi-stage screening and assessment protocol in 1990-1992 (Wave I) and again in 1993.1995 (Wave II). In Wave 1, the 12,709 men who were screened had a mean age of 67 (s.d. = 2.9) years. In Wave II, 11,160 men were screened for dementia. In Wave I and II, we have identified a total of 72 twin pairs in which at least one member of the pair has AD and for whom zygosity i5 known. Of these, 7 of 35 monozygotic pairs and 7 of 37 dizygotic pairs are concordant for AD. An additional 3 monozygotic and 3 dizygotic pairs are likely concordant, but one member of the pair has somewhat atypical symptoms for AD. Thus, we have postponed classifying them as concordant until follow-up information is obtained. We suspect that the low concordance rates, especially in monozygotic pairs, are due to the relatively young age of the sample. We predict that the concordance rates will increase as the sample approaches the typical age of onset for AD. We analyzed the Wave I data using a multiple threshold model for onset of AD that imputes the degree of genetic liability from the onset age, assuming that greater genetic influence yields earlier onset. We used the MX program to estimate the influence of additive genetic effects (A), shared environment (C) and unique environment (E). Using just the AD

Disease and Related Dementias

Alzheimer’s

II

cases from Wave I, we could reject the null hypotheses of no familial aggregation, but could not demonstrate superior tit of an AE, CE, or ACE model. The data from Wave II are currently being analyzed, and we will present the results of similar modeling analyses in the combined Wave I and Wave 11data. This larger dataset should provide clarification on whether the familial aggregation is due primarily to additive genetic or shared environmental effects.

ROLE 13631

OF FAMILIAL

BRITISH

PEPTIDES

ABRI

IN

DEMENTIA

ASSOCIATED

GLUTAMATERGIC

BRI/

SYNAPTIC

TRANSMISSION.

An&e Chicago,

T Parent,

Seong H Kim,

Chicago,

Stephen

C Meredith,

Sangram

S Sisodia,

Univ

of

IL

Familial British Dementia (FBD) is an autosomal dominant neurodegenerative disorder characterized by progressive dementia, spastic tetraparesis and cerebellar ataxia. Recently, a peptide, termed ABri, was identified as a component of the plaque deposition characteristic of FBD (Nature 399: 776; 1999). ABri and the wild-type equivalent, Bri, are generated by furin-mediated proteolysia of longer precursor protein, termed BRI-L and BRI (mutant and wild-type, respectively). Futhermore, ABri peptides assemble into fibrils (Nature Neurosci., 2: 984; 1999). We hypothesize that production and subsequent deposltion of fibrillogenic ABri peptides initiate the pathological cascades and clinical sequella of FBD. To better understand the biology of Bri and ABri peptides, we have evaluated potential interactions of these molecules with pre and post-synaptic components of glutamate receptors. NMDAIAMPAI kainate receptor-mediated synaptic currents were recorded from pyramidal or Purkinje neurons using whole-cell patch-clamp recordings. Acute application of ABrilBri synthetic peptides (100 nM: 5 min) produced a long-lasting inhibition of NMDA receptor-mediated spontaneous EPSCs. However, Bri application produced a longlasting potentiation of AMPA/kainate receptor-mediated currents, an effect not seen with ABri application. Mini EPSC analysis reveal that application of ABrilBri may also affect the frequency and the amplitude of EPSCs. Intracellular Ca’+ imaging was also performed using Fura- ratioing. An increase in the basal level and frequency of Ca*’ flux was observed following application of synthetic ABri peptides. In addition, treatment of primary neurons with conditioned medium from transfected cells expressing BRI or BRI-L lead to a decrease in the glutamate-induced increase of Ca’+ flux evoked by direct application of glutamate (10 uM; IO xc). Our results indicate that ABri and Bri peptides induce both pre and post-synaptic alterations of glutamatergic responses in hippocampal and cerebellar neuronal populations.

RECENT Michael

Serby,

FINDINGS

V. Hamutunian,

IN LEWY Stevrn

BODY

C Snmuets,

Sch of Medicine,

New

York, NY: Dushwmt

Sch of Medicine.

New

York, NY

DEMENTIA

Adam

P Pwohit,

Brickmon.

Kenneth

The Mount

L Davis,

Mount

Sinal Sinai

We have recently reported a number of clinical and pathological finding\ in Lewy Body Dementia (LBD), the second most common degenerative dementia. The Consensus criteria for the diagnosis of LBD have received widespread acceptance. We performed a meta-analysis of 305 cases from clinicopathologic studies of LBD to verify the frequency of the major criteria, i.e. parkinsonism; the co-occurrence with dementia within 12 months; visual hailucmdtions (VH) and cognitive fluctuations (CF). The data supported parkinsonism and its co-occurrence with dementia as valid criteria; VH and CF, however, were not found to be reliable signs of this disease. We have also reported results of autopsy studies performed at Mount Sinai involving brain specimens from 273 consecutive autopsies of elderly subjects residing in a nursing home. The severity of dementia correlated significantly with the density of lewy bodies (LB), independent of Alzheimers Disease (AD) pathology. We then compared groups of patients with pure LBD, pure AD, and combined LB and AD neuropathology (LBV). Despite similar demographic/clinical characteristics (age at admission to nursing home; age at death; time in home; gender), the LBV group was significantly more demented than AD and LBD, and the LBV brains demonstrated a significantly greater number of LBs than LBD brains. These findings suggest that: (a) there is a need for prospective clinicopathologic studies of dementia to establish a valid criteria set for diagnosis of LBD. (b) LBs contribute to cognitive impairment in the elderly independent of AD. (c) the co-occurrence of AD and LB pathology is associated with a higher number of LBs and a greater degree of dementia than in either process alone.