Primary familial brain calcification linked to deletion of 5' noncoding region of SLC20A2.

OBJECTIVES: Primary familial brain calcification (PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients. MATERIALS AND METHODS: A Finnish family with three PFBC patients and five unaffected subjects was studied. Sanger sequencing was used to exclude mutations in the coding and splice site regions of SLC20A2, PDGFRB, and PDGFB. Whole-exome (WES) and whole-genome sequencing (WGS) were performed to identify the causative mutation. A SNP array was used in segregation analysis. RESULTS: Copy number analysis of the WGS data revealed a heterozygous deletion of ~578 kb on chromosome 8. The deletion removes the 5' UTR region, the noncoding exon 1 and the putative promoter region of SLC20A2 as well as the coding regions of six other genes. CONCLUSIONS: Our results support haploinsufficiency of SLC20A2 as a pathogenetic mechanism in PFBC. Analysis of copy number variations (CNVs) is emerging as a crucial step in the molecular genetic diagnostics of PFBC, and it should not be limited to coding regions, as causative variants may reside in the noncoding parts of known disease-associated genes.

APOE and AGT in the Finnish p.Arg133Cys CADASIL population.

BACKGROUND: CADASIL is an inherited systemic small vessel disease, the affected status of brain vessels leading to subcortical vascular dementia. The defective gene is NOTCH3 in which over 230 different pathogenic mutations have been identified. The clinical course of CADASIL is highly variable even within families. Previous studies have shown that additional genetic factors modify the phenotype. AIMS AND METHODS: Altogether, 134 Finnish CADASIL patients with p.Arg133Cys mutation were analysed for possible associations between the apolipoprotein E (APOE) genotype, angiotensinogen (AGT) p.Met268Thr polymorphism or neutral p.Ala202Ala NOTCH3 polymorphism and earlier first-ever stroke or migraine. RESULTS: We found no association between the APOE genotypes, AGT polymorphism, NOTCH3 polymorphism and earlier first-ever stroke or migraine. CONCLUSIONS: The APOE, AGT and NOTCH3 polymorphism did not modify the onset of strokes or migraine in our CADASIL sample, which is one of the largest mutationally homogenous CADASIL populations published to date. International collaboration, pooled analyses and genomewide approaches are warranted to identify the genetic factors that modify the highly variable CADASIL phenotype.

[11C]PIB, [18F]FDG and MR imaging in patients with mild cognitive impairment.

PURPOSE: Cortical glucose metabolism, brain amyloid ß accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer's disease (AD). The aim of this study was to compare the prognostic ability of [(11)C]PIB PET, [(18)F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI. METHODS: The study group comprised 29 patients with MCI who underwent [(11)C]PIB PET and MR imaging. Of these, 22 also underwent [(18)F]FDG PET. All subjects were invited back for clinical evaluation after 2 years. RESULTS: During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [(11)C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p < 0.05) predicted conversion to AD. Also reduced [(18)F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p < 0.05), but quantitative hippocampal volumes did not (p > 0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [(11)C]PIB retention in the lateral frontal cortex and [(18)F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other. CONCLUSION: The findings indicate that [(11)C]PIB and [(18)F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI.

Update of the original HDLS kindred: divergent clinical courses.

BACKGROUND: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first identified among a Swedish kindred with 17 cases. The average age of onset was 36 years. Autopsy in four cases revealed the presence of axonal spheroids. The causative gene is unknown. METHODS: We performed genealogical and longitudinal observations of the original kindred. Forty members were examined, five telephone-interviewed, and one of the original HDLS cases from 1984 was neuropathologically examined. The clinical course was documented. The cerebrospinal fluid (CSF) findings of two recently affected cases were examined, and one of those autopsied. RESULTS: Of those examined, two developed HDLS during our survey and 38 were healthy. Those interviewed by telephone were healthy. One had symptoms suggestive of HDLS in 1984, but autopsy during our survey showed no spheroids. This patient, two relatives healthy at our examination and one without symptoms at telephone interview had HDLS diagnoses in the 1984 report. Thus, four HDLS diagnoses were unconfirmed. The number of identified patients amounts to 15 among 75 individuals in four generations, including two recent cases who demonstrated a subacute multisystem encephalopathy in Case 1 and an insidious course in Case 2. CSF showed signs of neurodegeneration without inflammation, and autopsy verified HDLS in Case 1. CONCLUSIONS: Some HDLS cases were misdiagnosed with unspecified psychiatric diagnoses in affected relatives from the original 1984 publication. However, HDLS is an encephalopathy dominated by a frontal lobe syndrome with an inexorably progressive and fatal course, where the different symptomatology in two recent cases confirmed the existence of acute and chronic variants.

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Quality of life among lower extremity peripheral arterial disease patients who have undergone endovascular or surgical revascularization: a case-control study.

OBJECTIVES: To assess the quality of life (QoL) of peripheral arterial disease (PAD) patients who have undergone either percutaneous transluminal angioplasty (PTA) only and/or one or more surgical revascularizations. DESIGN: A postal questionnaire study in which a case-control methodology was applied. MATERIALS AND METHODS: 131 patients with PTAs (mean age 70.7, SD 10.4 yrs; range 39-89, 58% men) and 100 with surgical revascularizations (mean age 67.8, SD 10.4 yrs; range 43-91, 62% men), in 1998-2003, and their age- and gender-matched controls were studied. The mean time since the last revascularization for PTA was 2.7, SD 1.3 yrs and for operated patients 3.5, SD 1.8 yrs. Ankle-brachial pressure index (ABI) and Mini-Mental-State Examination (MMSE) score were obtained from 70% of the patients. QoL was assessed using 15D Health-related QoL instrument, Rand-36 Physical Functioning subscale, 6-item Brief Social Support Questionnaire, Geriatric Depression Scale (GDS), Self-reported Life Satisfaction (LS) score, and one 'perceived state of health' question. RESULTS: Patients after endovascular and/or surgical revascularization (most with ABIs 0.5-0.89 and without cognitive impairment), had similarly lower QoL, GDS and LS indicated more depression than their controls. CONCLUSION: Poor QoL and depression should be thoroughly considered, alongside proper follow-up and ABI-measurements.

Homocysteine and holo-transcobalamin and the risk of dementia and Alzheimers disease: a prospective study.

BACKGROUND: Elevated total homocysteine (tHcy) levels may be caused by vitamin B12 deficiency and are linked to Alzheimers disease (AD) in some studies, although the evidence is mixed. Another marker of vitamin B12 deficiency, holo-transcobalamin (holo-TC), has not been studied in a prospective setting. OBJECTIVE: To investigate the association between tHcy and holo-TC and the subsequent development of dementia and AD in a prospective study. METHODS: A sub-sample of 228 non-demented subjects was taken from the Kungsholmen Project, a population-based longitudinal study amongst persons 75+ years. tHcy and holo-TC were analysed at baseline. RESULTS: Increasing tHcy levels were related to an increased risk of dementia (n = 83) and AD (n = 61) after a mean follow-up time of 6.7 years. Persons with high tHcy (the fourth quartile) had more than twice as high a risk of developing AD than persons with low tHcy, even after adjusting for confounding or mediating factors. The third quartile of holo-TC was associated with a reduced risk of AD, after adjusting for Hcy and other confounders. CONCLUSIONS: These results suggest that Hcy is involved in the development of dementia and AD. The role of holo-TC was less clear and this marker needs to be studied further.

PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease.

Variant Alzheimer's disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1Delta E9). VarAD is neuropathologically characterized by the presence of unusually large, Abeta42 positive, non-cored 'cotton wool' plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [(11)C]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [(11)C]PIB binding to the amount and type of Abeta deposits in another group of deceased VarAD patients' brains. We studied four patients with VarAD and eight healthy controls with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 60-90 min. Group differences in [(11)C]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [(11)C]PIB uptake was compared to the immunohistochemically demonstrated deposition of Abeta in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [(11)C] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [(11)C]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43% greater than the mean of the control group. The increases in the anterior (28%) and posterior (27%) cingulate gyrus, occipital cortex (21%) and thalamus (14%) were smaller. All VarAD patients showed this similar topographical pattern of increased [(11)C]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [(11)C]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to detect amyloid accumulation in vivo in these patients. The pattern of increased [(11)C]PIB uptake is different from that described in sporadic Alzheimer's disease and resembles that seen in Alzheimer's disease patients with certain presenilin-1 mutations or amyloid precursor protein gene duplication showing predominantly striatal increase in [(11)C]PIB uptake.

The tau S305S mutation causes frontotemporal dementia with parkinsonism.

Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.

Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.

Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.

Assessment of driving after stroke--a pluridisciplinary task.

UNLABELLED: The aim of the study was to analyze the assessment procedure and identify predictors for the team decision when assessing fitness to drive a car after stroke. The material used was a retrospective data set with 200 stroke clients from Queen Elisabeth's Foundation Mobility Centre at Banstead UK. Fifty-four percent of clients were considered fit to continue driving where 9% could resume driving after car adaptation and training. Important factors for the outcome were vision (acuity and field), neuropsychological functions (divided attention), and track and/or on road test (reaction time, anticipation, speed, and positioning). Cognitive impairment was the main problem in those who failed the driving test and judged not fit for continued driving. Car adaptation, mainly comprising infrared transmitted secondary controls together with automatic transmission was recommended in 35% of the cases. CONCLUSIONS: The contribution of different specialist groups appears to be necessary for an effective evaluation, but the assessment procedure can be done more cost-effectively by dividing it into two separate parts and removing certain subtests. The in-car track test is an important part of the assessment procedure with a high face validity and could in many cases make it unnecessary to perform in-traffic tests with unsafe drivers. Car adaptation is often necessary for a client with pronounced hemi-paresis and a full road test can for those only be performed after training the use of car controls.

Stearic acid is well absorbed from short- and long-acyl-chain triacylglycerol in an acute test meal.

OBJECTIVE: Absorption of stearic acid from natural oils has been shown to be efficient, but it is claimed to be lower from short- and long-acyl-chain triacylyglycerol molecules (Salatrim). The aim was to measure the apparent absorption of stearic acid from Salatrim fat in an acute test meal. DESIGN: Double-blind crossover study. SUBJECTS: Ten healthy male volunteers, of whom eight completed the study. METHODS: The subjects were studied on two occasions after consumption of a single high-fat meal either without (control) or with 30 g of Salatrim. Fecal samples were collected for 96 h after the meal and the fat was extracted for analysis of the content and composition of free and esterified long-chain fatty acids. RESULTS: Baseline fecal fat was 5.6+/-2.6 g/day increasing to 10.4+/-4.9 g/day after addition of Salatrim (P=0.001). During the whole collection period, the baseline fecal free and esterified fatty acids were 2.6+/-2.3 and 0.8+/-0.7 g, respectively. After Salatrim meal the corresponding figures increased to 5.9+/-3.6 g (P=0.001) and 1.5 (+/-1.2) g (P=0.003), respectively. The total fecal stearic acid after control meal was 0.97+/-0.9 g. Consumption of Salatrim with 16.7+/-0.5 g of stearic acid increased the content to 3.12+/-1.6 g (P<0.001), with apparent absorption of 87%. CONCLUSIONS: The apparent absorption of stearic acid does not differ from its absorption from natural fats. The status of Salatrim as a low-energy fat substitute needs to be re-evaluated. SPONSORSHIP: University of Turku.

Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation.

BACKGROUND AND PURPOSE: CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. METHODS: The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. RESULTS: The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. CONCLUSIONS: Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.

Long-term treatment with tacrine (THA) in Alzheimer's disease--evaluation of neuropsychological data.

Long-term effects of tacrine (THA) on cognitive functions of very mild AD patients were studied. The stability of possible positive changes following prolonged treatment and the effect of increased dose was also studied. Three patients were treated with tacrine (80 mg/day) and the effect on cognitive functions was measured with a neuropsychological test battery. Two of the patients (Pats 1 and 4) showed clear positive changes in all parameters measured. The third patient (Pat 5) did not show as clear positive responses. The effect of the initial treatment dose diminished over time. After raising the dose two of the patients showed improvement in cognitive tests reaching their initial level of performance or even better in most of the tests. This positive effect was not as clear in patient 5. After 13 months of tacrine all patients still showed positive changes in some of the tests. Compared to a hypothetical progression curve for untreated AD patients the patients treated with tacrine seemed to have slower progression. In conclusion, it seems that long-term positive effects on cognitive functions of AD patients can be reached with tacrine and it seems to be possible to slow down the progression of the disease. However, to reach long-term positive effects increasing doses seem to be needed. AD patients seem to differ in their response to tacrine.

EEG regional changes during long-term treatment with tetrahydroaminoacridine (THA) in Alzheimer's disease.

Three patients with Alzheimer's disease of mild type received long-term treatment with THA at doses between 40 mg to 160 mg daily. This study describes the effects of THA on EEG, seen during long-term and high dose treatments. After short-term treatment, the changes of the mean frequency in the temporal and parieto-occipital regions varied between patients, but in the frontal region a significant increase of the mean frequency was seen in all patients. The EEG improvement seen in the frontal region was more significant than that for the other regions at low dose of THA (80 mg). During long-term treatment, we observed different types of EEG changes. The early improvement seen in two patients was temporary and reverted to the pre-treatment value. In a third patient who did not show marked improvement after short-term treatment, an improvement was seen in all regions after longer treatment. Treatment with high doses of THA (120 mg or 160 mg) induced a marked increase in the mean frequency not only in the frontal region but also in the temporal and parieto-occipital regions. Higher doses of THA seem to affect larger areas of the brain than lower doses of THA.

Serum dehydroepiandrosterone sulfate in Alzheimer's disease and in multi-infarct dementia.

Circulating levels of dehydroepiandrosterone sulfate (DHEAS) and cortisol were studied in 86 patients with dementia; 45 with Alzheimer's disease and 41 with multi-infarct dementia. Compared to an elderly control group, after adjustment for age and sex, patients with Alzheimer's disease were found to have lower serum levels of DHEAS. We found a covariation between serum albumin and DHEAS levels, which may be of importance regarding peripheral hormone concentration in patients with dementia. These findings may provide evidence for a role of DHEAS in amnestic disorder in humans, either reflecting or contributing to the course of dementing diseases.

Blunted adrenocorticotropin and increased adrenal steroid response to human corticotropin-releasing hormone in Alzheimer's disease.

Previous studies suggest disturbances in the central regulation of the hypothalamic-pituitary-adrenocortical axis (HPA) in advanced Alzheimer's disease (AD). In this study the reactivity of the HPA axis was evaluated by stimulation with corticotropin-releasing hormone (CRH) of patients with mild to moderate AD. Twenty-three patients with AD (aged 61-88 yr) and 19 healthy elderly (aged 62-84 yr) received an intravenous bolus injection of human CRH (1 microgram/kg) at 3:00 PM. CRH-stimulated plasma ACTH levels were significantly lower in AD patients, while serum cortisol, dehydroepiandrosterone, and androstenedione responses relative to the amount of ACTH released were higher in AD patients. Significant correlations were found between low basal plasma ACTH levels and temporal lobe atrophy (p=0.02) and between peak plasma ACTH levels and hippocampal atrophy (p = 0.01). These findings suggest abnormalities at several levels of HPA axis in AD.

Depression and dementia in relation to apolipoprotein E polymorphism in a population sample age 75+.

The aim of this study was to define the co-occurrence of depression and dementia in relation to apolipoprotein E (APOE) polymorphism. Physicians extensively examined 806 persons aged 78 years and over. DNA was extracted from peripheral white blood cells, and APOE genotype was determined using a microsequencing method on microtiter plates. The prevalence of dementia was 22.8% and was found to increase with the number of epsilon 4 alleles present. Depression was found in 11.4% of the demented subjects compared to 3.5% of the nondemented subjects. The overrepresentation of depression in demented subjects was found for each of the common genotypes. Depression was not strongly associated with APOE polymorphism. In spite of the association between dementia and APOE polymorphism, as well as dementia and depression, there was no association between APOE polymorphism and depression.

Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography.

Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [18F]-fluoro-deoxy-glucose (18F-FDG) (tracer for glucose metabolism); 11C-butanol (cerebral blood flow) and (S)(-)- and (R)(+)-[N-11C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of 11C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(-)- and (R)(+)11C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(-)11C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.

Clinical diagnosis of Alzheimer's disease and other dementias in a population survey. Agreement and causes of disagreement in applying Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, Criteria.

In a population survey aimed to detect cases of Alzheimer's disease and other dementias, two preliminary diagnoses were made independently with the purpose of using the concordant diagnoses as final diagnoses. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, diagnostic criteria were followed. The 668 subjects examined were selected from the population of an area in Stockholm, Sweden, aged 75 years or more, with the Mini-Mental State Examination used as a screening test. The agreement on dementia diagnosis was moderate (kappa = .54) and could be clearly improved (kappa = .70) with modifications to the diagnostic criteria, such as adding a category of questionable dementia and giving more guidelines in the definition of impairment of a function. The agreement on the diagnosis of Alzheimer's disease vs vascular dementia vs secondary dementia was substantial (kappa = .67) when the cases with concordant dementia diagnoses were examined.