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Biomedical subjects

I R Mackenzie

Publications and source records attributed to I R Mackenzie.

At least 19 recordsLinked to original sources
PubMed2006

Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia.

Frontotemporal lobar degeneration (FTLD) refers to a focal, non-Alzheimer form of cerebral degeneration that encompasses the distinct clinical syndromes of frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA) and semantic dementia. Some patients show tau-based pathological changes and in familial cases mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21. However, many cases are tau-negative, showing instead ubiquitin-immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions and neurites, and in some familial cases UBQ-ir neuronal intranuclear inclusions of a lentiform appearance. Very recently, mutations have been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21. Clinical, pathological and molecular diversity within FTLD highlights the importance of careful examination of clinical-pathological-genetic relationships. This paper reports, for the first time, a clinico-pathological investigation of two FTLD families with PGRN mutations, and compares the clinical characteristics with those of patients studied in the department with MAPT mutations. The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family. Patients with PGRN mutations exhibited phonological deficits, whereas in patients with MAPT mutations language abnormalities, when present in addition to the prominent behavioural disorder, take the form of semantic disturbance. The findings provide compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and PGRN mutations.

Aged↗
PubMed2006

Autosomal dominant dystonia-plus with cerebral calcifications.

OBJECTIVE: To report genealogic, clinical, imaging, neuropathologic, and genetic data from a Canadian kindred with dystonia and brain calcinosis originally described in 1985. METHODS: The authors performed clinical examinations and CT and PET studies of the head and analyzed blood samples. One autopsy was performed. RESULTS: The family tree was expanded to 166 individuals. No individuals were newly affected with dystonia, but postural tremor developed in two. The mean age at symptom onset was 19 years. Eight individuals had dystonia: three focal, one segmental, one multifocal, and three generalized. Seven displayed additional signs: chorea, intellectual decline, postural tremor, and dysarthria. CT studies were performed on five affected and 10 at-risk family members. All affected individuals and eight at-risk individuals had brain calcinosis. PET scans in two individuals showed reduced D(1)- and D(2)-receptor binding and reduced uptake of 6-[(18)F]fluoro-l-dopa. Autopsy of one affected individual showed extensive depositions of calcium in the basal ganglia, thalamus, cerebral white matter, and cerebellum. No specific immunohistochemistry abnormalities were seen. Genome search data showed no evidence of linkage to the previously described loci IBGC1, DYT1, and DYT12. CONCLUSIONS: The phenotype of this family consists of dystonia-plus syndrome. Brain calcium deposits vary in severity and distribution, suggesting that calcifications alone are not entirely responsible for the observed clinical signs. Further studies are needed to elucidate the etiology of this heterogeneous group of disorders.

Adolescent↗
PubMed2006

Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation mimicking a myopathy.

A 71-year-old woman with a family history of amyotrophic lateral sclerosis (ALS) was investigated for symmetrical, proximal limb and abdominal muscle weakness. Initial examination showed mild proximal muscle weakness in the arms and legs, slightly elevated serum creatine kinase (CK) level, and normal electromyographic (EMG) findings. A myopathy was the presumed diagnosis. Over the next year, weakness became severe and tendon reflexes became unelicitable; no upper motor signs were present. EMG then showed acute and chronic denervation and a muscle biopsy showed target fibers and grouped atrophy. DNA analysis revealed a G72C CuZn-superoxide dismutase (SOD1) mutation. Fasciculations were absent throughout the disease. The patient died 53 months after symptom onset and autopsy revealed loss of lower motor neurons (LMN) and SOD1-positive inclusions. This case expands the phenotypic spectrum of ALS associated with SOD1 mutations to include presenting features that mimic a myopathy.

Aged↗
PubMed2003

[Frontotemporal dementia. Results from "Frontotemporal Demential and Pick's Disease Conference"].

At the Frontotemporal Dementia and Pick's Disease Conference, recent data concerning the epidemiology, diagnosis, and therapy of frontotemporal dementia were presented. Topics included clinical manifestations, differential diagnosis, pathologic and genetic bases of the disease, therapy, and specific problems facing patients and care givers. A consensus in the terminology of this condition was sought.

Dementia↗
PubMed2001

Myositis associated graft-versus-host-disease presenting as respiratory muscle weakness.

Myositis associated with graft-versus-host-disease (GVHD) typically presents with proximal muscle weakness, myalgias, and a raised creatinine phosphokinase (CPK) level. We report a case of a 51 year old man who developed respiratory muscle weakness five years after an allogeneic bone marrow transplant for multiple myeloma. His symptoms included tachypnoea, abdominal paradox, and orthopnoea. Pulmonary function tests revealed diminished vital capacity and maximal inspiratory and expiratory pressures. Serum CPK levels were raised and a peripheral muscle biopsy specimen was consistent with GVHD. He improved with immunosuppressive therapy.

Bone Marrow Transplantation↗
PubMed2000

Activated microglia in dementia with Lewy bodies.

To investigate the role of cerebral inflammation in dementia with Lewy bodies (DLB), activated microglial cells were quantified in postmortem brain tissue. Patients with pure DLB (LB but no AD pathology) had significantly greater numbers of cells than nondemented control subjects, but fewer than patients with either pure AD or DLB combined with AD. There was a positive correlation between the numbers of activated microglia and LB in different brain regions. This study demonstrates the presence of significant inflammation in DLB, even in the absence of AD pathology.

Aged↗
PubMed2000

Anti-inflammatory drugs and Alzheimer-type pathology in aging.

Anti-inflammatory drugs have been suggested as a treatment for AD. The authors examined the AD-type pathology in postmortem brain tissue from elderly nondemented individuals who were chronically exposed to anti-inflammatory drugs. The results suggest that 1) these drugs do not affect the formation of either senile plaques or neurofibrillary tangles and 2) nonsteroidal anti-inflammatory drugs may be more effective than steroids in treating AD because of their ability to suppress the microglial activation associated with senile plaques.

Aged↗
PubMed1999

Central neurocytoma: histologic atypia, proliferation potential, and clinical outcome.

BACKGROUND: Although central neurocytomas are considered benign, recent reports suggest that some patients with histologic atypia and/or elevated proliferation potential may have a poor outcome. METHODS: A retrospective review identified 15 cases of central neurocytoma. Clinical follow-up was available for 14 patients. Each tumor was evaluated for the presence of atypical histologic features, including cellular pleomorphism, endothelial proliferation, and necrosis. The proliferation potential was assessed by MIB-1 immunohistochemistry. The correlation among histology, MIB-1 labeling index (MIB-1 LI), and clinical outcome was evaluated. RESULTS: Histologic atypia was identified in 3 tumors (20%). The MIB-1 LI ranged from 0.1% to 6.0%, and 5 cases (33%) had an MIB-1 LI >2%. The correlation between histologic atypia and MIB-1 LI was poor, with only 1 tumor having both atypia and MIB-1 LI >2%. Clinical follow-up ranged from 13 to 255 months postoperatively (mean, 68 months). Although most patients were alive and well at last follow-up, three developed symptomatic recurrence and one died as a result of increased tumor growth. The tumors from all 4 patients with a poor outcome had MIB-1 LI >2%, but only 1 had histologic atypia. CONCLUSIONS: The proliferation potential of central neurocytoma is a useful predictor of clinical outcome, whereas histologic atypia alone is not prognostically significant. It would be appropriate to recognize a subgroup of central neurocytomas with elevated proliferation potential as WHO Grade 2 lesions. The terms "atypical" and "anaplastic" are not appropriate to describe these lesions, as they imply a certain histologic appearance. The most accurate designation would be "proliferating neurocytoma."

Adult↗
PubMed1998

Phenotypic variability of Gerstmann-Sträussler-Scheinker disease is associated with prion protein heterogeneity.

Gerstmann-Sträussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the prion protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.

Adult↗
PubMed1998

Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging.

Anti-inflammatory drugs have been suggested as a possible treatment for Alzheimer's disease (AD). The association of immune proteins and immune-competent microglial cells with senile plaques (SP) in both AD and normal aging suggests that these drugs may be able to modify the course of AD, either by interfering with SP formation or by suppressing the inflammation associated with SP. We compared postmortem brain tissue from elderly, nondemented, arthritic patients with a history of chronic nonsteroidal anti-inflammatory drug (NSAID) use (n = 32, aged 77 +/- 7 years) and nondemented control subjects with no history of arthritis or other condition that might promote the regular use of NSAIDs (n = 34, aged 77 +/- 6 years). In both the NSAID-treated group and control subjects, 59% of patients had some SP. There was no difference between the two groups in the mean number of plaques or in the number of specific SP subtypes (diffuse or neuritic). The degree of neurofibrillary pathology was also similar. Activated microglia were identified using CR3/43, an anti-MHC class II antibody. Both patient age and the presence of SP correlated positively with the number of CR3/43+ microglia (p < 0.02), whereas NSAID use was associated with less microglial activation (p < 0.01). Control patients with SP had almost three times the number of activated microglia as NSAID-treated patients with SP (11 versus 4 cells/mm2, p < 0.02). These results suggest that if NSAID use is effective in treating AD, the mechanism is more likely to be through the suppression of microglial activity than by inhibiting the formation of SP or neurofibrillary tangles.

Aged↗
PubMed1998

Manson's schistosomiasis presenting as a brain tumor. Case report.

Neurological complications arising from schistosomiasis are uncommon, and reports of Manson's schistosomiasis presenting as an intracerebral mass lesion are particularly rare. The authors describe the case of a 26-year-old man with a 3-month history of headaches and visual abnormalities. He had immigrated to Canada from Brazil 4 years previously. The patient's general physical and neurological examinations were unremarkable. Magnetic resonance (MR) imaging revealed an enhancing lesion with surrounding edema and mild mass effect in the right occipital lobe. A stereotactic brain biopsy demonstrated intraparenchymal granulomas surrounding Schistosoma masoni eggs. The patient's symptoms resolved following treatment with praziquantel and steroid medications; follow-up MR imaging yielded normal findings. This case demonstrates that neuroschistosomiasis should be considered when an individual presenting with an intracerebral mass has lived in a region in which this disease is endemic.

Adult↗
PubMed1998

MR in temporal lobe epilepsy: analysis with pathologic confirmation.

PURPOSE: We evaluated the MR findings in patients with temporal lobe epilepsy to determine the predictive value of MR imaging in assessing patient outcome. METHODS: MR studies from 186 of 274 consecutive patients who underwent temporal lobectomy for intractable epilepsy were reviewed retrospectively. Images were interpreted by an experienced neuroradiologist, who was blinded to the side of seizure activity and to pathologic findings. RESULTS: MR imaging exhibited 93% sensitivity and 83% specificity in detecting hippocampal/amygdalar abnormalities (n = 121), and 97% sensitivity and 97% specificity in detecting abnormalities in the rest of the temporal lobe (n = 60). Abnormal high signal of the hippocampus on T2-weighted images had a sensitivity of 93% and specificity of 74% in predicting mesial temporal sclerosis (n = 115). The presence of hippocampal atrophy on MR correlated with the duration of seizures. Sensitivity and specificity of MR imaging in detecting temporal lobe tumors (n = 42) were 83% and 97%, respectively, based on abnormal signal and mass effect. After surgery, 63% of patients were seizure free and 28% had a significant reduction of seizure frequency at an average of 24 months (range, 12 to 78 months) after surgery. Patients with a single lesion in the anterior temporal lobe or hippocampus/amygdala had a better outcome than patients with multiple lesions (n = 22). Interrater agreement varied from 0.4 to 0.93, with best agreement for tumors or abnormal hippocampal signal on T2-weighted images. CONCLUSION: MR imaging is highly sensitive in detecting and locating abnormalities in the temporal lobe and the hippocampus/amygdala in patients with temporal lobe epilepsy. Hippocampal atrophy appears to correspond to the duration of seizure disorder.

Adult↗
PubMed1997

Increased apolipoprotein E epsilon 4 in epilepsy with senile plaques.

Inheritance of the apolipoprotein E (ApoE) epsilon 4 allele is a risk factor for Alzheimer's disease (AD) and is associated with increased deposition of beta-amyloid (A beta) in AD, Down's syndrome, and normal aging. A beta deposition in the form of senile plaques (SPs) has recently been described in patients with temporal lobe epilepsy (TLE). We studied the relationship between ApoE epsilon 4 genotype and the deposition of A beta in temporal lobe tissue from patients who underwent temporal lobectomy for intractable epilepsy. TLE patients with SPs had a 70% ApoE epsilon 4 carrier frequency compared with a 27% carrier frequency among age-matched TLE controls without SPs. Our data suggest that the association between ApoE epsilon 4 and intracerebral A beta accumulation is not unique to the elderly or to those with dementia, and may be a feature of conditions in which there is both an ApoE epsilon 4 allele and over-production of A beta precursor protein, and, presumably, A beta.

Amyloid beta-Peptides↗