Changes in fall-related mortality in older adults in Quebec, 1981-2009.

INTRODUCTION: Our purpose was to evaluate changes in fall-related mortality in adults aged 65 years and over in Quebec and to propose a case definition based on all the causes entered on Return of Death forms. METHODS: The analysis covers deaths between 1981 and 2009 recorded in the Quebec vital statistics data. RESULTS: While the number of fall-related deaths increased between 1981 and 2009, the adjusted falls-related mortality rate remained relatively stable. Since the early 2000s, this stability has masked opposing trends. The mortality rate associated with certified falls (W00-W19) has increased while the rate for presumed falls (exposure to an unspecified factor causing a fracture) has decreased. CONCLUSION: For fall surveillance, analyses using indicators from the vital statistics data should include both certified falls and presumed falls. In addition, a possible shift in the coding of fall-related deaths toward secondary causes should be taken into account.

TITRE: Évolution de la mortalité associée aux chutes chez les personnes âgées au Québec, 1981 à 2009. INTRODUCTION: Cette étude a pour objectif d'apprécier l'évolution de la mortalité associée aux chutes chez les adultes de 65 ans et plus au Québec et de proposer une définition de cas reposant sur l'ensemble des causes inscrites sur les bulletins de décès. MÉTHODOLOGIE: L'analyse porte sur les décès survenus entre 1981 et 2009, enregistrés dans le fichier des décès québécois. RÉSULTATS: Bien que le nombre de décès reliés à une chute se soit accru entre 1981 et 2009, le taux ajusté de mortalité associée aux chutes est demeuré relativement stable. Depuis le début des années 2000, cette stabilité camoufle des tendances opposées. Le taux de mortalité associé aux chutes certifiées (W00-W19) s'est accru, alors que celui associé aux chutes présumées (exposition à un facteur non précisé causant une fracture) s'est réduit. CONCLUSION: Pour la surveillance des chutes, les analyses effectuées à l'aide d'indicateurs utilisant le fichier des décès devraient inclure ces deux catégories. Par ailleurs, un glissement possible de la codification des décès dus aux chutes vers les causes secondaires devrait être pris en compte.

Founder mutation for α-sarcoglycan-LGMD2D in a Magdalen Islands Acadian cluster.

BACKGROUND: We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence. METHODS: Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region. RESULTS: All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c. 229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22. CONCLUSION: The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XIXth century, largely by Acadian immigrants.

Pituitary choriocarcinoma in an adolescent male: tumor-derived CG and GH delay diagnosis.

BACKGROUND: Primary intracranial germ cell tumors usually present in the first two decades of life, often with precocious puberty. The most common location is in the pineal gland; suprasellar germ cell tumors are rare. We present an additional case of a suprasellar choriocarcinoma producing GH, and review the literature. CASE: This French Canadian, 17 year-old male presented to the ER with a history of mild weight loss and an episode of syncope while hiking in Mexico, but with no other neurological symptoms. Puberty began at age 13 years (growth spurt: 15-16 years), and he attained an adult height within genetic target by age 16 years. Past medical history was negative except for myopia diagnosed during childhood. System review revealed increased thirst and nocturia. The mother was treated for an oligo-astrocytoma in 2007. Clinical examination showed a euthyroid, well-looking young man with 20 ml testicles. Endocrine evaluation revealed elevated testosterone, mildly elevated PRL, borderline low FT4, and decreased IGF-I, morning cortisol and urine osmolality; tumor markers were positive in serum and CSF (hCG>50 IU/L, AFP>10 ng/mL). A transphenoidal biopsy of a 4.5 cm, homogeneous, non-calcified, suprasellar mass was compatible with the diagnosis of choriocarcinoma and stained intensely for hCG and hGH, presumably the placental variant (GH-V) as previously found in vitro in choriocarcinoma cell lines. Combined chemotherapy and irradiation led to tumor regression and undetectable serum hCG to 36 months of follow-up. He is doing well with no evidence of tumor progression and is on complete hormone replacement therapy. CONCLUSIONS: Choriocarcinomas can have a hormonal profile that delays the development of symptoms, due to hCG stimulation of both the gonadal and thyroid axes. This report corroborates previous in vitro evidence that choriocarcinoma cells are able to make GH-V. To what extent the patient's tumor-derived GH contributed to his normal growth is not known. Prognosis for this intracranial neoplasm is very reserved, although combined radiotherapy and chemotherapy has been successful in our patient now 36 months post-diagnosis.

A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13-p12.

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of pathologies. We have identified a cohort of 14 French-Canadian patients from eight different families displaying a novel form of LGMD with an autosomal recessive inheritance. These patients share some features with previously described cases of 'quadriceps myopathy' that evolved into an LGMD. All demonstrate quadriceps femoris asymmetrical atrophy. Creatine kinase values were variable from normal to 6000 U/l. Clinical evaluations and MRI studies demonstrate a variable intrafamilial and interfamilial phenotype. Asymmetrical muscle involvement was clinically observed and confirmed by imaging. MRI studies suggest that the hamstrings and the adductor magnus are the first limb muscles to demonstrate fatty infiltration. Muscle pathology shows no sign of active inflammation but increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization. A genome-wide scan using the two largest families uncovered linkage to marker D11S1360 on chromosome 11p12 [multipoint logarithm of the odds (LOD) score of 2.78]. Further genotyping for the eight families confirmed linkage to this new LGMD locus (multipoint LOD score of 4.56). Fine mapping subsequently defined a less than 3.3 cM candidate interval on 11p13-p12. Haplotype analysis of carrier chromosomes suggests that the most frequent mutation may account for up to 81.3% of French-Canadian mutations. In this study, we describe the chromosomal locus of a new form of recessive LGMD with prominent quadriceps femoris atrophy.

A new form of congenital muscular dystrophy with joint hyperlaxity maps to 3p23-21.

Congenital muscular dystrophies (CMDS) are a heterogeneous group of disorders. A growing number of CMDS have been found to be associated with joint hyperlaxity. We recruited 14 French-Canadian cases belonging to 11 families affected by a novel autosomal recessive congenital muscular dystrophy with hyperlaxity (CMDH). All cases come from the southwestern part of Quebec, suggesting a new French-Canadian founder effect. All patients present muscle weakness, proximal contractures coexisting with distal joint hyperlaxity. Pathological and genetic studies have excluded that mutations in the three genes coding for collagen VI subunits are responsible for this disease. A genome-wide scan established linkage of two CMDH families to a region on chromosome 3p23-21. Further linkage analysis confirmed that all families are linked to the same region (log of the odds score of 5.3). Haplotype analysis defines a 1.6-cM candidate interval and suggests that two common mutations may account for 78% of carrier chromosomes. This study describes and maps a new form of recessive CMD with joint hyperlaxity distinct from Ullrich and Bethlem myopathies with a founder effect in the French-Canadian population.

Cellular distribution of insulin-like growth factor-II/mannose-6-phosphate receptor in normal human brain and its alteration in Alzheimer's disease pathology.

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a multifunctional membrane glycoprotein, which binds different classes of ligands including IGF-II and M6P-bearing lysosomal enzymes. Besides participating in the process of endocytosis this receptor functions in the trafficking of lysosomal enzymes from the trans-Glogi network (TGN) or the cell surface to lysosomes. In Alzheimer's disease (AD) brain, marked overexpression of certain lysosomal enzymes in vulnerable neuronal populations and their association to beta-amyloid (Abeta) containing neuritic plaques has been correlated to altered metabolic functions. In the present study, we measured the levels of IGF-II/M6P receptor and characterized its distribution profile in selected regions of AD and age-matched normal postmortem brains. Western blot analysis revealed no significant alteration in the levels of IGF-II/M6P receptor either in the hippocampus, frontal cortex or cerebellum between AD and age-matched control brains. However, a significant gene dose effect of apolipoprotein E (APOE) epsilon4 allele on IGF-II/M6P receptor levels was evident in the hippocampus of the AD brain. At the cellular level, immunoreactive IGF-II/M6P receptors were localized in the neurons of the frontal cortex, hippocampus and cerebellum of control brains. In AD brains, the labeling of the neurons was less intense in the frontal cortex and hippocampus than in the age-matched control brains. Additionally, IGF-II/M6P receptor immunoreactivity was observed in association with a subpopulation of Abeta-containing neuritic plaques as well as tau-positive neurofibrillary tangles both in the frontal cortex and the hippocampus. Reactive glial cells localized adjacent to the plaques also occasionally exhibited IGF-II/M6P receptor immunoreactivity. These results, when analyzed in context of the established role of the IGF-II/M6P receptor in the regulation of the intracellular trafficking of lysosomal enzymes, suggest that alterations in IGF-II/M6P receptor levels/distribution are possibly associated with altered functioning of the lysosomal enzymes and/or loss of neurons observed in AD brains, especially in patients carrying APOE epsilon4 alleles.

Fetal magnetic resonance imaging in the prenatal diagnosis of cerebellar hemorrhage.

We report the case of a fetus with a sonographic mid-gestation diagnosis of hyperechogenic cerebellum suspected to be of hemorrhagic origin on fetal brain magnetic resonance imaging (MRI). No etiological factors for fetal hemorrhage were found other than a maternal heterozygocity for factor V Leiden. Following termination of the pregnancy, autopsy confirmed the prenatal diagnosis of massive cerebellar hemorrhage without underlying vascular anomaly. As an additional tool to ultrasonography, fetal brain MRI can affirm the hemorrhagic origin of hyperechogenic cerebellar lesions, especially by showing a high signal on T1-weighted images.

Long term effects of a home visit to prevent childhood injury: three year follow up of a randomized trial.

OBJECTIVE: To assess the long term effect of a home safety visit on the rate of home injury. DESIGN: Telephone survey conducted 36 months after participation in a randomized controlled trial of a home safety intervention. A structured interview assessed participant knowledge, beliefs, or practices around injury prevention and the number of injuries requiring medical attention. SETTING: Five pediatric teaching hospitals in four Canadian urban centres. PARTICIPANTS: Children less than 8 years of age presenting to an emergency department with a targeted home injury (fall, scald, burn, poisoning or ingestion, choking, or head injury while riding a bicycle), a non-targeted injury, or a medical illness. RESULTS: We contacted 774 (66%) of the 1172 original participants. A higher proportion of participants in the intervention group (63%) reported that home visits changed their knowledge, beliefs, or practices around the prevention of home injuries compared with those in the non-intervention group (43%; p<0.001). Over the 36 month follow up period the rate of injury visits to the doctor was significantly less for the intervention group (rate ratio = 0.74; 95% CI 0.63 to 0.87), consistent with the original (12 month) study results (rate ratio = 0.69; 95% CI 0.54 to 0.88). However, the effectiveness of the intervention appears to be diminishing with time (rate ratio for the 12-36 month study interval = 0.80; 95% CI 0.64 to 1.00). CONCLUSIONS: A home safety visit was able to demonstrate sustained, but modest, effectiveness of an intervention aimed at improving home safety and reducing injury. This study reinforces the need of home safety programs to focus on passive intervention and a simple well defined message.

Quality of information on risk factors reported by ski patrols.

OBJECTIVE: To determine the reliability of reporting of information on risk factors from a standard accident report form used by ski patrols and a follow up mail questionnaire or telephone interview among injured skiers and snowboarders. SETTING: 19 ski areas in the Canadian province of Quebec between November 2001 and April 2002. PARTICIPANTS: 4377 injured skiers and snowboarders seen by the ski patrol, who completed a follow up mail questionnaire or telephone interview. MAIN OUTCOME MEASURES: Kappa and weighted kappa statistics were used to measure the chance corrected agreement for self reported ability, age, skiing time on day of injury, lessons, type of practice, use of helmet at time of injury, and hill difficulty. RESULTS: The kappa value for helmet use at the time of injury was 0.88 (95% confidence interval 0.87 to 0.90) and for other risk factors ranged from 0.45 (skiing time on day of injury) to 0.98 (age). Few differences were seen in reporting by body region of injury. Reporting consistency was lower for respondents who completed telephone interviews compared with those who completed mail questionnaires and those who responded more than four months after the injury. CONCLUSIONS: Moderate to almost perfect agreement, depending on the risk factor, exists between ski patrols' accident report forms and follow up information. Ski patrol reports can be a reliable and readily available source of information on risk factors for skiing and snowboarding.

Coexistence of reactive plasticity and neurodegeneration in Alzheimer diseased brains.

Alzheimer's disease (AD) is a pathological process characterized by neuron degeneration and, as recently suggested, brain plasticity. In this work, we compared the reactive plasticity in AD brains associated to O-glycosydically linked glycans, recognized by lectins from Amaranthus leucocarpus (ALL) and Macrobrachium rosenbergii (MRL), and the tau neuritic degeneration. The neuritic degenerative process was evaluated by the quantification of aggregated neuritic structures. Lesions were determined using antibodies against hyperphosphorylated-tau (AD2), amyloid-beta, and synaptophysin. In these conditions, we classified and quantified three pathological structures associated to the neuritic degenerative process: 1) Amyloid-beta deposits (AbetaDs), 2) Classic neuritic plaques (NPs), and 3) Dystrophic neurites clusters (DNCs) lacking amyloid-beta deposits. Reactive plasticity structures were constituted by meganeuritic clusters (MCs) and peri-neuronal sprouting in neurons of the CA4 region of the hippocampus, immunoreactive to synaptophysin (exclusively in AD brains) and GAP-43. Besides, MCs were associated to sialylated O-glycosydically linked glycans as determined by positive labeling with ALL and MRL. Considering that these lectins are specific for the synaptic sprouting process in AD, our results suggest the co-occurrence of of several areas of reactive plasticity and neuron degeneration in AD.

The pathological basis of temporal lobe epilepsy in childhood.

OBJECTIVE: To characterize the pathologic findings of temporal lobe epilepsy (TLE) in children undergoing temporal lobectomy for refractory seizures and to correlate these findings with clinical presentation. METHODS: The authors reviewed the charts of all children who underwent anterior temporal lobectomy for refractory TLE from 1979 through 1999. A new neuropathologic analysis was performed blinded to clinical features and outcome. RESULTS: Twenty-two children met inclusion criteria. Mean age at onset of epilepsy was 3 years, 7 months (range 1 month to 10 years). Mean age at surgery was 10 years, 11 months (range 1 to 18 years). All patients had complex partial seizures, 48% with secondary generalization. Most had daily seizures. Auras were reported in 45% of patients. Post-resection follow-up averaged 5 years, 2 months (range 2 to 19 years). Seizure-free status was achieved in 41% of patients, and 14% had residual auras only. The most frequent neuropathologic abnormalities were cortical dysplasia (CD) of the temporal neocortex (14 of 22) and mesial temporal sclerosis (MTS) (12 of the 15 children with available hippocampal tissue). These two findings coexisted in seven children. MTS was associated with extra-hippocampal pathology in 8 of 12 (67%) of the cases. CONCLUSIONS: MTS occurs frequently in association with CD in this population of children. The high incidence of dual pathology could explain the early age of seizure onset and high seizure frequency rate observed. TLE in childhood may constitute a different entity than in adults, from both the clinical and neuropathologic perspectives.

The effectiveness of a home visit to prevent childhood injury.

OBJECTIVE: To examine the effectiveness of a home visit program to improve home safety and decrease the frequency of injury in children. We examined the effects of the program on 1) parental injury awareness and knowledge; 2) the extent that families used home safety measures; 3) the rate of injury; and 4) the cost effectiveness of the intervention. DESIGN: A randomized, controlled trial. SETTING: A multicenter trial conducted at 5 hospitals in 4 Canadian urban centers. PARTICIPANTS: Children <8 years old, initially enrolled in an injury case-control study, were eligible to participate. Intervention. Subsequent to a home inspection conducted to determine baseline hazard rates for both groups, participants in the intervention group received a single home visit that included the provision of an information package, discount coupons, and specific instruction regarding home safety measures. MAIN RESULTS: The median age was 2 years, with males comprising ~60% of participants. The experimental groups were comparable at outset in terms of case-control status, age, gender, and socioeconomic status. Parental injury awareness and knowledge was high; 73% correctly identified injury as the leading cause of death in children, and an intervention effect was not demonstrated. The adjusted odds ratios (ORs) for the home inspection items indicated that significant safety modifications only occurred in the number of homes having hot water not exceeding 54 degrees C (OR: 1.31, 95% confidence interval [CI]: 1.14, 1.50) or the presence of a smoke detector (OR: 1.45, 95% CI: 0.94, 2.22). However, the intervention group reported home safety modifications of 62% at 4 months and significantly less injury visits to the doctor compared with the nonintervention group (rate ratio: 0.75; 95% CI: 0.58, 0.96). The total costs of care for injuries were significantly lower in the intervention group compared with the nonintervention group with a cost of $372 per injury prevented. CONCLUSIONS: An intervention using a single home visit to improve the extent to which families use safety measures was found to be insufficient to influence the long-term adoption of home safety measures, but was effective to decrease the overall occurrence of injuries. Future programs should target a few, well-focused, evidence-based areas including the evaluation of high-risk groups and the effect of repeated visits on outcome.

Neuropathology of NFHgp160 transgenic mice expressing HIV-1 env protein in neurons.

The physiopathology of HIV-1 dementia remains largely hypothetical. Although several sets of evidence point towards an indirect multicellular inflammatory pathway, gp120, one of the HIV-1 env products, was shown to be very cytotoxic for neurons in vitro. To explore a direct pathway in the physiopathology of dementia in AIDS, we developed transgenic mouse models carrying the HIV-1 env proteins gp 120 and gp 41 (gp 160) under the control of the human light neurofilament and murine heavy neurofilament promoters. To date, this is the first mouse model in which the HIV-1 env protein can be detected in neurons by immunohistochemistry. The expression is found in several brainstem and spinal cord gray structures and in the cerebellum in one of the mouse lines bearing the NFHgp160 transgene. The morphological findings at 3 months are subtle and are dominated by a watery, dendritic degeneration and a reactive gliosis. At 12 months, the evidence of neuronal degeneration and loss is present along with various degenerative phenomena involving synapses, dendrites and axons, including axonal swellings. Cytoskeletal abnormalities were found by immunohistochemistry. Chronic inflammation was also observed in the leptomeninges of the spinal cord and brainstem and in the cerebellar white matter. These models thus offer an exciting sequence of morphological findings initiated by the neuronal expression of the HIV-1 env proteins and offer a different tool to explore the neuronal dysfunction in AIDS.

O-Glycosylation in sprouting neurons in Alzheimer disease, indicating reactive plasticity.

Reactive plasticity, including axonal and dendritic sprouting and reactive synaptogenesis, has been proposed to contribute to the pathogenesis of several neurological disorders. This work was aimed at identifying the possible role of protein glycosylation in the brain from patients with Alzheimer disease (AD), using lectin histochemistry, as determinants of reactive plasticity. Results indicate an increase in the production of cryptic O-glycosidically linked proteins (NeuAcalpha2,6 Galbeta1,3GalNAcalpha1,0 Ser/Thr or sialyl-T-antigen) in neuritic sprouting in AD brains as determined by positive labeling with Amaranthus leucocarpus (ALL, T-antigen-specific) and Macrobrachium rosenbergii (MRL, specific for NeuAc5,9Ac2) lectins. Immunohistochemistry indicated that lectin staining was specific for the synaptic sprouting process (meganeurites) in AD. These results were confirmed using anti-synaptophysin and anti-GAP 43 antibodies, which recognized meganeurites and dystrophic neurites around amyloid-beta deposits. In normal control brains, labeling with the aforementioned lectins was restricted to microvessels. Control experiments with neuraminidase-treated brain samples revealed positivity to the lectin from Arachis hypogaea (PNA), which is specific for galactose. Our results suggest specific O-glycosylation patterns of proteins closely related to neuronal plasticity in AD.

Surface characteristics, equipment height, and the occurrence and severity of playground injuries.

OBJECTIVES: To evaluate whether surface characteristics (absorption level (g-max), material) and the height of play equipment are related to the occurrence and severity of injuries from falls. SETTING AND METHODS: During the summers of 1991 and 1995, conformity of play equipment to Canadian standards was assessed in a random sample (n = 102) of Montreal public playgrounds. Surface absorption (g-max) was tested using a Max Hic instrument and the height of equipment was measured. Concurrently, all injuries presenting at the emergency department of Montreal's two children's hospitals were recorded and parents were interviewed. Inspected equipment was implicated in 185 injuries. The g-max measurements (1995 only) were available for 110 of these playground accidents. RESULTS: One third of falls (35 %) occurred on a surface exceeding 200 g and the risk of injury was three times greater than for g level lower than 150 (95% confidence interval (CI) 1.45 to 6.35). On surfaces having absorption levels between 150 g and 200 g, injuries were 1.8 times more likely (95% CI 0.91 to 3.57). Injuries were 2.56 times more likely to occur on equipment higher than 2 m compared with equipment lower than 1.5 m. Analysis of risk factors by severity of injury failed to show any positive relationships between the g-max or height and severity, whereas surface material was a good predictor of severity. CONCLUSIONS: This study confirms the relationships between risk of injury, surface resilience, and height of equipment, as well as between type of material and severity of injury. Our data suggest that acceptable limits for surface resilience be set at less than 200 g, and perhaps even less than 150 g, and not exceed 2 m for equipment height. These findings reinforce the importance of installing recommended materials, such as sand, beneath play equipment.

Insulin-like growth factor-I and its receptor in the frontal cortex, hippocampus, and cerebellum of normal human and alzheimer disease brains.

Assimilated evidence indicates that the neurotoxic potential of amyloid beta (Abeta) peptide and an alteration in the level of growth factor(s) may possibly be involved in the loss of neurons observed in the brain of patients suffering from Alzheimer disease (AD), the prevalent cause of dementia in the elderly. In the present study, using receptor binding assays and immunocytochemistry, we evaluated the pharmacological profile of insulin-like growth factor-I (IGF-I) receptors and the distribution of IGF-I immunoreactivity in the frontal cortex, hippocampus, and cerebellum of AD and age-matched control brains. In control brains, [(125)I]IGF-I binding was inhibited more potently by IGF-I than by Des(1-3)IGF-I, IGF-II or insulin. The IC(50) values for IGF-I in the frontal cortex, hippocampus, and cerebellum of the normal brain did not differ significantly from the corresponding regions of the AD brain. Additionally, neither K(D) nor B(max) values were found to differ in the hippocampus of AD brains from the controls. At the regional levels, [(125)I]IGF-I binding sites in the AD brain also remained unaltered compared to the controls. As for the peptide itself, IGF-I immunoreactivity, in normal control brains, was evident primarily in a subpopulation of astrocytes in the frontal cortex and hippocampus, and in certain Purkinje cells of the cerebellum. In AD brains, a subset of Abeta-containing neuritic plaques, apart from astrocytes, exhibit IGF-I immunoreactivity. These results, taken together, suggest a role for IGF-I in compensatory plasticity and/or survival of the susceptible neurons in AD brains.

Ataxin 1 and ataxin 3 in neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a multisystem neurodegenerative disorder characterized by large intranuclear aggregates in neurons of the central and peripheral nervous system. These ubiquitinated intranuclear inclusions are morphologically similar to the intraneuronal aggregates that have been identified in the CAG/polyglutamine expansion diseases. As rare aggregates in NIID contain a polyglutamine epitope, we further investigated the relationship between this disease and the CAG/polyglutamine expansion diseases. Here, we show that ataxin 1 and ataxin 3 proteins are recruited into aggregates in NIID in the absence of a CAG expansion in the SCA1 and SCA3 genes. These data support an association of NIID with the polyglutamine disorders and provide evidence of in vivo recruitment of proteins with polyglutamine tracts into intraneuronal aggregates.

Synapses in the hereditary ataxias.

The goal of this investigation was the systematic assessment of synapses in the hereditary ataxias by the immunocytochemical and immunofluorescent visualization of SNAP-25, a protein of the presynaptic membrane. Sections were prepared from the cerebellar cortex, dentate nucleus, basis pontis, inferior olivary nuclei, and the spinal cord in 57 cases of autosomal dominant and recessive ataxia. The neuropathological phenotype included 18 cases of olivopontocerebellar atrophy (OPCA), 14 cases of familial cortical cerebellar atrophy (FCCA), 4 cases of Machado-Joseph disease (MJD), and 21 cases of Friedreich's ataxia (FA). Among the autosomal dominant ataxias, spinocerebellar ataxia type 1 (SCA-1), SCA-2, MJD/SCA-3, and SCA-6 were represented. Expanded guanine-adenine-adenine trinucleotide repeats were confirmed in 7 patients with FA. The abundance of SNAP-25 was estimated by comparing the fluorescence of the regions of interest to that of the frontal cortex, which was considered unaffected by the disease process. Despite severe Purkinje cell loss, abundant SNAP-25 reaction product remained in the molecular layer of FCCA and OPCA. Among the cases of OPCA, those identified as SCA-2 showed the most severe overall synaptic destruction in cerebellum and brain stem. In SCA-1, which caused either OPCA or FCCA, significant synaptic loss was restricted to the inferior olivary nuclei. Sparing of cerebellar cortex and inferior olivary nuclei was the rule for MJD/SCA-3 and FA, though the dentate nucleus showed reduced SNAP-25 immunoreactivity in both ataxias. In FA, preservation of SNAP-25 in the dentate nucleus was characteristic of long survival. Severe cases with short survival revealed synaptic depletion of the dentate nucleus. At the level of the spinal cord, synaptic loss in the dorsal nuclei of Clarke characterized FA and MJD/SCA-3. The inexorable clinical progression of the hereditary ataxias could not be attributed to synaptic loss in a single anatomic structure of cerebellum, brain stem, or spinal cord. Nevertheless, synaptic loss in dentate and inferior olivary nuclei correlated more precisely with the severity of the ataxia than the changes in the cerebellar cortex.

Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population.

The activity of cytochrome oxidase (CO), the terminal enzyme of the mitochondrial electron transport chain, has been reported to be lower in the brains of Alzheimer disease (AD) patients. This suggests that a modification of mitochondrial DNA (mtDNA) may be responsible for this decrease of CO activity. Many mtDNA variants were found by different studies at a higher frequency in AD patients, suggesting that mtDNA variants could confer a genetic susceptibility to AD. In this study, we sequenced the entire mitochondrial genome region that encompasses the three CO genes and the 22 mitochondrial tRNA in 69 AD patients and 83 age-matched controls. We detected a total of 95 mtDNA variants. The allele frequencies of the majority of these variants were similar in patients and controls. However, a haplotype composed of three different modifications (positions: 5633, 7476, and 15812) was present in three of the 69 late-onset AD patients (4.3%) and also in 1 of 16 early-onset AD patients (6.2%) but not in control individuals. Given that one of these variants (15812) has already been shown to be associated with another neurodegenerative disease and that all three modifications are relatively conserved and their frequencies in the general population is only 0.1%, our data suggest that the presence of this haplotype may represent a risk factor for AD. We also found a significant association (P < 0.05) of two other variants at positions 709 (rRNA 12S) and 15928 (tRNA(Thr)). These two mtDNA variants are three times more frequent in control individuals compared with AD patients, suggesting that they may be protective against AD.