more genes that are in the deleted region.”Dr. St. Clair and others explained that

these microdeletions can be inherited oroccur de novo (as new mutations) at con-ception, which is why someone can de-velop schizophrenia without any familyhistory. That these mutations occur at ahigh rate in the population (about onepercent) could explain why the incidenceof schizophrenia remains at one percent,even though many patients do not go onto have children of their own.

The genes they linked to schizophre-nia seem to have a variety of functions inbrain development and neuronal signal-ing. “These findings establish beyond adoubt that genetic abnormalities cancause schizophrenia and they explain whysome cases seem sporadic because thereis no family history,” Dr. St. Clair added.

In an additional data set of 3,285 casesand 7,951 controls, the association waseven stronger. Seven of 4,213 cases hadone of the chromosome 15 deletions(15q13.3) compared to 8 of 39,800 con-trols. One of the genes in this region is the

alpha-7 nicotinic receptor gene that the au-thors said is “targeted to axons by neureg-ulin 1, and has been implicated in bothschizophrenia and mental retardation.”

The International Schizophrenia Con-sortium (ISC) found genetic deletions as-sociated with schizophrenia in chromo-somes 1,15, and 22. “As a group, these

may be rare events, but individually thesecopy number variants may confer a largeincreased risk for schizophrenia,” saidShaun Purcell, PhD, of MassachusettsGeneral Hospital, who led the study.

He said that people with large dele-tions in these regions may have a ten-foldincreased risk for schizophrenia. Thelargest effect was found on chromosome22, with a 20-fold increased risk.

Dr. Lehner remains optimistically cau-tious about these findings. “We are still miss-ing the environment and other factors thatinfluence how these genes are expressed.”He suspects that complex psychiatric con-ditions, including schizophrenia, are disor-ders of genetic dysregulation that work in

concert with environmental triggers. “We now have the technology and the

large sample sizes. In a few years, we willhave the answers.” •

30 | | NEUROLOGY TODAY | OCTOBER 2, 2008

REFERENCES:• Stefansson H, Rujescu D, Steffans-

son, et al., for the SGENE Consor-tium. Large recurrent microdele-tions associated with schizophre-nia. Nature 2008;455:232-236.

• International Schizophrenia Con-sortium. Rare chromosomal dele-tions and duplications increase riskof schizophrenia. Nature 2008;455:237-241.

SchizophreniaContinued from page 28

The neuropathology of dementia incognitively impaired people, 90-107 years old, appears different

from that of 60-to 80 year old dementedpatients, a new study published in theSeptember Archives of Neurology reports.

The study, led by Vahram Haroutun-ian, PhD, professor of psychiatry and di-rector of clinical and biological studies ofearly AD at the Mount Sinai School ofMedicine, set out to explore the relation-ship between cognitive dysfunction andneurofibrillary tangles (NFTs) and neu-ritic plaques (NPs) — the hallmark le-sions of Alzheimer disease and dementiain the elderly.

The investigators examined post-mortem tissue of 317 people, grouped byage at death — the youngest-old (60-80years), middle-old (81-89 years), and old-

est-old (90-107 years). They compareddata on severity of dementia — measuredby the Clinical Dementia Rating (CDR)scale — and the density of NPs and NFTs.[A CDR score of 0 means nondemented,0.5 is questionably demented, and 1 to 5reflects increasing levels of severity of de-mentia.]

STUDY FINDINGSInvestigators observed increased NP andNFT densities in postmortem brain tissueof moderately to severely demented 60-to 80-year-olds (with CDR scores of 2-5),but not in those older than 90 years —even when the oldest-old had CDR scoresindicating marginal or mildest dementia,Dr. Haroutunian said.

The data were reported as the ratio ofNP and NFT densities in each dementiaand age category relative to the densitiesof NPs and NFTs in the same age groupwith no significant dementia.

Dr. Haroutunian noted that the non-demented oldest subjects did not havegreater NP and NFT lesion densities thantheir younger counterparts.

EXPERTS COMMENT David S. Knopman, MD, professor of neu-rology at the Mayo Clinic College of Med-

icine in Rochester, MN, who was not in-volved in the study, said he was im-pressed by the data. He noted, however,that the oldest cognitively-intact (normal)group may have a much higher burden ofAD pathology than the 60- to 80-year-oldnormals, so the ratio of the amount of le-sions in the normal group to the lesionsin the severely demented group is atten-uated in the oldest-old.

The difference in the ratios is entirelydriven by the very small amount of ADpathology in young normals, even though

the amount in the demented group wasalmost the same. In other words, olderpeople have more AD pathology even ifnot demented, and therefore there is lessof a parallel of AD pathology and severityof clinical evidence of dementia. That inturn affects how the different age groupscan be compared. (Higher disease burdenmeans more pathology: more plaques andtangles.)

He pointed out that in the current studyless AD pathology was seen with severe de-mentia in the oldest group. As noted by theauthors, he said, the oldest people hadother pathology, such as occlusive mi-crovascular disease and synaptic loss thatcould be attributed to aging or other dis-eases, reducing the threshold for cognitiveimpairment; that is, less AD pathology wascould lead to severe dementia.

William E. Klunk, MD, PhD, professorof psychiatry and neurology at the Uni-

Neuropathology of Dementia Differs Across AgeGroups — Less Pathology Evident in Oldest AgesB y E l i z a b e t h S t u m p

ARTICLE IN BRIEF

� The neuropathology of dementia in cognitively

impaired people, 90-107 yearsold, appears different from thatof 60-to 80 year old dementedpatients — there are increasedNP and NFT lesion densities inyounger demented people butthis increase in densities is absentin the demented oldest patients.

Continued on page 32

‘These findings establish beyond adoubt that genetic abnormalities cancause schizophrenia and they explainwhy some cases seem sporadic be-cause there is no family history.’

DR. THOMAS LEHNER: “Thesefindings are all exciting but wedon’t have definite answers yet.We need to take a comprehen-sive look at all the factors thatcontribute to schizophrenia.”

DR. VAHRAM HAROUTUNIANsaid that the current age-associatedscale may have to be reconsideredbecause the association may notbe linear — instead, the associationof NPs and NFTs with age and de-mentia may only hold up to a cer-tain age, such as 85.

versity of Pittsburgh, said he drew dif-ferent conclusions from the data than didthe authors.

He plotted the lesion data by CDRscore and found that in those aged 90 andolder, there is a clear increase in NPs inthose with scores of CDR 0-1 — the mostclinically important range, because the di-agnosis of AD and the initiation of treat-ment almost always occurs in these stages— and in NFTs from stages with CDRscores 0.5-5, which was very similar tothe pattern is seen in the younger groups.

“The most striking differences I candiscern in the oldest age group are alower ceiling for plaque (NP) countabove CDR 3 and a higher NFT count inthe non-demented (CDR=0) group,” hesaid. (Lower ceiling means that theplaque count in the 90 and older grouplevels off at lower numbers of plaquesthan seen in the 60- to 80-year-oldgroup.) In other words, the clinical sever-ity and pathological severity run parallelfor a while and then severity of pathol-ogy hits a maximal level.

“The lower plaque ceiling may be dueto the expected lower prevalence of

apolipoprotein E 4 [ApoE4, the AD riskgene] in this very late-onset group — thatis, ApoE4 causes earlier onset and heav-ier plaque burden, thus the younger ADgroup has a higher plateau,” Dr. Klunksaid. “The higher NFT count in the old-est non-demented subjects is also notsurprising given the well-known increaseof limbic NFTs with age in non-de-mented cohorts.”

Dr. Klunk agreed with the study’s sug-gestion that there may be other physio-logical and molecular substrates of de-mentia that have yet to be uncovered inthe very old. It makes “great sense thatother factors that allow or add to the ex-pression of clinical symptoms accumu-late with age,” he said.

In response to Dr. Klunk’s comments,Dr. Haroutunian said that it is true thatdespite the lack of significant increase inlesion density, there was an association,albeit small, between CDR and NP andNFT density.

“This was within the context of veryfew lesions even in the maximally de-mented subjects,” Dr. Haroutunian said.“As noted astutely by Dr. Klunk, this as-sociation does raise the question of lesionthreshold. It is quite possible that thedensity of lesions needed to impair cog-nition in the oldest-old may be substan-tially less than the necessary lesion load

for cognitive impairment in those 60- to80-year- olds. This is why we suggest re-evaluating the contribution of age to thecriteria for the neuropathological diag-nosis of AD in the oldest-old.”

The current age-associated scale mayhave to be reconsidered because the as-sociation may not be linear — instead,the association of NPs and NFTs with ageand dementia may only hold up to a cer-tain age, such as 85, Dr. Haroutuniansaid.

Dr. Knopman agreed, adding: “De-mentia is a clinical diagnosis, and thepathological basis for the dementia, whilecritical for therapeutic decisions, shouldnot change the way dementia is diag-nosed.”

The study raises the key issue of theapproach to therapy, he said, suggestingthat “anti-AD therapies may be less spe-cific for persons over age 90.” •

32 | | NEUROLOGY TODAY | OCTOBER 2, 2008

Researchers have identified mole-cular mutations in cell receptorsassociated with dopamine in

two inherited forms of epilepsy — one arare form of the disease that causessleep-related seizures and the other, avery common type of juvenile epilepsy.

In two small studies published in theSept. 9 Neurology, researchers in Australiaand Sweden used PET and specially irra-diated molecules (radioligands) to exam-ine defects in binding and signaling ac-tivity associated with dopamine delivery.One team looked at dopamine defects inpatients with autosomal dominant noc-turnal frontal lobe epilepsy (ADNFLE),and the other in patients with juvenilemyoclonic epilepsy (JME).

Ligands are molecules that interactwith proteins by binding to specific re-ceptors on cell membranes. In thedopamine transport system, these ligandreceptors include D1, D2, and D3. The de-velopment of receptor-specific radioli-gands have enabled scientists to look moreclosely than ever before at the dopamin-ergic system in different parts of the brain.

NOCTURNAL FRONTAL LOBE EPILEPSYIn the first paper, a team led by MarcoFedi, MD, and David C. Reutens, MD, atMonash Medical Center in Victoria, Aus-tralia, examined a mutation of presynap-tic neuronal nicotinic acetylcholine(nACh) binding in 12 patients with AD-NFLE, which causes sudden convulsionsduring sleep. They compared dopaminelevels in different parts of the brain andcompared them with those in a similargroup of normal controls.

Specifically, the team zeroed in on a spe-cific mutation (a4-Ser248Phe), known to beinvolved in nACh binding, and measuredextracellular dopamine at the D1 receptorsite, a key transfer point for dopamine in thestriatum and putamen. Patients with the

Images of [11C]-SCH23390 binding demonstrating reduced striatal D1receptor binding in 12 subjects with the alpha4-Ser248Phe mutationcompared to 19 healthy volunteers. The voxel-based analysis detecteda cluster of reduced [11C] SCH23390 binding in patients with autoso-mal dominant nocturnal frontal lobe epilepsy in the right putamen.

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Dopamine System Defects Implicated in Two Forms of Epilepsy B y K u r t S a m s o n

ARTICLE IN BRIEF

� Investigators in Australiaand Sweden used PET and

specially irradiated molecules(radioligands) to examine de-fects in binding and signalingactivity associated withdopamine delivery in patientswith autosomal dominant noc-turnal frontal lobe epilepsy andjuvenile myoclonic epilepsy.

Continued on page 33

Neuropathology, DementiaContinued from page 30

REFERENCE:• Haroutunian V, Schnaider-Beeri M,

Schmeidler J, et al. Role of the neu-ropathology of Alzheimer Diseasein dementia in the oldest-old. ArchNeurol 2008;65(9):1211-1217.

DR. WILLIAM KLUNK agreedwith the study’s suggestion thatthere may be other physiologicaland molecular substrates of de-mentia that have yet to be unco-vered in the very old.