Correction: Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.

Carotid artery disease in post-stroke survivors and effects of enriched environment on stroke pathology in a mouse model of carotid artery stenosis.

AIMS: Carotid artery disease (CAD) is an important risk factor for stroke. We first evaluated CAD and stroke pathology in elderly post-stroke survivors. To simulate CAD, we assessed long-term consequences of bilateral common carotid artery stenosis (BCAS) in mice and exposed them to environmental enrichment (EE). METHODS: Histopathological methods were used to determine degrees of CAD (% area stenosis), brain infarct types, sizes and distribution in post-stroke survivors and BCAS mice. Adult male C57BL/6J mice after BCAS or sham surgery were randomly assigned to standard housing (Std) or limited (3 h) or full-time (Full) exposure to EE per day for 12 weeks. RESULTS: High frequencies of moderate carotid artery stenosis (51-75%) were evident in post-stroke survivors whereas those with severe CAD (>75% stenosis) exhibited greater numbers of cortical rather than subcortical infarcts and, were at higher risk of developing dementia. BCAS in mice reduced cerebral blood flow by 52% (P < 0.01) and thickened carotid artery walls, regardless of EE duration. Remarkably, the total and cortical infarcts declined by >50% in BCAS mice exposed to EE compared with BCAS-Std (P < 0.01). Frontal lobe and cortical strokes were associated with worsening working memory tested in a radial maze paradigm. Proteomic analysis revealed EE, both BCAS-3 h and BCAS-Full attenuated coagulation cascade factors including fibrinogen and von Willebrand factor, markers of blood-brain barrier damage. CONCLUSION: Small cortical and subcortical infarcts were evident in both post-stroke survivors with CAD and BCAS mice. Experimental evidence suggested that moderate exposure to EE is sufficient to reduce subsequent stroke lesions.

CAIDE Dementia Risk Score, Alzheimer and cerebrovascular pathology: a population-based autopsy study.

BACKGROUND: CAIDE Dementia Risk Score is a tool for estimating dementia risk in the general population. Its longitudinal associations with Alzheimer or vascular neuropathology in the oldest old are not known. AIM: To explore the relationship between CAIDE Dementia Risk Score at baseline and neuritic plaques, neurofibrillary tangles, cerebral infarcts and cerebral amyloid angiopathy (CAA) after up to 10-year follow-up in the Vantaa 85 +  population. METHODS: Study population included 149 participants aged ≥85 years, without dementia at baseline, and with available clinical and autopsy data. Methenamine silver staining was used for ß-amyloid and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, CAA and α-synuclein pathologies. The CAIDE Dementia Risk Score was calculated based on scores for age, sex, BMI, total cholesterol, systolic blood pressure, physical activity and APOEε4 carrier status (range 0-18 points). RESULTS: A CAIDE Dementia Risk Score above 11 points was associated with more cerebral infarctions up to 10 years later: OR (95% CI) was 2.10 (1.06-4.16). No associations were found with other neuropathologies. CONCLUSION: In a population of elderly aged ≥85 years, higher CAIDE Dementia Risk Score was associated with increased risk of cerebral infarcts.

Muscle hypertrophy as the presenting sign in a patient with a complete FHL1 deletion.

Four and a half LIM protein 1 (FHL1/SLIM1) has recently been identified as the causative gene mutated in four distinct diseases affecting skeletal muscle that have overlapping features, including reducing body myopathy, X-linked myopathy, X-linked dominant scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. FHL1 localises to the sarcomere and the sarcolemma and is believed to participate in muscle growth and differentiation as well as in sarcomere assembly. We describe in this case report a boy with a deletion of the entire FHL1 gene who is now 15 years of age and presented with muscle hypertrophy, reduced subcutaneous fat, rigid spine and short stature. This case is the first, to our knowledge, with a complete loss of the FHL1 protein and MAP7D3 in combination. It supports the theory that dominant negative effects (accumulation of cytotoxic-mutated FHL1 protein) worsen the pathogenesis. It extends the phenotype of FHL1-related myopathies and should prompt future testing in undiagnosed patients who present with unexplained muscle hypertrophy, contractures and rigid spine, particularly if male.

Mitochondrial DNA deletions and depletion within paraspinal muscles.

AIMS: Although mitochondrial abnormalities have been reported within paraspinal muscles in patients with axial weakness and neuromuscular disease as well as with ageing, the basis of respiratory deficiency in paraspinal muscles is not known. This study aimed to determine the extent and basis of respiratory deficiency in paraspinal muscles from cases undergoing surgery for degenerative spinal disease and post mortem cases without a history of spinal disease, where age-related histopathological changes were previously reported. METHODS: Cervical and lumbar paraspinal muscles were obtained peri-operatively from 13 patients and from six post mortem control cases (age range 18-82 years) without a neurological disease. Sequential COX/SDH (mitochondrial respiratory chain complex IV/complex II) histochemistry was performed to identify respiratory-deficient muscle fibres (lacking complex IV with intact complex II activity). Real-time polymerase chain reaction, long-range polymerase chain reaction and sequencing were used to identify and characterize mitochondrial DNA (mtDNA) deletions and determine mtDNA copy number status. Mitochondrial respiratory chain complex subunits were detected by immunohistochemistry. RESULTS: The density of respiratory-deficient fibres increased with age. On average, 3.96% of fibres in paraspinal muscles were respiratory-deficient (range 0-10.26). Respiratory deficiency in 36.8% of paraspinal muscle fibres was due to clonally expanded mtDNA deletions. MtDNA depletion accounted for further 13.5% of respiratory deficiency. The profile of immunohistochemically detected subunits of complexes was similar in respiratory-deficient fibres with and without mtDNA deletions or mtDNA depletion. CONCLUSIONS: Paraspinal muscles appeared to be particularly susceptible to age-related mitochondrial respiratory chain defects. Clonally expanded mtDNA deletions and focal mtDNA depletion may contribute towards the development of age-related postural abnormalities.

Prevalence and severity of cerebral amyloid angiopathy: a population-based study on very elderly Finns (Vantaa 85+).

BACKGROUND: Cerebral amyloid angiopathy (CAA) is frequent in patients with Alzheimer's disease while its prevalence in different populations is variable. We investigated the prevalence and severity of CAA in a very elderly Finnish population. METHODS: Neuropathological investigation was performed on 306 subjects from the population-based Vantaa 85+ Study (253 women, 53 men, mean age at death 92.3 years). The presence of CAA was analysed in six brain regions by using Congo red and immunohistochemistry with an antibody against amyloid beta peptide. The severity of CAA was assessed by counting the percentage of the CAA-positive blood vessels. RESULTS: In total, 69.6% of the participants (170 women, 43 men) had CAA, with median severity of 1.0%, inter-quartile range (IQR) 0-5.4% and range 0-72.7%. CAA was more prevalent (81.1% vs. 67.2%; P = 0.046) and severe (median 2.7%, IQR 0.4-7.5%, range 0-72.7%) in the men than in the women (median 1.0%, IQR 0-4.6%, range 0-52.8%; P = 0.004). Parietal lobe showed the highest prevalence (57.8%) whereas the severity was highest (median 1.0%, IQR 0-6.0%, range 0-77%) in the frontal lobe. Prevalence of CAA in the six regions was variable, but the severity indices between those regions correlated highly (P < 0.001 for all regions). Meningeal CAA was more prevalent (69.5%) than cortical (59.3%; P < 0.001). CONCLUSION: CAA was highly prevalent, albeit mild, in the very old. The prevalence and severity of CAA were found to be highest in the frontal and parietal lobes respectively - independent of the staining method used (Congo red or amyloid beta peptide).

Reappraisal of a consecutive autopsy series of patients with primary degenerative dementia: Lewy-related pathology.

Dementia with Lewy bodies (DLB) is a common but underdiagnosed dementing disorder. Its criteria were defined in 1996, and revised in 2005. DLB is characterised neuropathologically by widely distributed cortical Lewy bodies (LBs), usually associated with Alzheimer-type pathology. We have re-evaluated the neuropathology of 55 autopsied patients with clinically diagnosed primary degenerative dementia to determine the frequency of DLB in this cohort, which was originally examined when neither the entity of DLB nor its diagnostic criteria had been defined. We also evaluated how discovery of a new entity affects previous diagnoses. Of the 55 brains, 16 (29%) contained LBs. All 16 originally had a neuropathological diagnosis of Alzheimer's disease (AD). 11 (20%) fulfilled the neuropathological criteria for DLB. Three patients had AD with LBs in the brain stem only, and two patients had LBs in the limbic cortex only. Because the criteria and reliable markers for DLB were not available at the time of the autopsies, the diagnosis of DLB had not been possible. The common co-occurrence of AD-type pathology in DLB makes the clinical diagnosis of DLB problematic even today. This study also raises the question of the relative significances of Lewy-related and AD-type pathologies to the development of dementia.

Carotid sinus hypersensitivity associated with focal alpha-synucleinopathy of the autonomic nervous system.

A case of an 82-year-old woman who experienced repeated falls is described. She exhibited a cardioinhibitory carotid sinus hypersensitivity after right carotid sinus massage (CSM), but without evidence of orthostatic hypotension. After a pacemaker was implanted, she did not experience any falls, dizziness or syncope. Her balance eventually deteriorated, but she remained cognitively intact and died from lung cancer at the age of 89 years. Neuropathological examination showed only age-related Alzheimer's disease pathology and a few alpha-synuclein-positive granular deposits and neurites in the dorsal nucleus of the vagus and solitary tract nucleus in the medulla, but a marked alpha-synuclein pathology in the stellate ganglia. The cardioinhibitory element of her CSM was possibly because of the alpha-synuclein pathology in the ganglion, which impaired sympathetic transmission. This case shows another phenotype among patients with alpha-synucleinopathy.

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.

OBJECTIVE: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. METHODS: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. RESULTS: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. CONCLUSIONS: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into "myopathic" or "neuropathic" forms may be misleading in some instances, and future treatments need to address the pathology in both tissues.

APOE alleles in Alzheimer's disease and vascular dementia in a population aged 85+.

Apolipoprotein E genotyping was carried out in a stratified random sample of 52 patients with Alzheimer's disease, 48 patients with vascular or mixed dementia, and 49 nondemented controls in a population-based study of people aged 85 and older (the Vantaa 85+ Study). Our results indicate that the apolipoprotein E epsilon 4 allele is associated with approximately a twofold increase in clinically diagnosed Alzheimer's disease in this very old general population aged 85+. When combined with previous studies, our data also suggest that the association is decreasing with age. In contrast, there appears to be no relation between apolipoprotein E alleles and clinically diagnosed vascular dementia.

APOE epsilon4 does not predict mortality, cognitive decline, or dementia in the oldest old.

OBJECTIVE: To examine the effect of the epsilon 4 allele on cognitive decline in the oldest old. METHODS: We studied all 601 citizens of the city of Vantaa age 85 years and older in 1991. A total of 553 subjects (92%) took part in the study, which used the Mini-Mental State Examination (MMSE) and assessment of dementia according to the Diagnostic and Statistical Manual of Mental Disorders, third ed., revised (DSM-III-R) criteria. The survivors were re-examined 3 years later. APOE genotype was determined in 510 subjects, representing 83.2% of the original population. RESULTS: Approximately one-half of the subjects (n = 250) died before the follow-up, and 253 subjects (97.3% of the survivors) were re-examined. The occurrence of the APOE epsilon 4 allele did not have any significant effect on survival. Of the 187 previously nondemented subjects, 58 (31%) had developed dementia. The OR for the epsilon 4 carriers to develop dementia was not significant: OR = 1.78; 95% CI = 0.88 to 3.60. In individuals with a follow-up MMSE score (n = 222), the mean decline in the score was 3.1 points. APOE epsilon 4 carrier status did not have a significant effect on the mean MMSE change except in the previously demented subjects, among whom the drop was larger in the APOE epsilon 4 carriers. CONCLUSIONS: The lack of association between APOE epsilon 4 carrier status and mortality, or development of dementia, or cognitive decline in these very elderly people, whether analyzed in the whole population or among the nondemented subjects only, suggests that the APOE epsilon 4 effect in younger subjects is age-dependent, and that it is no longer present in very old age.

Prevalence of Alzheimer's disease in very elderly people: a prospective neuropathological study.

BACKGROUND: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. OBJECTIVE: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. METHODS: A population-based sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. RESULTS: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p < 0.001) association between the APOE epsilon4 allele and AD: Sixty-three percent of APOE epsilon4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. CONCLUSIONS: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.

Cardiovascular risk factors and Alzheimer's disease: a genetic association study in a population aged 85 or over.

Increasing evidence suggests a relation between vascular disorders and late-onset Alzheimer's disease (AD). We performed an association analysis of low-density lipoprotein receptor-related protein (LRP), lipoprotein lipase (LPL), and angiotensin converting enzyme (ACE) genes, known to be involved in vascular disorders, and AD. Genotyping was carried out in 113 patients with clinically defined Alzheimer's disease (NINCDS-ADRDA criteria) and 203 non-demented controls in a prospective, population-based study of people aged 85 years or over (Vantaa 85+ Study). Corresponding analysis was performed on 121 neuropathologically verified AD patients (CERAD criteria) and 75 controls derived from the same study population. We did not find significant associations between the polymorphisms studied and AD. However, analysis of the LPL polymorphism showed a weak trend (uncorrected P-value 0.095) towards protection against neuropathologically defined AD. Our study is based on very elderly Finns. Therefore, further studies are warranted in other populations.

No association between TAU haplotype and Alzheimer's disease in population or clinic based series or in familial disease.

We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.

Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture.

OBJECTIVE: Resident macrophages play an important role in atheromatous plaque rupture. The macrophage gene expression signature associated with plaque rupture is incompletely defined due to the complex cellular heterogeneity in the plaque. We aimed to characterise differential gene expression in resident plaque macrophages from ruptured and stable human atheromatous lesions. METHODS AND RESULTS: We performed genome-wide expression analyses of isolated macrophage-rich regions of stable and ruptured human atherosclerotic plaques. Plaques present in carotid endarterectomy specimens were designated as stable or ruptured using clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from 5 ruptured and 6 stable plaques by laser micro-dissection. Transcriptional profiling was performed using Affymetrix microarrays. The profiles were characteristic of activated macrophages. At a false discovery rate of 10%, 914 genes were differentially expressed between stable and ruptured plaques. The findings were confirmed in fourteen further stable and ruptured samples for a subset of eleven genes with the highest expression differences (p < 0.05). Pathway analysis revealed that components of the PPAR/Adipocytokine signaling pathway were the most significantly upregulated in ruptured compared to stable plaques (p = 5.4 × 10(-7)). Two key components of the pathway, fatty-acid binding-protein 4 (FABP4) and leptin, showed nine-fold (p = 0.0086) and five-fold (p = 0.0012) greater expression respectively in macrophages from ruptured plaques. CONCLUSIONS: We found differences in gene expression signatures between macrophages isolated from stable and ruptured human atheromatous plaques. Our findings indicate the involvement of FABP4 and leptin in the progression of atherosclerosis and plaque rupture, and suggest that down-regulation of PPAR/adipocytokine signaling within plaques may have therapeutic potential.

Relationships between white matter hyperintensities, cerebral amyloid angiopathy and dementia in a population-based sample of the oldest old.

Previous reports suggest that brain white matter changes, a surrogate for small vessel disease, are related to cerebral amyloid angiopathy (CAA). However, this relationship has not been explored in population-based studies or in the oldest old (>85 years of age). We studied the relationships between white matter hyperintensities (WMH) determined by post-mortem magnetic resonance imaging (MRI) and neuropathologically assessed CAA in demented and nondemented subjects enrolled in the prospective community-based Finnish Vantaa 85+ Study. In this analysis, we evaluated scans and brain samples from 123 subjects (86% women) with a mean age of 90.6 years. We found CAA to be present in 63 % of the 123 subjects, whereas WMH was present in 74%, and dementia in 59 %. The presence of WMH of any severity did not relate to the presence or the degree of CAA severity, irrespective of the dementia status of the subjects. Furthermore, multivariate regression analysis showed a clear association between CAA and dementia but WMH was not related to dementia in this very old sample. We conclude that severe WMH may not be determined by CAA in this very elderly population.

Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study.

OBJECTIVE: To investigate the relation of diabetes to dementia, Alzheimer disease (AD), and vascular dementia (VaD), through analyses of incidence, mortality, and neuropathologic outcomes in a prospective population-based study of the oldest old. METHODS: The Vantaa 85+ study included 553 residents living in the city of Vantaa, Finland, and aged ≥85 years on April 1, 1991. Survivors were reexamined in 1994, 1996, 1999, and 2001. Autopsies were performed in 291 persons who died during the follow-up (48% of total population). Diabetes was assessed according to self-report, medical record of physician-diagnosed diabetes, or use of antidiabetic medication. Macroscopic infarcts were identified from 1-cm coronal slices of cerebral hemispheres, 5-mm transverse brainstem slices, and sagittal cerebellum slices. Methenamine silver staining was used for ß-amyloid, methenamine silver-Bodian staining for neurofibrillary tangles, and modified Bielschowsky method for neuritic plaques. Cox proportional hazards and multiple logistic regression models were used to analyze the association of diabetes with dementia and neuropathology, respectively. RESULTS: Diabetes at baseline doubled the incidence of dementia, AD, and VaD, and increased mortality. Individuals with diabetes were less likely to have ß-amyloid (hazard ratio [HR] [95% confidence interval (CI)] was 0.48 [0.23-0.98]) and tangles (HR [95% CI] 0.72 [0.39-1.33]) but more likely to have cerebral infarcts (HR [95% CI] 1.88 [1.06-3.34]) after all adjustments. CONCLUSION: Elderly patients with diabetes develop more extensive vascular pathology, which alone or together with AD-type pathology (particularly in APOE ε4 carriers) results in increased dementia risk.

Frontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old.

BACKGROUND: Current studies suggest an interaction between vascular mechanisms and neurodegenerative processes that leads to late-onset Alzheimer disease (AD). We tested whether AD pathology was associated with white matter hyperintensities (WMH) or cerebral infarcts in the oldest old individuals. METHODS: Brains from 132 subjects over 85 years old, who came to autopsy from the Vantaa 85+ population-based cohort, were scanned by postmortem MRI and examined for neuropathologic changes. Coronal images were analyzed to determine the degree of frontal and parietal periventricular WMH (PVWMH) and deep WMH (DWMH) and cerebral infarcts. Neuropathologic variables included Consortium to Establish a Registry for Alzheimer's Disease scores for neuritic plaques and Braak staging among subjects in 5 groups: normal aging (NA), borderline with insufficient AD pathology, AD, AD plus other pathology, and other primary degenerative diseases. RESULTS: Frontal DWMH were detected in >50% of the sample. Both frontal PVWMH and DWMH were significantly more extensive in the AD group compared to the NA group or the NA and borderline groups combined. Frontal PVWMH and DWMH were also associated with increased Braak staging (p = 0.03) and the neuritic plaque load (p = 0.01). Further analysis revealed there were a greater number of cerebral infarcts associated with frontal DWMH (p = 0.03) but not with frontal PVWMH. CONCLUSIONS: Our study showed an association between neurofibrillary pathology and frontal PVWMH and DWMH (rather than parietal), as a surrogate of small vessel disease, particularly in very old community-dwelling individuals.