Limbic-predominant age-related TDP-43 encephalopathy in the oldest old: a population-based study.

Population-based cohort studies are essential for understanding the pathological basis of dementia in older populations. Previous studies have shown that limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) increases with age, but there have been only a few studies, which have investigated this entity in a population-based setting. Here we studied the frequency of LATE-NC and its associations with other brain pathologies and cognition in a population aged ≥ 85 years. The population-based Vantaa 85+ study cohort includes all 601 individuals aged ≥ 85 years who were living in Vantaa, Finland in 1991. A neuropathological examination was performed on 304 subjects (50.5%) and LATE-NC staging was possible in 295 of those. Dementia status and Mini-Mental State Examination (MMSE) scores were defined in the baseline study and 3 follow-ups (1994-99). The LATE-NC stages were determined based on TDP-43 immunohistochemistry, according to recently updated recommendations. Arteriolosclerosis was digitally assessed by calculating the average sclerotic index of five random small arterioles in amygdala and hippocampal regions, and frontal white matter. The association of LATE-NC with arteriolosclerosis and previously determined neuropathological variables including Alzheimer's disease neuropathological change (ADNC), Lewy-related pathology (LRP), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA), and cognitive variables were analysed by Fisher's exact test, linear and logistic regression (univariate and multivariate) models. LATE-NC was found in 189 of 295 subjects (64.1%). Stage 2 was the most common (28.5%) and stage 3 the second most common (12.9%), whereas stages 1a, 1b and 1c were less common (9.5%, 5.1% and 8.1%, respectively). Stages 1a (P < 0.01), 2 (P < 0.001) and 3 (P < 0.001) were significantly associated with dementia and lower MMSE scores. LATE-NC was associated with ADNC (P < 0.001), HS (P < 0.001), diffuse neocortical LRP (P < 0.002), and arteriolosclerosis in amygdala (P < 0.02). In most cases LATE-NC occurred in combination alongside other neuropathological changes. There were only six subjects with dementia who had LATE-NC without high levels of ADNC or LRP (2% of the cohort, 3% of the cases with dementia), and five of these had HS. In all multivariate models, LATE-NC was among the strongest independent predictors of dementia. When LATE-NC and ADNC were assessed in a multivariate model without other dementia-associated pathologies, the attributable risk was higher for LATE-NC than ADNC (24.2% vs. 18.6%). This population-based study provides evidence that LATE-NC is very common and one of the most significant determinants of dementia in the general late-life aged population.

Primary age-related tauopathy in a Finnish population-based study of the oldest old (Vantaa 85+).

AIMS: Few studies have investigated primary age-related tauopathy (PART) in a population-based setting. Here, we assessed its prevalence, genetic background, comorbidities and features of cognitive decline in an unselected elderly population. METHODS: The population-based Vantaa 85+ study includes all 601 inhabitants of Vantaa aged ≥ 85 years in 1991. Neuropathological assessment was possible in 301. Dementia (DSM IIIR criteria) and Mini-Mental State Examination (MMSE) scores were assessed at the baseline of the study and follow-ups. PART subjects were identified according to the criteria by Crary et al and were compared with subjects with mild and severe Alzheimer's disease (AD) neuropathological changes. The effects of other neuropathologies were taken into account using multivariate and sensitivity assays. Genetic analyses included APOE genotypes and 29 polymorphisms of the MAPT 3' untranslated region (3'UTR region). RESULTS: The frequency of PART was 20% (n = 61/301, definite PART 5%). When PART subjects were compared with those with severe AD pathology, dementia was less common, its age at onset was higher and duration shorter. No such differences were seen when compared with those with milder AD pathology. However, both AD groups showed a steeper decline in MMSE scores in follow-ups compared with PART. APOE ε4 frequency was lower, and APOE ε2 frequency higher in the PART group compared with each AD group. The detected nominally significant associations between PART and two MAPT 3'UTR polymorphisms and haplotypes did not survive Bonferroni correction. CONCLUSIONS: PART is common among very elderly. PART subjects differ from individuals with AD-type changes in the pattern of cognitive decline, associated genetic and neuropathological features.

Cerebral amyloid angiopathy related hemorrhage after stroke thrombolysis: case report and literature review.

Cerebral amyloid angiopathy (CAA) predisposes to symptomatic intracerebral hemorrhage (sICH) after combined thrombolytic and anticoagulant treatment of acute myocardial infarction. However, the role of CAA in stroke thrombolysis has not been established. Here, we describe a confirmed case of CAA-related hemorrhage in a patient receiving thrombolysis for acute ischemic stroke. On autopsy, immunohistochemistry revealed amyloid-ß positive staining in thickened cortical and meningeal arteries at sites of hemorrhage. Further research is urgently needed to determine the hemorrhage risk related to CAA in stroke thrombolysis and develop better diagnostic tools to identify CAA in the emergency room.

Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study.

Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer's disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged ≥85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-ß 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, cerebral amyoloid angiopathy, and α-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28-5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-ß accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88-7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12-12.79) for more severe medial temporal atrophy and 4.69 (1.14-19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or α-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged ≥85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology.

Amyloid in parenchymal organs in gelsolin (AGel) amyloidosis.

Objectives: Previous clinical studies have shown frequent cardiac symptoms in patients with hereditary gelsolin (AGel) amyloidosis, possibly related to amyloid deposition in the heart and other internal organs. Previous studies on internal organ amyloid deposition in AGel amyloidosis have been based on small patient series. Methods: Paraffin-embedded tissue sections from 25 autopsied individuals (age at death 44.4-88.6 years) with AGel amyloidosis were stained with HE, Congo red and Herovici stains and immunohistochemistry against the low molecular weight gelsolin fraction was performed. The amount of amyloid was estimated semi-quantitatively. Results: AGel-based amyloid deposits were found in the myocardium and cardiac blood vessels in every patient. The deposits were mainly small and co-localized with regions with excess fibrosis in the myocardium. The lungs were positive for amyloid in 79%, renal parenchyma in 54% and renal blood vessels in 71% of the cases. The amount of myocardial, renal and hepatic amyloid correlated with age at death of the patients. Conclusions: We show the constant presence of AGel amyloid in the hearts of patients with AGel amyloidosis. Although the deposits were mainly small, the co-localization of amyloid with fibrosis may amplify the effect of pure amyloid deposition, possibly leading to clinical signs and symptoms.

Prediction models for dementia and neuropathology in the oldest old: the Vantaa 85+ cohort study.

BACKGROUND: We developed multifactorial models for predicting incident dementia and brain pathology in the oldest old using the Vantaa 85+ cohort. METHODS: We included participants without dementia at baseline and at least 2 years of follow-up (N = 245) for dementia prediction or with autopsy data (N = 163) for pathology. A supervised machine learning method was used for model development, considering sociodemographic, cognitive, clinical, vascular, and lifestyle factors, as well as APOE genotype. Neuropathological assessments included ß-amyloid, neurofibrillary tangles and neuritic plaques, cerebral amyloid angiopathy (CAA), macro- and microscopic infarcts, α-synuclein pathology, hippocampal sclerosis, and TDP-43. RESULTS: Prediction model performance was evaluated using AUC for 10 × 10-fold cross-validation. Overall AUCs were 0.73 for dementia, 0.64-0.68 for Alzheimer's disease (AD)- or amyloid-related pathologies, 0.72 for macroinfarcts, and 0.61 for microinfarcts. Predictors for dementia were different from those in previous reports of younger populations; for example, age, sex, and vascular and lifestyle factors were not predictive. Predictors for dementia versus pathology were also different, because cognition and education predicted dementia but not AD- or amyloid-related pathologies. APOE genotype was most consistently present across all models. APOE alleles had a different impact: ε4 did not predict dementia, but it did predict all AD- or amyloid-related pathologies; ε2 predicted dementia, but it was protective against amyloid and neuropathological AD; and ε3ε3 was protective against dementia, neurofibrillary tangles, and CAA. Very few other factors were predictive of pathology. CONCLUSIONS: Differences between predictors for dementia in younger old versus oldest old populations, as well as for dementia versus pathology, should be considered more carefully in future studies.

Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+).

OBJECTIVE: To test the association of distinct neuropathologic features of Alzheimer disease (AD) with risk loci identified in genome-wide association studies. METHODS: Vantaa 85+ is a population-based study that includes 601 participants aged ≥85 years, of which 256 were neuropathologically examined. We analyzed 29 AD risk loci in addition to APOE ε4, which was studied separately and used as a covariate. Genotyping was performed using a single nucleotide polymorphism (SNP) array (341 variants) and imputation (6,038 variants). Participants with Consortium to Establish a Registry for Alzheimer Disease (CERAD) (neuritic Aß plaques) scores 0 (n = 65) vs score M + F (n = 171) and Braak (neurofibrillary tangle pathology) stages 0-II (n = 74) vs stages IV-VI (n = 119), and with capillary Aß (CapAß, n = 77) vs without (n = 179) were compared. Cerebral amyloid angiopathy (CAA) percentage was analyzed as a continuous variable. RESULTS: Altogether, 24 of the 29 loci were associated (at p < 0.05) with one or more AD-related neuropathologic features in either SNP array or imputation data. Fifteen loci associated with CERAD score, smallest p = 0.0002122, odds ratio (OR) 2.67 (1.58-4.49) at MEF2C locus. Fifteen loci associated with Braak stage, smallest p = 0.004372, OR 0.31 (0.14-0.69) at GAB2 locus. Twenty loci associated with CAA, smallest p = 7.17E-07, ß 14.4 (8.88-20) at CR1 locus. Fifteen loci associated with CapAß smallest p = 0.002594, OR 0.54 (0.37-0.81) at HLA-DRB1 locus. Certain loci associated with specific neuropathologic features. CASS4, CLU, and ZCWPW1 associated only with CAA, while TREM2 and HLA-DRB5 associated only with CapAß. CONCLUSIONS: AD risk loci differ in their association with neuropathologic features, and we show for the first time distinct risk loci for CAA and CapAß.

Severe ataxia with neuropathy in hereditary gelsolin amyloidosis: a case report.

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder caused by a G654A or G654T gelsolin mutation, reported from Europe, North America, and Japan. Principal clinical signs are corneal lattice dystrophy, cutis laxa and cranial neuropathy, often deleterious at advanced age. Peripheral neuropathy, if present, is usually mild. We report a 78-year-old male Finnish patient who presented with ataxia and mainly sensory peripheral polyneuropathy (PNP) signs, causing severe disability and ambulation loss. Electrophysiological studies showed severe generalized chronic mainly axonal sensorimotor PNP with facial paralysis. In magnetic resonance imaging proximal lower limb and axial muscle atrophy with fatty degeneration as well as moderate spinal cord atrophy were seen. A G654A gelsolin mutation was demonstrated but no other possible causes of his disability were found. At age 79 years he became bedridden and died of pulmonary embolism. Neuropathological examination revealed marked gelsolin amyloid deposition at vascular and connective tissue sites along the entire length of the peripheral nerves extending to the spinal nerve roots, associated with severe degeneration of nerve fibers and posterior columns. Our report shows that advanced AGel amyloidosis due to degeneration of central and distal sensory nerve projections results in deleterious ataxia with fatal outcome. Severe posterior column atrophy may reflect radicular AGel deposition, although even altered gelsolin-actin interactions in neural cells possibly contribute to neurodegeneration with successive ataxia in carriers of a G654A gelsolin mutation.

Population-based analysis of pathological correlates of dementia in the oldest old.

OBJECTIVE: The aim of this study was to analyze brain pathologies which cause dementia in the oldest old population. METHODS: All 601 persons aged ≥85 years living in the city of Vantaa (Finland), on April 1st, 1991 formed the study population of the Vantaa85 +  study, 300 of whom were autopsied during follow-up (79.5% females, mean age-at-death 92 ± 3.7 years). Alzheimer's disease (AD) pathology (tau and beta-amyloid [Aß]), cerebral amyloid angiopathy (CAA) and Lewy-related pathologies were analyzed. Brain infarcts were categorized by size (<2 mm, 2-15 mm, >15 mm) and by location. Brain hemorrhages were classified as microscopic (<2 mm) and macroscopic. RESULTS: 195/300 (65%) were demented. 194/195 (99%) of the demented had at least one neuropathology. Three independent contributors to dementia were identified: AD-type tau-pathology (Braak stage V-VI), neocortical Lewy-related pathology, and cortical anterior 2-15 mm infarcts. These were found in 34%, 21%, and 21% of the demented, respectively, with the multivariate odds ratios (OR) for dementia 5.5, 4.5, and 3.4. Factor analysis investigating the relationships between different pathologies identified three separate factors: (1) AD-spectrum, which included neurofibrillary tau, Aß plaque, and neocortical Lewy-related pathologies and CAA (2) >2 mm cortical and subcortical infarcts, and (3) <2 mm cortical microinfarcts and microhemorrhages. Multipathology was common and increased the risk of dementia significantly. INTERPRETATION: These results indicate that AD-type neurodegenerative processes play the most prominent role in twilight cognitive decline. The high prevalence of both neurodegenerative and vascular pathologies indicates that multiple preventive and therapeutic approaches are needed to protect the brains of the oldest old.

Senile systemic amyloidosis, cerebral amyloid angiopathy, and dementia in a very old Finnish population.

Senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) are amyloid disorders, which typically manifest with old age. The aim of our study was to examine the possible association of these disorders in very old Finns. We performed a prospective, population-based post mortem study and used histological and immunohistochemical staining methods to verify the presence of these types of amyloid. All 63 subjects (59% of the 107 individuals 95 years of age or more, who died during the 10-year follow-up study), 53 women and 10 men), had been neurologically examined. The prevalence of SSA and its association with CAA, dementia, and neuropathologically verified AD was analyzed. Overall SSA occurred in 23 (37%) and CAA in 28 (44%) of the 63 subjects. At clinical examination 41 individuals (65%) were demented; 24 (38%) had Alzheimer's disease. SSA showed no association with the presence of CAA (P = 0.45), clinical dementia (P = 0.09), or Alzheimer's disease (P = 0.21), or sex (P = 0.53). Our prospective population based study shows that SSA and CAA are frequent in very old Finns, but they do not associate.

Increasing amount of amyloid are associated with the severity of clinical features in hereditary gelsolin (AGel) amyloidosis.

BACKGROUND: Patients with hereditary gelsolin (AGel) amyloidosis (HGA) present with hanging skin (cutis laxa) and bilateral cranial neuropathy, and require symptomatic plastic surgery. Our clinical observation of tissue fragility prompted us to design a prospective study. METHODS: Twenty-nine patients with HGA undergoing surgery were interviewed and clinically examined. The height and thickness of skin folds in standard anatomical localizations were measured. The presence and distribution of amyloid in skin samples were analyzed using Congo red staining and immunohistochemistry using antibodies against gelsolin amyloid (AGel) subunit. RESULTS: The measured skin folds stretched more in patients with HGA (e.g. skin over olecranon, p < 0.001). The skin folds were thinner in patients with HGA (e.g. forehead skin, p < 0.001). The skin and subcutaneous fat were abnormally fragile during surgery. The total amount of AGel amyloid, and its presence in the deep layers of the skin and subcutaneous fat correlated with the measurements of skin folds, age and extent of cranial neuropathy. CONCLUSIONS: The AGel amyloid in the skin and subcutis, together with morphologic changes in the dermal stroma and skin adnexa contribute to the atrophied and fragile structure of HGA skin. This is the first study to demonstrate the correlation between AGel amyloid accumulation and clinical disease severity.

Capillary amyloid-ß protein deposition in a population-based study (Vantaa 85+).

BACKGROUND: Capillary amyloid-ß (capAß) deposition in the cerebral cortex is the neuropathological feature providing the basis for categorizing cerebral amyloid angiopathy (CAA) into two distinct types, CAA-Type1 with capAß and CAA-Type2 without capAß. OBJECTIVE: We investigated the neuropathological and clinical characteristics of capAß deposition in a prospective population-based study. METHODS: Vantaa 85+ includes 601 individuals aged ≥85 years, of which 300 were studied clinically and neuropathologically. 278 subjects were analyzed for the apolipoprotein E (APOE) genotype. The diagnosis of capAß was determined using immunohistochemistry against Aß, and of CAA using Congo red confirmed by Aß immunohistochemistry, both analyzed in six brain areas. The severity of capAß was graded semi-quantitatively, and the severity of CAA was based on the percentage of affected vessels. Alzheimer's disease (AD)-type neuropathology (CERAD score and Braak stage) was analyzed using standard methods. RESULTS: CAA-Type1 was present in 86/300, CAA-Type2 in 135/300, and 79/300 had no CAA. CapAß was most frequent in the occipital lobe (79/86). CAA-Type1 was associated with the severity of CAA (p <  0.001), dementia (p <  0.001), severe AD-type neuropathology (p-value 0.09 for CERAD C and 0.017 for Braak stages V-VI), and APOE ɛ4 allele carrier status (p <  0.001). CONCLUSIONS: This population-based study confirmed the presence of distinct CAA-Type1 and its association with the severity of CAA, severe AD-type neuropathology, and the APOE ɛ4 carrier status. Both the severity and localization of the deposition seemed to determine the clinical significance of capAß.

Causes of death and life span in Finnish gelsolin amyloidosis.

BACKGROUND: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients' life span. METHODS: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates, we recorded the patients' underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs. RESULTS: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR = 114.2; 95% CI: 85.6-149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR = 0.47; 95% CI: 0.31-0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR = 2.82 95% CI: 1.13-5.81). The mean life span for male patients was 73.9 years (95% CI: 72.0-75.6) and 78.0 years for female patients (95% CI: 76.4-79.5) compared to 72.1 and 80.1 years for the general population. CONCLUSIONS: Our results suggest that the disease increases the risk of fatal renal complications but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers. Key Messages AGel amyloidosis may increase the risk of renal complications, especially among female patients. The frequency of fatal cancers is significantly lower. The patients' life span is comparable to that of the general population.

A novel transthyretin Lys70Glu (p.Lys90Glu) mutation presenting with vitreous amyloidosis and carpal tunnel syndrome.

OBJECTIVE: We describe a novel TTR mutation with vitreous opacities and carpal tunnel syndrome. MATERIALS AND METHODS: A 78 year-old woman with vitreous opacities, her daughter with dry eye syndrome, and brother with carpal tunnel syndrome were tested for a mutation in the TTR gene. The vitreous opacities were removed and stained with Congo red and immunohistochemistry against wild type TTR. Skin and gut biopsies and specimens of soft tissue were examined histopathologically. Leukocyte DNA from the proband was analysed by direct sequencing of exons 1 to 4 of the TTR gene and DNA from her daughter and brother using segregation analysis. RESULTS: A point mutation c.268 A>C, in the TTR gene, leading to a missense mutation p.Lys90Glu was found in all subjects. The vitreous opacities were pearl string-like. Histopathology showed red to green birefringence in Congo red, typical to amyloid, and the specimens were immunoreactive with antibodies against TTR. CONCLUSION: We present a novel autosomally inherited Lys90Glu mutation in the TTR gene. This is the first reported FAP family with this mutation in Finland.

Low trypsinogen-1 expression in pediatric ulcerative colitis patients who undergo surgery.

AIM: To investigate whether matrix metalloproteinases-9 (MMP-9) or trypsinogens could serve as histological markers for an aggressive disease course in pediatric ulcerative colitis (UC). METHODS: We identified 24 patients with pediatric onset (≤ 16 years) UC who had undergone surgery during childhood/adolescence a median of 2.1 years (range 0.1-7.4 years) after the diagnosis (between 1990 and 2008) in Children's Hospital, Helsinki, Finland. We also identified 27 conservatively treated UC patients and matched them based on their age at the time of diagnosis and follow-up at a median of 6 years (range 3-11 years) to serve as disease controls. Twenty children for whom inflammatory bowel disease (IBD) had been excluded as a result of endoscopy served as non-IBD controls. Colon biopsies taken by diagnostic endoscopy before the onset of therapy were stained using immunohistochemistry to study the expression of MMP-9, trypsinogen-1 (Tryp-1), Tryp-2, and a trypsin inhibitor (TATI). The profiles of these proteases and inhibitor at diagnosis were compared between the surgery group, the conservatively treated UC patients and the non-IBD controls. RESULTS: The proportions of Tryp-1 and Tryp-2 positive samples in the colon epithelium and in the inflammatory cells of the colon stroma were comparable between the studied groups at diagnosis. Interestingly, the immunopositivity of Tryp-1 (median 1; range 0-3) was significantly lower in the epithelium of the colon in the pediatric UC patients undergoing surgery when compared to that of the conservatively treated UC patients (median 2; range 0-3; P = 0.03) and non-IBD controls (median 2; range 0-3; P = 0.04). For Tryp-2, there was no such difference. In the inflammatory cells of the colon stroma, the immunopositivities of Tryp-1 and Tryp-2 were comparable between the studied groups at diagnosis. Also, the proportion of samples positive for TATI, as well as the immunopositivity, was comparable between the studied groups in the colon epithelium. In the stromal inflammatory cells of the colon, TATI was not detected. In UC patients, there were significantly more MMP-9 positive samples and a higher immunopositivity in the stromal inflammatory cells of the colon when compared to the samples from the non-IBD patients (P = 0.006 and P = 0.002, respectively); the immunopositivity correlated with the histological grade of inflammation (95%CI: 0.22-0.62; P = 0.0002), but not with the other markers of active disease. There were no differences in the immunopositivity or in the proportions of MMP-9 positive samples when examined by epithelial staining. The staining profiles in the ileal biopsies were comparable between the studied groups for all of the studied markers. CONCLUSION: For pediatric UC patients who require surgery, the immunopositivity of Tryp-1 at diagnosis is lower when compared to that of patients with a more benign disease course.

Xerostomia in hereditary gelsolin amyloidosis.

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a rare, dominantly inherited systemic disease with worldwide distribution, caused by c.654G > A or c.654G > T gelsolin gene mutation. The disease mainly manifests with late-onset dystrophy of the cornea, laxity of the skin and dysfunction of the cranial nerves whereas the oral manifestations have remained less-studied. To examine if AGel amyloidosis also affects salivary gland function, we studied 27 patients. In a questionnaire, 89% of them reported oral dryness, and 74% oral and ocular dryness. Unstimulated (UWS) and stimulated whole salivary flow (SWS) rates were measured, and salivary proteins were analyzed in the patients and controls. Hyposalivation according to UWS was detected in 67% of the patients, while decreased SWS occurred in 63% of the patients and 19% of the controls (p = 0.001). The secretion rates of salivary total protein and IgA were significantly lower in patients than controls. Histopathological analyses of labial salivary gland biopsies showed deposition of gelsolin amyloid, atrophy and inflammation. This study showed that AGel amyloidosis belongs to the differential diagnostic choices to be kept in mind in the patients presenting with xerostomia, low secretion rates of salivary total protein and IgA and/or deposition of amyloid in the minor salivary glands. AGel amyloidosis patients should be advised for efficient dental care.

Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population.

Pathogenic mutations of the APP gene, leading to early-onset Alzheimer's disease (AD) have been known for more than 20 years. Recently, it was discovered that APP mutations might also be protective. A rare variant A673T reportedly protects against AD and age-related cognitive impairment and might functionally inhibit proteolytic cleavage at the ß-secretase site of APP. We sequenced APP exon 16 in a population-based sample of 515 Finnish subjects aged 85 or older. Neuropathologic data were available in 274. We found the A673T variant in 1 subject (0.2%), who lived until age 104.8 years (second highest age-at-death in the cohort). Neuropathologic analysis showed little beta-amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease score 0). Some vascular amyloid was detected in meningeal arteries suggesting that vascular ß-amyloid accumulation might be less inhibited than the parenchymal. She was demented at the age of 104, most likely because of hippocampal sclerosis. The low amount of parenchymal ß-amyloid pathology at the age of 104.8 years supports the concept that the A673T variant protects the brain against ß-amyloid pathology and AD.

Intracerebral hemorrhage in the oldest old: a population-based study (vantaa 85+).

AIMS: Very elderly subjects represent the fastest growing population in the world. Most of the recent studies on intracerebral hemorrhage (ICH) have been carried out on younger patients and/or preferably using novel radiological techniques. We investigated the prevalence, risk factors, and histopathological characteristics of the ICH in the oldest old. MATERIALS AND METHODS: The brains of 300 autopsied individuals (248 females, 52 males, mean age at death 92.4 ± 3.7 years) were investigated as part of the prospective population-based Vantaa 85+ study. After macroscopic investigation, the presence and extent of microscopic brain hemorrhages (MH) were analyzed by counting the number of iron containing macrophages (siderophages) by Prussian blue staining. Deposits with >5 siderophages were defined as MH+, forming a subgroup of MH. Genotyping of apolipoprotein E (APOE) and the analysis of microscopic (MI) or larger infarctions and cerebral amyloid angiopathy (CAA) were performed using standardized methods. Regression analysis was used to predict the presence of ICH, with and without co-localized CAA, and was adjusted for age at death and gender. RESULTS: The prevalence of macroscopic ICH was 2.3% in total; consisting of 1% large lobar hemorrhage (LH), 1% deep hemorrhage (DH), and 0.3% of subarachnoid hemorrhage (SAH). 62% had MH and 15.3% MH+. All MH+ lesions were found to be >2 mm wide. 55.9% of subjects with MH and 81.2% of those with MH+ showed MH/MH+ and CAA in the same brain region (MHCAA and MH+CAA, respectively). MH was associated with none of the neuropathological or clinical conditions, nor with the APOE carrier status. The subjects with MH+, MHCAA or MH+CAA carried the APOE ε4 allele more frequently than controls (OR 3.681, 3.291, 7.522, respectively). Siderophages in MH+CAA co-localized with CAA and with two-thirds of the MI in the tissue sections. CONCLUSION: Macroscopic ICH was rare in the very elderly. MH was frequent and clinically insignificant. MH+ was rare but closely related with the APOE ε4 genotype and the presence of severe CAA and infarction.

Matrix metalloproteinase-ß19 expressed in cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a frequent finding in the brains of patients with Alzheimer's disease (AD). CAA may be complicated with CAA-associated intracerebral haemorrhage (CAAH). Previous studies have revealed matrix metalloproteinase (MMP) expression in a mouse model of CAA and in human intracerebral haemorrhage. Here we studied the involvement of MMPs in human CAA and CAAH. MATERIAL AND METHODS: To investigate the putative expression of MMPs in human CAA and CAAH (Step 1), immunohistochemistry (IHC) against MMPs-1, -2, -7, -9, -19 and -26 was applied on tissue microarray (TMA) constructed of cerebral samples from 29 individuals with AD, 15 with CAAH and 2 controls. The findings in TMA were confirmed (Step 2) in tissue samples from 64 individuals, 45 presenting with CAA (including 36 with CAAH) and 19 without CAA (including 11 with hypertensive cerebral haemorrhage). RESULTS: In Step 1, immunoreactivity against MMPs-19 and -26 was detected in cerebral blood vessels in CAA. The results were confirmed in Step 2, where CAA (p<0.001) and intracerebral haemorrhage (p=0.045) were associated with vascular immunoreactivity against MMP-19. Multivariate analysis showed that the association between vascular MMP-19 and intracerebral haemorrhage was dependent from CAA. MMP-26 associated with CAA (p=0.021) but not with intracerebral haemorrhage. CONCLUSION: This is the first human study showing local MMP-19 immunoreactivity in the Aß-amyloid-laden blood vessels in CAA, suggesting that MMPs may be involved in CAA.

APOE and AßPP gene variation in cortical and cerebrovascular amyloid-ß pathology and Alzheimer's disease: a population-based analysis.

Cortical and cerebrovascular amyloid-ß (Aß) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) ε4 is a major genetic modulator of Aß deposition and AD risk. Variants of the amyloid-ß protein precursor (AßPP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and AßPP variants in cortical and cerebrovascular Aß deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged ≥ 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the ε4 allele with cortical (p = 4.91 × 10-17) and cerebrovascular (p = 9.87 × 10-11) Aß deposition as well as with NIA-RI AD (p = 1.62 × 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the AßPP locus. In single SNP or haplotype analyses there were no statistically significant AßPP locus associations with cortical or cerebrovascular Aß deposition or with NIA-RI AD. We sequenced the promoter of the AßPP gene in 40 subjects with very high Aß deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular Aß depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE ε4 variant. Promoter mutations or common allelic variation in the AßPP gene do not have a major contribution to cortical or cerebrovascular Aß deposition, or very late-onset AD in this Finnish population based study.