David Mann

CLAC: a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC‐P/collagen type XXV

We raised monoclonal antibodies against senile plaque (SP) amyloid and obtained a clone 9D2, which labeled amyloid fibrils in SPs and reacted with ∼50/100 kDa polypeptides in Alzheimers disease (AD) brains. We purified the 9D2 antigens and cloned a cDNA encoding its precursor, which was a novel type II transmembrane protein specifically expressed in neurons. This precursor harbored three collagen‐like Gly–X–Y repeat motifs and was partially homologous to collagen type XIII. Thus, we named the 9D2 antigen as CLAC (collagen‐like Alzheimer amyloid plaque component), and its precursor as CLAC‐P/collagen type XXV. The extracellular domain of CLAC‐P/collagen type XXV was secreted by furin convertase, and the N‐terminus of CLAC deposited in AD brains was pyroglutamate modified. Both secreted and membrane‐tethered forms of CLAC‐P/collagen type XXV specifically bound to fibrillized Aβ, implicating these proteins in β‐amyloidogenesis and neuronal degeneration in AD.

A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

IMPORTANCEnWhile mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.nnnOBJECTIVEnTo establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.nnnSETTINGnEleven centers from sites around the world performing genotyping.nnnPARTICIPANTSnSeven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.nnnMAIN OUTCOME MEASURESnFrequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores.nnnCONCLUSIONS AND RELEVANCEnMutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

The clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships

Accuracy of clinical diagnosis of dementia is increasingly important for therapeutic and scientific investigations. In this study, we examine diagnostic accuracy in a consecutive series of 228 patients referred to a specialist early-onset dementia clinic, whose brains were subsequently examined at post-mortem. Diagnosis was based on structured history, neurological examination and neuropsychological assessment, with emphasis on qualitative as well as quantitative aspects of performance. Neuroimaging provided support for but did not alter the clinical diagnosis. We set out the principles that guided diagnosis: (i) time course of illness; (ii) weighting of physical, behavioural and cognitive symptoms and signs; (iii) anterior versus posterior hemisphere character of cognitive change; and (iv) specificity of deficit, paying attention to the differentiation between syndromes of frontotemporal lobar degeneration and focal forms of Alzheimers disease. Forty-two per cent of the patients had clinical diagnoses of one of the syndromes of frontotemporal lobar degeneration, the high proportion reflecting the research interests of the group. Forty-six per cent were diagnosed with Alzheimers disease and the remaining patients, dementia with Lewy bodies, Creutzfeldt-Jakob disease, vascular or unclassified dementia. Frontotemporal lobar degeneration was identified with 100% sensitivity and 97% specificity and Alzheimers disease with 97% sensitivity and 100% specificity. Patients with other pathologies were accurately identified on clinical grounds. Examination of subsyndromes of frontotemporal lobar degeneration showed a relatively predictable relationship between clinical diagnosis and pathological subtype. Whereas the behavioural disorder of frontotemporal dementia was associated with tau, transactive response DNA binding protein 43 and fused-in-sarcoma pathology, cases of frontotemporal dementia with motoneuron disease, semantic dementia and, with one exception, progressive non-fluent aphasia were associated with transactive response DNA binding protein 43 pathology, distinguished by ubiquitin subtyping (types B, C and A, respectively). Clinical diagnoses of progressive apraxia, corticobasal degeneration and progressive supranuclear palsy were, with one exception, associated with Pick, corticobasal and progressive supranuclear palsy subtypes of tau pathology, respectively. Unanticipated findings included Alzheimer pathology in two patients presenting with the behavioural syndrome of frontotemporal dementia and corticobasal pathology in four others with clinical frontotemporal dementia. Notwithstanding such anomalies, which serve as a reminder that there is not an absolute concordance between clinical phenotype and underlying pathology, the findings show that dementias can be distinguished in life with a high level of accuracy. Moreover, careful clinical phenotyping allows prediction of histopathological subtype of frontotemporal lobar degeneration. The principles guiding diagnosis provide the foundation for future prospective studies.

Cognitive Phenotypes in Alzheimer's Disease and Genetic Risk

Variation in the clinical characteristics of patients with Alzheimers disease (AD) is increasingly recognised, although the factors underlying variation are not fully understood. The study examined the cognitive characteristics of 523 AD patients at the time of their presentation to a neurological dementia clinic and explored the relationship to family history and apolipoprotein E (APOE) genotype. Distinct profiles were identified, which were mirrored by topographical differences on neuroimaging. Clinical distinctions were maintained over time. Two-thirds of patients showed a constellation of deficits at presentation which included memory, language, visuospatial and constructional difficulties. However, a quarter had circumscribed presentations of amnesia, aphasia, perceptuospatial disorder or apraxia. The rare presence of frontal lobe characteristics was associated with a younger age of onset, an increased incidence of myoclonus at presentation, a positive family history but not with possession of APOE epsilon4 allele. An amnestic presentation (severe, yet circumscribed amnesia) was strongly associated with an older age of onset, a positive family history and the presence of APOE epsilon4 allele. Posterior cortical presentations showed a female bias, were typically sporadic, and showed no association with APOE epsilon4. The findings support the notion of phenotypic variation in AD, and show that genetic risk factors can influence clinical presentation. The findings draw attention to the specific association between APOE epsilon4 allele and memory but challenge the commonly held notion that the presence of the epsilon4 allele inevitably reduces onset age. The findings indicate that risk factors other than APOE epsilon4 allele underlie the non-familial, early onset posterior hemisphere presentations of AD.

Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations

Two hundred and twenty-three consecutive patients fulfilling clinical diagnostic criteria for frontotemporal lobar degeneration (FTLD), and 259 patients with motor neuron disease (MND), for whom genomic DNA was available, were investigated for the presence of mutations in tau (MAPT) and progranulin (PGRN) genes. All FTLD patients had undergone longitudinal neuropsychological and clinical assessment, and in 44 cases, the diagnosis had been pathologically confirmed at post-mortem. Six different PGRN mutations were found in 13 (6%) patients with FTLD. Four apparently unrelated patients shared exon Q415X 10 stop codon mutation. However, genotyping data revealed all four patients shared common alleles of 15 SNPs from rs708386 to rs5848, defining a 45.8-kb haplotype containing the whole PGRN gene, suggesting they are related. Three patients shared exon 11 R493X stop codon mutation. Four patients shared exon 10 V452WfsX38 frameshift mutation. Two of these patients were siblings, though not apparently related to the other patients who in turn appeared unrelated. One patient had exon 1 C31LfsX34 frameshift mutation, one had exon 4 Q130SfsX130 frameshift mutation and one had exon 10 Q468X stop codon mutation. In addition, two non-synonymous changes were detected: G168S change in exon 5 was found in a single patient, with no family history, who showed a mixed FTLD/MND picture and A324T change in exon 9 was found in two cases; one case of frontotemporal dementia (FTD) with a sister with FTD+MND and the other in a case of progressive non-fluent aphasia (PNFA) without any apparent family history. MAPT mutations were found in 17 (8%) patients. One patient bore exon 10 + 13 splice mutation, and 16 patients bore exon 10 + 16 splice mutation. When PGRN and MAPT mutation carriers were excluded, there were no significant differences in either the allele or genotype frequencies, or haplotype frequencies, between the FTLD cohort as a whole, or for any clinical diagnostic FTLD subgroup, and 286 controls or between MND cases and controls. However, possession of the A allele of SNP rs9897526, in intron 4 of PGRN, delayed mean age at onset by approximately 4 years. Patients with PGRN and MAPT mutations did not differ significantly from other FTLD cases in terms of gender distribution or total duration of illness. However, a family history of dementia in a first-degree relative was invariably present in MAPT cases, but not always so in PGRN cases. Onset of illness was earlier in MAPT cases compared to PGRN and other FTLD cases. PNFA, combined with limb apraxia was significantly more common in PGRN mutation cases than other FTLD cases. By contrast, the behavioural disorder of FTD combined with semantic impairment was a strong predictor of MAPT mutations. These findings complement recent clinico-pathological findings in suggesting identifiable associations between clinical phenotype and genotype in FTLD.

Apolipoprotein E υ4 Allele Frequency in Vascular Dementia

Aim: The aim of the study was to investigate whether possession of the υ4 allelic form of the apolipoprotein E (APOE) gene increases the risk of developing vascular dementia (VaD). Methods:APOE allele and genotype frequencies were determined by PCR in 89 patients with possible and probable VaD and compared with those in 97 patients with possible and probable Alzheimer’s disease (AD) of similar age of disease onset and ethnic background, and with 766 control subjects drawn from the same geographical region. Results: The APOE υ4 allele frequency in all 97 patients with possible and probable AD was significantly higher (p < 0.001) than that in control subjects. However, the APOE υ4 allele frequency in all 89 patients with possible and probable VaD was also significantly higher (p < 0.001) than that in control subjects, but not significantly different from that in AD. The APOE υ4 allele frequency was similarly, and still significantly (p < 0.001), increased when only those patients with probable AD or probable VaD were considered. Conclusion: Possession of APOE υ4 allele increases the risk of VaD.

Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease

Consistent deficits in the cholinergic system are evident in Alzheimers disease (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine receptors in the brains of AD patients. Knockout mice for the beta2 subunit have impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2 respectively, for genetic associations with late-onset AD. A significant association for disease was observed for a non-coding polymorphism in CHRNB2 (odds ratio=0.57, 95% confidence interval=0.35-0.95, P=0.024). Replication analysis was performed in two further sample sets. While these did not individually yield significant results, a significant association remained when all samples were pooled (odds ratio=0.70, 95% confidence interval=0.52-0.95, P=0.019). These data suggest that this variant warrants further examination in large case-control series.

Analysis of the hexanucleotide repeat in C9ORF72 in Alzheimer's disease.

Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has recently been shown that the most common genetic cause of FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in C9ORF72. To investigate whether this expansion was specific to the FTLD/ALS disease spectrum, we genotyped the hexanucleotide repeat region of C9ORF72 in a large cohort of patients with Alzheimers disease (AD). A normal range of repeats was found in all cases. We conclude that the hexanucleotide repeat expansion is specific to the FTLD/ALS disease spectrum.

Interleukin-6 promoter polymorphism: risk and pathology of Alzheimer's disease

Inflammatory and immune responses are involved in the pathogenesis of Alzheimers disease (AD). Interleukin-6 (IL-6), an inflammatory cytokine, is thought to play a role in neurodegeneration of the central nervous system and has been associated with increased amyloid precursor protein expression in vitro and greater cognitive decline. Previously a C-174G polymorphism in the promoter of IL-6, which influences expression in vitro, has been found associated in some studies but not all. We investigated this polymorphism in a large independent UK sample of AD cases (n = 356) and controls (n 434) but found no association. We extended the study to genotype/phenotype correlations but found no correlation with age of onset (n = 338), brain amyloid load (n = 126) or Tau load (n = 101), brain microglial cell load (n = 65) or brain reactive astrocytes (n = 127). Our data do not support a pathogenic role in AD for the C-174G polymorphism in isolation.

Psychosis, C9ORF72 and dementia with Lewy bodies

Hexanucleotide repeat expansions in the C9ORF72 gene are an important cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis.1 ,2 Whether they have a role in other conditions remains unclear.3 ,4 We previously identified in FTD a strong association between repeat expansions in C9ORF72 and the presence of psychosis.4 This raises the question whether C9ORF72 expansions might also have a role in dementia with Lewy bodies (DLB), in which hallucinations and delusions are prevalent. The study addressed this question.nnThe cohort comprised 102 consecutive patients who fulfilled criteria for ‘probable DLB’, exhibiting at least two of the cardinal features: fluctuating …