Biomedical subjects

Richard Caselli

Publications and source records attributed to Richard Caselli.

5 recordsLinked to original sources

PubMed2006

Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment.

Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports have not examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and non-demented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease.

Aged↗

PubMed2006

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.

Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.

Adult↗

PubMed2006

Steroid-responsive encephalopathy associated with autoimmune thyroiditis.

BACKGROUND: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), often termed Hashimoto encephalopathy, is a poorly understood and often misdiagnosed entity. OBJECTIVE: To characterize the clinical, laboratory, and radiologic findings in patients with SREAT to potentially improve recognition of this treatable entity. DESIGN: Retrospective analysis of clinical features and diagnostic test data. SETTING: Two affiliated tertiary care referral institutions. PATIENTS: Twenty consecutive (6 male) patients diagnosed as having SREAT from 1995 to 2003. MAIN OUTCOME MEASURES: Clinical features and ancillary test findings associated with SREAT. RESULTS: The median age at disease onset was 56 years (range, 27-84 years). The most frequent clinical features were tremor in 16 (80%), transient aphasia in 16 (80%), myoclonus in 13 (65%), gait ataxia in 13 (65%), seizures in 12 (60%), and sleep abnormalities in 11 (55%). All patients were assigned an alternative misdiagnosis at presentation, most commonly viral encephalitis (n = 5), Creutzfeldt-Jakob disease (n = 3), or a degenerative dementia (n = 4). The most frequent laboratory abnormalities were increased liver enzyme levels in 11, increased serum sensitive thyroid-stimulating hormone levels in 11, and increased erythrocyte sedimentation rate in 5. In only 5 patients (25%) did cerebrospinal fluid abnormalities suggest an inflammatory process. Magnetic resonance imaging abnormalities believed to be related to the encephalopathy were present in 5 patients (26%). CONCLUSIONS: The clinical, laboratory, and radiologic findings associated with SREAT are more varied than previously reported. Misdiagnosis at presentation is common. This treatable syndrome should be considered even if the serum sensitive thyroid-stimulating hormone level and erythrocyte sedimentation rate are normal, the cerebrospinal fluid profile does not suggest an inflammatory process, and neuroimaging results are normal. Until the pathophysiologic mechanism of this and other autoimmune encephalopathies is better characterized, we believe that descriptive terms that reflect an association rather than causation are most appropriate for this syndrome.

Adult↗

PubMed2005

Gene expression correlates of neurofibrillary tangles in Alzheimer's disease.

Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.

Aged, 80 and over↗

PubMed2003

Hippocampal sclerosis dementia with tauopathy.

In some elderly individuals with dementia, hippocampal sclerosis (HS) is the only remarkable autopsy finding. The cause of HS in this setting is puzzling, since known causes of HS such as seizures or global hypoxic-ischemic episodes are rarely present. We here describe a series of HS cases that have a widespread neuronal and/or glial tauopathy. Of 14 consecutive cases of HS, 12 had been clinically diagnosed with dementia and/or Alzheimer's disease (AD) while 2 were non-demented; 7 cases had also been clinically diagnosed with parkinsonism. In addition to HS, 6 cases also met pathologic diagnostic criteria for AD. Gallyas silver staining and immunohistochemistry with the AT8 antibody revealed a glial and/or neuronal tauopathy in 12 of 14 cases, with frequent positive neurons and/or glial cells in the neocortex, basal ganglia, thalamus and/or limbic regions; in addition, 8 of the 14 cases had argyrophilic grains. Screening for known tau mutations was negative in all cases. Western blots of sarkosyl-insoluble tau protein showed a mixture of 3- and 4-repeat forms. The results suggest that most cases of HS dementia are sporadic multisystem tauopathies; we suggest the term "hippocampal sclerosis dementia with tauopathy" (HSDT) for these.

Aged↗