CAMD GBSC UPDATE - Alzheimer's Association | Alzheimer's ...
The twin approach to brain - behavior relationships in Alzheimer's disease
1
S66 THIRD INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE grees with FAD, and at other codon positions in families with other phenotypes (eg cere bra1 amyloidotic angiopathy). However muta tions in exons 16 and 17 have been absent from the majority of FAD and sporadic AD cases of Caucasian origin examined by this and other groups. Nevertheless, we have recently identified a new FAD pedigree bea ring a mutation in exon 17 of APP. We have documented 1) the presence of the mutation in two deceased family members with autopsy confirmed AD by PCR from paraf fin embedded post-mortem cerebral tissue sections; 2) presence of the mutation in three living clinically affected subjects; and 3) the absence of the mutation in an elderly clinically unaffected neuropathologi tally normal family member by PCR from paraf fin embedded tissue sections. The mutation showed evidence of co-segregation with the FAD phenotype (z=3.49 at O=O.OO). Additional details of the phenotype will be provide. We have also searched for mutations in exon 17 of APP in individuals with related phenotypes such as cerebral haemorrhage with autopsy proven amyloidotic angiopathy and dementia associated with familial strokes and autopsy proven amyloidotic angiopathy so far without success. 258 A TWIN STUDY OF GENETIC AND ENVIRONMENTAL CAUSES OF ALZHEIMER’S DISEASE, J.C.S. Breitner, K.A. Welsh, M.A. Helms and collaborating investigators of the Duke - NAS Twin Studies of AD. Depts of Psychiatry and Community and Family Medicine, Duke University, Durham, NC, & Johns Hopkins Medical Institutions, Baltimore, MD, USA Twin studies can identify both genetic and environmental causes of Alzheimer’s disease (AD). The Mendelian dominant hypothesis of AD suggests that all monozygotic (MZ) co-twins and about half of dizygotic (DZ) co-twins of AD probands are also predisposed to develop AD. It is known from studies of familial aggregation, however, that the age of onset of secondary cases, while correlated with that of the proband, may also vary considerably and is most likely in the 8th or 9th decade. Using previously published quantitative models for AD onset, one can thus predict the rates of concordance for AD in MZ and DZ pairs as a function of the proband’s age at onset and the current age of the pair. This model can be tested against empirical observations from twin studies. In 12 MZ pairs from the Duke - NAS Twin Studies of AD 4 of 12 co-twins appear also to have AD, while 0 of 8 DZ co-twins are affected. The average age of onset for MZ and DZ probands were 60.6 and 61.8 yrs. respectively, while the current agesof the to pair types averages 68 and 67 yrs. The results agree well with the model for MZ pairs (expected concordance .3787, p >.9). Fit also appears good for results of the Norwegian and Swedish twin studies of AD, reported separately: concordance rates are higher, but the samples are older. The lower than expected concordance among DZ pairs may be a statistical fluke (p=.20), or it may reflect epistatic effects resulting in increased variability in onset among DZ pairs. The co-twin control method has advantages for study of environmental risk factors for AD. Unaffected MZ co-twins share identical genetic make-up and (usually) early environmental influences with the proband. Disease discordance or discrepant ages at onset must then result from stochastic or environmental influences. We have now identified 40 MZ pairs (including volunteers) discordant for onset of AD. Full risk factor information for most will be available in July; information from about half this number now suggests that alcohol use and aluminum containing antacids may be positively associated with disease tendency or accelerated onset, while exposure to farm animals (?rural lifestyle) may be negatively related to AD risk (p for each of these 3 factors = .13). 259 THE TWIN APPROACH TO BRAIN - BEHAVIOR RELATIONSHIPS IN ALZHEIMER’S DISEASE, Kk Welsh, J.M. Hoffman, W. M. McDonald, N.L. Earl, & J.C.S. Breitner. Depts of Psychiatry, Radiology, and Medicine, and the Joseph & Kathleen Bryan Alzheimer’s Disease Research Center, Duke University, Durham, N.C., USA, 27710. Brain correlates of Alzheimer’s disease (AD) symptoms may be studied by techniques such as magnetic resonance imaging (MRI) and positron emis- sion tomography (PET), but such studies are complicated by variation in symptom manifestation, brain anatomy, and cerebral physiology. Monozy- gotic (MZ) twin pairs provide ideal matched controls and can reduce var- iance attributable to genetic differences. To illustrate this method, we discuss a pair of MZ twins, concordant for AD, who were studied as part of ongoing AD research in a large twin registry. Both twins presented with mild illness (CDR=O.S) and were followed over four years with serial neurodiagnostic examinations. Standard laboratory tests, brain imaging (MRI) and metabolic studies (FDG-PET) were obtained at entry. Brain volumetric measures were determined for 7 areas (total cortex, lateral ventricles, caudate, putamen, thalamus, hippocampal-amygdala complex, and occipital lobe). Brain metabolism was evaluated in the frontal, tem- poral, parietal, and occipital lobes bilaterally. Twin A had a typical present- ation for AD with prominent memory impairment, progressive course, and later involvement of language and praxis. By contrast, twin B had a less typical presentation dominated from the outset by visuospatial impairments. Brain MRI and neuro-ophthalmologic studies did not reveal structural abnormalities to cause these findings. However, more detailed volumetric and metabolic studies revealed correlates corresponding to the discrepan- cies in cognitive impairment. Against a background of nearly identical regional volumes for many brain structures (total cortical volume, caudate, putamen, and thalamus), the volumes of the occipital cortex and the hip- pocampal-amygdala complex were markedly reduced in twin B. Also, while metabolic reductions were noted in bilateral temporal, parietal and occipi- tal association cortices of both twins, the reduction in twin B was more marked. This pair illustrates the unique capability of twin studies to explore basic brain-behavior relationships. When differences in presentation occur, as in this pair, the study of MZ twins also permits exploration of environ- mental factors as potential determinants of disease manifestation and onset. 260 TWIN CONCORDANCE AND DISCORDANCE FOR VASCULAR DEMENTIA AND DEMENTIA OF THE ALZHEIMER TYPE. A.L.Mina Bergem*, Knut Engedal**, Einar Kringlen*. * Department of Psychiatry, University of Oslo, P.O.Box 85 Vinderen, 0319 Oslo, Norway. ** Department of Geriatric Medicine, Ullevdl hospital, Kirkevn. 166, 0450 Oslo, Norway. 70 twin pairs from a nursing home based sample covering the whole of Norway have been identified and diagnosed. DSM-III-R and NINCDS-ADRA diagnostic crite- ria have been used. The twins are diagnosed indepen- dently by the first and second author, the latter being blind to zygosity of twin pairs. Interrater reliability measured by kappa is 0,93. The probandwise method is applied in calculation of concordance (both twins affected). In the Alzheimer subgroup 85% (11/13) of the identical, monozygotic (MZ) twin pairs are concordant. Among the fraternal, dizy- gotic (DZ) twin pairs 42% (10/24) are concordant. These concordance rates indicate heridity to be amajor risk factor for developing dementia of the Alzheimer type. In the group of vascular demented twins, there is no significant difference in concordance rates between MZ and DZ twin pairs. The large portion of discordant MZ pairs indicates environmental factors to be of importance for developing vascular dementia. Cerebral computertomography (CT) examination is compared with clinical findings. Clinical twin discor- dance does not always correspond to CT findings. Mean age of the total sample is 79 years. Mean age of onset among Alzheimer twins is 73 years. All but 3 cases have late onset. There is no significant diffe- rence in age of onset between MZ and DZ twins nor between concordant and discordant pairs. The mean dis- cordance period is 3,5 years among MZ twins and 8 years among DZ twin pairs. As mean intrapair difference in age of onset is 3 years within concordant MZ pairs and 5 years within concordant DZ pairs, the 2 discordant MZ cotwins are still at high risk, and most of the 14 discordant DZ cotwins have passed their mean high risk period for developing the disease.
Transcript of The twin approach to brain - behavior relationships in Alzheimer's disease
S66 THIRD INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE
grees with FAD, and at other codon positions in families with other phenotypes (eg cere bra1 amyloidotic angiopathy). However muta tions in exons 16 and 17 have been absent from the majority of FAD and sporadic AD cases of Caucasian origin examined by this and other groups. Nevertheless, we have recently identified a new FAD pedigree bea ring a mutation in exon 17 of APP.
We have documented 1) the presence of the mutation in two deceased family members with autopsy confirmed AD by PCR from paraf fin embedded post-mortem cerebral tissue sections; 2) presence of the mutation in three living clinically affected subjects; and 3) the absence of the mutation in an elderly clinically unaffected neuropathologi tally normal family member by PCR from paraf fin embedded tissue sections. The mutation showed evidence of co-segregation with the FAD phenotype (z=3.49 at O=O.OO). Additional details of the phenotype will be provide.
We have also searched for mutations in exon 17 of APP in individuals with related phenotypes such as cerebral haemorrhage with autopsy proven amyloidotic angiopathy and dementia associated with familial strokes and autopsy proven amyloidotic angiopathy so far without success.
258 A TWIN STUDY OF GENETIC AND ENVIRONMENTAL CAUSES OF ALZHEIMER’S DISEASE, J.C.S. Breitner, K.A. Welsh, M.A. Helms and collaborating investigators of the Duke - NAS Twin Studies of AD. Depts of Psychiatry and Community and Family Medicine, Duke University, Durham, NC, & Johns Hopkins Medical Institutions, Baltimore, MD, USA
Twin studies can identify both genetic and environmental causes of Alzheimer’s disease (AD). The Mendelian dominant hypothesis of AD suggests that all monozygotic (MZ) co-twins and about half of dizygotic (DZ) co-twins of AD probands are also predisposed to develop AD. It is known from studies of familial aggregation, however, that the age of onset of secondary cases, while correlated with that of the proband, may also vary considerably and is most likely in the 8th or 9th decade. Using previously published quantitative models for AD onset, one can thus predict the rates of concordance for AD in MZ and DZ pairs as a function of the proband’s age at onset and the current age of the pair. This model can be tested against empirical observations from twin studies. In 12 MZ pairs from the Duke - NAS Twin Studies of AD 4 of 12 co-twins appear also to have AD, while 0 of 8 DZ co-twins are affected. The average age of onset for MZ and DZ probands were 60.6 and 61.8 yrs. respectively, while the current ages of the to pair types averages 68 and 67 yrs. The results agree well with the model for MZ pairs (expected concordance .3787, p >.9). Fit also appears good for results of the Norwegian and Swedish twin studies of AD, reported separately: concordance rates are higher, but the samples are older. The lower than expected concordance among DZ pairs may be a statistical fluke (p=.20), or it may reflect epistatic effects resulting in increased variability in onset among DZ pairs.
The co-twin control method has advantages for study of environmental risk factors for AD. Unaffected MZ co-twins share identical genetic make-up and (usually) early environmental influences with the proband. Disease discordance or discrepant ages at onset must then result from stochastic or environmental influences. We have now identified 40 MZ pairs (including volunteers) discordant for onset of AD. Full risk factor information for most will be available in July; information from about half this number now suggests that alcohol use and aluminum containing antacids may be positively associated with disease tendency or accelerated onset, while exposure to farm animals (?rural lifestyle) may be negatively related to AD risk (p for each of these 3 factors = .13).
259 THE TWIN APPROACH TO BRAIN - BEHAVIOR RELATIONSHIPS IN ALZHEIMER’S DISEASE, Kk Welsh, J.M. Hoffman, W. M. McDonald, N.L. Earl, & J.C.S. Breitner. Depts of Psychiatry, Radiology, and Medicine, and the Joseph & Kathleen Bryan Alzheimer’s Disease Research Center, Duke University, Durham, N.C., USA, 27710.
Brain correlates of Alzheimer’s disease (AD) symptoms may be studied by techniques such as magnetic resonance imaging (MRI) and positron emis- sion tomography (PET), but such studies are complicated by variation in symptom manifestation, brain anatomy, and cerebral physiology. Monozy- gotic (MZ) twin pairs provide ideal matched controls and can reduce var- iance attributable to genetic differences. To illustrate this method, we discuss a pair of MZ twins, concordant for AD, who were studied as part of ongoing AD research in a large twin registry. Both twins presented with mild illness (CDR=O.S) and were followed over four years with serial neurodiagnostic examinations. Standard laboratory tests, brain imaging (MRI) and metabolic studies (FDG-PET) were obtained at entry. Brain volumetric measures were determined for 7 areas (total cortex, lateral ventricles, caudate, putamen, thalamus, hippocampal-amygdala complex, and occipital lobe). Brain metabolism was evaluated in the frontal, tem- poral, parietal, and occipital lobes bilaterally. Twin A had a typical present- ation for AD with prominent memory impairment, progressive course, and later involvement of language and praxis. By contrast, twin B had a less typical presentation dominated from the outset by visuospatial impairments. Brain MRI and neuro-ophthalmologic studies did not reveal structural abnormalities to cause these findings. However, more detailed volumetric and metabolic studies revealed correlates corresponding to the discrepan- cies in cognitive impairment. Against a background of nearly identical regional volumes for many brain structures (total cortical volume, caudate, putamen, and thalamus), the volumes of the occipital cortex and the hip- pocampal-amygdala complex were markedly reduced in twin B. Also, while metabolic reductions were noted in bilateral temporal, parietal and occipi- tal association cortices of both twins, the reduction in twin B was more marked. This pair illustrates the unique capability of twin studies to explore basic brain-behavior relationships. When differences in presentation occur, as in this pair, the study of MZ twins also permits exploration of environ- mental factors as potential determinants of disease manifestation and onset.
260 TWIN CONCORDANCE AND DISCORDANCE FOR VASCULAR DEMENTIA AND DEMENTIA OF THE ALZHEIMER TYPE. A.L.Mina Bergem*, Knut Engedal**, Einar Kringlen*. * Department of Psychiatry, University of Oslo,
P.O.Box 85 Vinderen, 0319 Oslo, Norway. ** Department of Geriatric Medicine, Ullevdl hospital,
Kirkevn. 166, 0450 Oslo, Norway.
70 twin pairs from a nursing home based sample covering the whole of Norway have been identified and diagnosed. DSM-III-R and NINCDS-ADRA diagnostic crite- ria have been used. The twins are diagnosed indepen- dently by the first and second author, the latter being blind to zygosity of twin pairs. Interrater reliability measured by kappa is 0,93.
The probandwise method is applied in calculation of concordance (both twins affected). In the Alzheimer subgroup 85% (11/13) of the identical, monozygotic (MZ) twin pairs are concordant. Among the fraternal, dizy- gotic (DZ) twin pairs 42% (10/24) are concordant. These concordance rates indicate heridity to be amajor risk factor for developing dementia of the Alzheimer type.
In the group of vascular demented twins, there is no significant difference in concordance rates between MZ and DZ twin pairs. The large portion of discordant MZ pairs indicates environmental factors to be of importance for developing vascular dementia.
Cerebral computertomography (CT) examination is compared with clinical findings. Clinical twin discor- dance does not always correspond to CT findings.
Mean age of the total sample is 79 years. Mean age of onset among Alzheimer twins is 73 years. All but 3 cases have late onset. There is no significant diffe- rence in age of onset between MZ and DZ twins nor between concordant and discordant pairs. The mean dis- cordance period is 3,5 years among MZ twins and 8 years among DZ twin pairs. As mean intrapair difference in age of onset is 3 years within concordant MZ pairs and 5 years within concordant DZ pairs, the 2 discordant MZ cotwins are still at high risk, and most of the 14 discordant DZ cotwins have passed their mean high risk period for developing the disease.
