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Idiopathic normal pressure hydrocephalus (iNPH) is a late-onset surgically alleviated, progressive disease. We characterize a potential familial subgroup of iNPH in a nation-wide Finnish cohort of 375 shunt-operated iNPH-patients. The patients were questionnaired and phone-interviewed, whether they have relatives with either diagnosed iNPH or disease-related symptomatology. Then pedigrees of all families with more than one iNPH-case were drawn. Eighteen patients (4.8%) from 12 separate pedigrees had at least one shunt-operated relative whereas 42 patients (11%) had relatives with two or more triad symptoms. According to multivariate logistic regression analysis, familial iNPH-patients had up to 3-fold risk of clinical dementia compared to sporadic iNPH patients. This risk was independent from diagnosed Alzheimer's disease and APOE epsilon 4 genotype. This study describes a familial entity of iNPH offering a novel approach to discover the potential genetic characteristics of iNPH. Discovered pedigrees offer an intriguing opportunity to conduct longitudinal studies targeting potential preclinical signs of iNPH. (C) 2016 Elsevier B.V. All rights reserved.

The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH).We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age65 years).While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52-67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers.This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.

Recent studies have shown an epidemiological and immunological association between bullous pemphigoid (BP) and several neurological or psychiatric diseases. Here, our aim was for the first time to specify whether an association exists between BP and frontotemporal lobar degeneration (FTLD). Medical histories of FTLD patients (N = 196) were screened for clinical comorbidity, and BP180 and BP230 autoantibodies were analyzed in the sera of FTLD patients (N = 70, including 24 C9orf72 repeat expansion carriers) by BP180-NC16A-ELISA and BP230-ELISA. One FTLD patient (C9orf72 repeat expansion carrier) had a comorbid diagnosis of BP. Increased levels of serum BP180 autoantibodies (cutoff value >9 U/ml) were detected more often in FTLD patients (10.0%) than in controls (4.9%). Moreover, elevated levels of both BP180 and BP230 autoantibodies were found more often in C9orf72 repeat expansion-carrying FTLD than non-carrying patients or controls. However, none of these differences reached a statistical significance likely due to our limited cohort size. In conclusion, our findings suggest that subset of FTLD patients especially with the C9orf72 repeat expansion may have an immunological association with BP.

Background The longitudinal pattern of medication use among family caregivers of people with dementia is not well understood, despite the potential for medication over- or under-use. Objectives To investigate caregiver medication use over a five-year follow-up using data obtained via self-report and from a national prescription register, and compare agreement between medication data obtained from the two sources. Methods Medication data for 222 family caregivers of people with Alzheimer’s disease were obtained via self-report and from the Finnish Social Insurance Institution. Generalised estimating equations, Kappa statistics and related samples Wilcoxon signed rank test were used to analyse medication use over time. Results The mean number of medications used by caregivers increased from 3.4 to 4.1 (self-reported current regular medications) and 2.4 to 2.8 (reimbursed prescription medications during the past 90 days) over five years (p Conclusion Caregivers use an increasing number of medications in the first five years of caring for persons with dementia, and self-report using a higher number of medications than data from the national prescription register suggest.

Background Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer's disease (AD), but their relationship is unclear. Objectives To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD. Methods We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer's Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up period were used. Results Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL. Conclusion Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD.

Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study.

Background The neuropathology of Alzheimer's disease (AD) has previously been shown to be rather common among the elderly. Objective The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEɛ4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. Methods This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEɛ4 status were analyzed. Results Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. Conclusion AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes.

Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer’s disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD. In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients. Electronic supplementary material The online version of this article (10.1186/s40478-018-0605-2) contains supplementary material, which is available to authorized users.

Objective Occasionally, a favorable clinical disease-specific outcome does not reflect into improved generic health-related quality of life (HRQoL) in patients with idiopathic normal-pressure hydrocephalus (iNPH) at 1 year after the installation of a cerebrospinal fluid shunt. Our aim was to identify factors causing this discrepancy. Methods The 1-year HRQoL outcomes of 141 patients with iNPH were evaluated with the generic 15D instrument, in which the minimum clinically important change/difference on the 0–1 scale has been estimated to be ±0.015. A 12-point iNPH grading scale (iNPHGS) was used as a clinical disease-specific outcome measure, in which a 1-point decrease is considered to be clinically important. We identified 29 (21%) patients with iNPH from our prospective study whose HRQoL deteriorated or remained the same despite of a favorable iNPHGS outcome. We analyzed this discrepancy using patients' clinical variables and characteristics. Results Multivariate binary logistic regression analysis indicated that a greater (worse) iNPHGS score at baseline (adjusted odds ratio [OR], 1.7; 95% confidence interval [CI] 1.3–2.3; P < 0.001), comorbid chronic pulmonary disease (40% vs. 20%; adjusted OR 17.8; 95% CI 3.6–89.9; P < 0.001), and any comorbid nonmetastatic tumor (62% vs. 17%; adjusted OR 11.5; 95% CI 1.5–85.3; P = 0.017) predicted discrepancy between iNPHGS and 15D outcomes. Conclusions Frail patients suffering from certain pre-existing comorbidities may not experience improvement in generic HRQoL despite of a favorable clinical disease-specific response. Acknowledging the comorbidity burden of the patient may help clinicians and the patients to understand the conflict between patient-reported and clinical outcomes., final draft, peerReviewed

BACKGROUND Alzheimer's disease (AD) is characterized by deterioration in cognition, decline in physical function, and increase in behavioral disturbances. These symptoms are associated with dependence. OBJECTIVE We investigated the use of anti-dementia drugs in relation to change in cognition, function, and behavior over a 3-year period. METHODS Data were collected as part of the prospective follow-up ALSOVA study. All study participants (n = 236) had very mild or mild AD at baseline. All participants and their informal caregivers underwent annual clinical and medication assessments. Repeated measures logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with anti-dementia drug use and disease progression measures over time. RESULTS The overall prevalence of anti-dementia drug use remained stable (from 89% to 92%) during the follow-up period. The use of memantine and cholinesterase inhibitor-memantine combination treatment increased with disease severity. After adjustment for confounding, a one-point increase in the disease severity scale (CDR-SOB) was associated with 15.6% increased odds of memantine use. A one-point decrease in CERAD Neuropsychological battery (CERAD-NB) total score was associated with 2.4% increased odds of memantine use. The overall unadjusted rate of switching between anti-dementia drugs was 9.17 (95% CI 7.10 to 11.88) changes per 100 person-years. CONCLUSION Nearly 90% of newly diagnosed persons with AD were prescribed anti-dementia drugs. Use of memantine was found to be associated with disease progression. Switching and use of anti-dementia drugs was consistent with Finnish and European clinical practice guidelines for AD.

Various radiological markers have been proposed for diagnostics in idiopathic normal pressure hydrocephalus (iNPH). We examined the usefulness of radiological markers in the diagnostics and prediction of shunt response in iNPH. In this retrospective cohort study, we evaluated brain CT or MRI scans of 390 patients with suspected iNPH. Based on a 24-h intraventricular pressure monitoring session, patients were classified into a non-NPH (n = 161) or probable iNPH (n = 229) group. Volumes of cerebrospinal fluid compartments (lateral ventricles, sylvian and suprasylvian subarachnoid spaces and basal cisterns) were visually assessed. Disproportionally enlarged subarachnoid spaces, flow void, white matter changes, medial temporal lobe atrophy and focally dilated sulci were evaluated. Moreover, we measured quantitative markers: Evans’ index (EI), the modified cella media index, mean width of the temporal horns and callosal angle. iNPH was more likely in patients with severe volumetric disproportion between the suprasylvian and sylvian subarachnoid spaces than in those without disproportion (OR 7.5, CI 95 % 4.0–14.1, P

Background and purpose Factors affecting health-related quality of life (HRQoL) were explored in patients with idiopathic normal pressure hydrocephalus (iNPH). Methods Using the 15D instrument HRQoL was evaluated in 132 patients diagnosed with iNPH by clinical and neuroradiological examinations. The severity of iNPH symptoms was measured with the iNPH grading scale (iNPHGS), depressive symptoms with the Beck Depression Inventory (BDI-21) and cognitive impairment with the Mini-Mental State Examination. Results The mean (SD) 15D score (on a 0–1 scale) of patients with iNPH was significantly lower than that of an age- and gender-matched sample of the general population [0.718 (0.103) vs. 0.870 (0.106); P

Background/Aims: Measuring and predicting Alzheimer's disease (AD) progression is important in order to adjust treatment and allocate care resources. We aimed to identify a combination of subtests from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) that best correlated with AD progression in follow-up as well as to predict AD progression. Method: A total of 236 participants with very mild [Clinical Dementia Rating (CDR) = 0.5] or mild AD (CDR = 1.0) at baseline were followed up for 3 years. The CERAD-NB and Mini-Mental State Examination (MMSE) were used to assess cognition, and the CDR scale sum of boxes (CDR-sb) was employed to evaluate AD progression. Generalized estimating equations were used to develop models to predict and follow up disease progression. Results: Performance declined on all CERAD-NB subtests. The ability of the separate subtests to distinguish between groups (baseline CDR = 0.5 or 1.0) diminished during follow-up. The best combination of subtests that explained 62% of CDR-sb variance in follow-up included verbal fluency, constructional praxis, the clock drawing test, and the MMSE. Baseline values of the same combination predicted 37% of the CDR-sb change. Conclusion: A short version of the CERAD-NB subtests provides a promising and time-efficient alternative for measuring cognitive deterioration during AD follow-up. Although the initial signs of AD include memory difficulties, it may be useful to assess non-memory tasks in follow-up.

OBJECTIVES Family caregivers (FCs) face a variety of demands while caring for persons with Alzheimer disease (AD). Longitudinal studies identifying the specific AD-related neuropsychiatric symptoms (NPS) that contribute to FC distress are rare. We analyzed which NPS in association with care recipient and caregiver demographic factors are associated with FC psychological distress over a 36-month follow-up period. DESIGN This is a longitudinal study with annual follow-up. Participants were people with AD (n = 226) and their FCs (n = 226). MEASUREMENTS The Neuropsychiatric Inventory was used to assess NPS, and The General Health Questionnaire was used as a measure of caregiver distress. The effect of NPS on FC psychological distress over time was analyzed using a linear-mixed effect model. RESULTS Delusions (P = .003), agitation (P

BACKGROUND Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH. OBJECTIVE We aim to evaluate the role of AD-related polymorphisms in iNPH. METHODS Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. RESULTS Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. CONCLUSIONS Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

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International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

BACKGROUND Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. OBJECTIVE To investigate the individual and combined risk effects of the newly identified AD loci. METHODS Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. RESULTS Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-e4 associated with CSF Aβ42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction. CONCLUSIONS AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.

Background: Poly-T repeat lengths of rs10524523 in TOMM40 together with APOE polymorphism have been reported to affect the risk of late-onset Alzheimer's disease (LOAD) and the age of onset (AOO). Objective: To explore whether the AOO and cerebrospinal fluid biomarkers Aβ42, total tau and phosphorylated tau are associated with different repeat lengths. Methods: We conducted both the fragment and sequencing analysis of rs10524523 in 336 LOAD patients with a known APOE genotype. Results: AOO and Aβ42 levels associated significantly with certain poly-T repeat lengths of rs10524523 in LOAD patients encompassing APOE 34/44 genotype. Conclusion: We conclude that the poly-T repeat associations of rs10524523 in TOMM40 reflect the APOE ε4-dependent association in LOAD.

Backgound/Objective: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [18F]flutemetamol and the level of amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. Methods: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [18F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. Results: Four of the 17 patients (23.5%) had amyloid-ß pathology based on the overall pathology read and also showed increased [18F]flutemetamol uptake. [18F]Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-ß levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-ß level and uptake of [18F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [18F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. Conclusions: [18F]Flutemetamol detects brain amyloid-ß in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population.

ObjectiveTo evaluate the role of the copy number loss in SFMBT1 in a Caucasian population.MethodsFive hundred sixty-seven Finnish and 377 Norwegian patients with idiopathic normal pressure hydrocephalus (iNPH) were genotyped and compared with 508 Finnish elderly, neurologically healthy controls. The copy number loss in intron 2 of SFMBT1 was determined using quantitative PCR.ResultsThe copy number loss in intron 2 of SFMBT1 was detected in 10% of Finnish (odds ratio [OR] = 1.9, p = 0.0078) and in 21% of Norwegian (OR = 4.7, p < 0.0001) patients with iNPH compared with 5.4% in Finnish controls. No copy number gains in SFMBT1 were detected in patients with iNPH or healthy controls. The carrier status did not provide any prognostic value for the effect of shunt surgery in either population. Moreover, no difference was detected in the prevalence of hypertension or T2DM between SFMBT1 copy number loss carriers and noncarriers.ConclusionsThis is the largest and the first multinational study reporting the increased prevalence of the copy number loss in intron 2 of SFMBT1 among patients with iNPH, providing further evidence of its role in iNPH. The pathogenic role still remains unclear, requiring further study.

Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce.To elucidate the long-term cognitive condition of shunt-responsive iNPH patients.The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years.At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition.The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH-related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities.

This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical biopsy.Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain.[18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-β levels contralateral (r = 0.86, P 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003).[18F]Flutemetamol detects brain amyloid-β in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-β pathology, both in patients with possible NPH and among the wider population.

Objectives: Optimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer's disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH. Methods: In this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients' memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure. Results: Our analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC?=?0.58). Conclusions: Prediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.

To examine the association between neuropsychiatric symptoms (NPS) with self- and caregiver-rated Quality of Life (QoL) for patients with Alzheimer's disease (AD) during a 5-year follow-up.The ALSOVA 5-year follow-up study included, at baseline, 236 patients with either very mild (Clinical Dementia Rating Scale (CDR) 0.5), or mild (CDR 1) AD, together with their caregivers from three Finnish hospital districts. QoL was evaluated using patient self-reported, and caregiver-rated, QoL in AD (QoL-AD) scores. NPS were assessed using the Neuropsychiatric Inventory (NPI), and AD severity was evaluated using the CDR, with cognition tested by the mini-mental state examination. The performance of daily activities was assessed using the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory.Over the 5-year follow-up period, patient self-reported QoL-AD scores did not change significantly (p = 0.245), despite increases in their NPS. However, caregiver-rated patient QoL-AD scores declined significantly (p ≤ 0.001), as total NPI scores increased during follow-up. No NPS at baseline, and only apathy at follow-up, correlated significantly (p = 0.007) with patient self-rated QoL-AD scores. Caregiver-rated patient QoL-AD scores correlated significantly with most NPS, especially (p ≤ 0.001) apathy, agitation, anxiety, irritability, depression, and delusions at baseline, and delusions, hallucinations, apathy, appetite disturbances, and anxiety during follow-up.Patient rated QoL-AD scores are an unreliable tool with which to evaluate the success of therapy for NPS. Instead, caregiver-rated scores for patients correlated well with NPI scores, and health care professionals in the clinic should preferentially use these. Copyright © 2017 John WileySons, Ltd.

It remains unclear how intracranial pressure (ICP) measures are associated with brain biopsies and radiological markers. Here, we aim to investigate associations between ICP and radiological findings, brain biopsies, and shunt surgery outcome in patients with suspected idiopathic normal pressure hydrocephalus (iNPH). In this study, we retrospectively analyzed data from 73 patients admitted with suspected iNPH to Kuopio University Hospital. Of these patients, 71% underwent shunt surgery. The NPH registry included data on clinical and radiological examinations, 24-h intraventricular pressure monitoring, and frontal cortical biopsy. The mean ICP and mean ICP pulse wave amplitude were not associated with the shunt response. Aggregations of Alzheimer’s disease (AD)-related proteins (amyloid-β, hyperphosphorylated tau) in frontal cortical biopsies were associated with a poor shunt response (P = 0.014). High mean ICP was associated with Evans’ index (EI; P = 0.025), disproportional sylvian and suprasylvian subarachnoid spaces (P = 0.014), and focally dilated sulci (P = 0.047). Interestingly, a high pulse wave amplitude was associated with AD-related biopsy findings (P = 0.032), but the mean ICP was not associated with the brain biopsy. The ICP was not associated with medial temporal lobe atrophy, temporal horn widths, or white matter changes. ICP B waves were associated with less atrophy of the medial temporal lobe (P = 0.018) and more severe disproportionality between the sylvian and suprasylvian subarachnoid spaces (P = 0.001). The EI and disproportional sylvian and suprasylvian subarachnoid spaces were associated with mean ICP. Disproportionality was also associated with ICP B waves. These associations, although rather weak, with elevated ICP in 24-h measurements, support their value in iNPH diagnostics and suggest that these radiological markers are potentially related to the pathogenesis of iNPH. Interestingly, our results suggested that elevated pulse wave amplitude might be associated with brain amyloid accumulation.

Bullous pemphigoid (BP) is a subepidermal blistering skin disease, which has shown a strong association with neurological diseases in epidemiological studies. The BP autoantigens BP180 and BP230 are expressed in the cutaneous basement membrane and the central nervous system. Using BP180 and BP230 ELISA assays and immunoblotting against BP180, we analyzed the IgG reactivity in the sera of 115 patients with Alzheimer's disease (AD) and 40 neurologically healthy controls. BP180 autoantibodies were found in 18% of patients with AD, whereas only 3% of controls had positive results (P = 0.019). BP230 values were higher and more often elevated in patients with AD than controls, but not significantly. None of the positive AD sera that recognized the full-length human BP180 in immunoblotting reacted with the cutaneous basement membrane in indirect immunofluorescence analysis. Moreover, a retrospective evaluation of the hospital records of the patients with AD revealed neither BP diagnosis nor BP-like symptoms. Interestingly, increased BP180-NC16A autoantibody values correlated with cognitive decline measured by mini-mental state examination scores, but not with the concentration of AD biomarkers in cerebrospinal fluid. Our findings further the understanding of the role of BP180 as a shared autoantigen in neurodermatological interactions and the association between BP and neurodegenerative diseases.

Background Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known. Objectives We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH. Methods A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years. Results Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer's disease (n = 94, 36%), followed by vascular dementia (n = 68, 26%). Conclusions One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized.

Background and purpose This prospective study explored the factors affecting the health-related quality-of-life (HRQoL) outcome in patients with idiopathic normal-pressure hydrocephalus (iNPH) 1 year after the installation of the cerebrospinal fluid shunt. Methods The HRQoL outcome was evaluated using a 15D instrument, in which the minimum clinically significant change/difference has been estimated to be ±0.015. The follow-up data (15D, Mini-Mental State Examination, Beck Depression Inventory, iNPH Grading Scale), frontal cortical biopsy, Charlson Age Comorbidity Index and body mass index of 145 patients diagnosed with iNPH by clinical and radiological examination were analyzed. Results At 1-year follow-up, 63 (43%) patients had experienced a clinically significant improvement in HRQoL. Multivariate binary logistic regression analysis indicated that the absence of amyloid-β and hyperphosphorylated tau pathology in the frontal cortical biopsy (53% vs. 33%; absolute risk difference, 20%; adjusted odds ratio, 2.27; 95% confidence interval, 1.07–4.84; P < 0.05) and lower body mass index (adjusted odds ratio, 0.90, 95% confidence interval, 0.82–0.98; P < 0.05) predicted favorable HRQoL outcome 1 year after the shunting. Conclusions Less than half of the patients with iNPH experienced clinically significant favorable HRQoL outcome, partly explained by the patient's characteristics and comorbidities. The HRQoL approach reveals aspects that are important for the patient's well-being, but may also improve the quality of the outcome assessment of cerebrospinal fluid shunting. Study results may help clinicians to estimate which patients will benefit shunt surgery.

To examine caregivers’ health-related quality of life (HRQoL) and well-being during the first 3 years after their family member’s Alzheimer’s disease (AD) diagnosis and assessed the relationship between caregivers’ HRQoL, well-being, and the severity of AD. Further, to compare of caregivers’ HRQoL to general population. Longitudinal design (36 months) after AD diagnosis of 236 caregiver–patient dyads. Linear regression was used to assess age- and gender-adjusted association between repeated measurements of caregivers’ HRQoL and the severity of AD. For comparison with general population, the National Health 2011 Health Examination Survey data was utilized. Caregivers had significantly lower HRQoL than age- and gender-standardized counterparts. Severity of AD was significantly (p

Family caregivers provide the majority of home care of people with Alzheimer's disease. In this study, we discuss family caregivers' life orientation and changes in life orientation during the first year after the diagnosis of Alzheimer's disease. Family caregivers' unstructured diaries (n = 83), of the first six months after diagnosis (years 2002-2004), were analyzed using qualitative content analysis. Two core themes emerged from the data analysis: the meaning of the onset of Alzheimer's disease for the lives of family caregivers, and restructuring life in its entirety. Family caregivers face challenges in their life orientation after the onset of their family members' Alzheimer's disease. Their personal milieu, familial cohesion, and conception of the future consequentially change. They face multiple challenges in the process of becoming caregivers. In this study, it was revealed that the process starts before the diagnosis of Alzheimer's disease and has an impact on their future. We conclude that family caregivers' well-being should be assessed at the time of the diagnosis of Alzheimer's disease.

Objective To investigate the association of apolipoprotein E ( APOE ) genotype, especially the APOE4 allele, to (1) idiopathic normal pressure hydrocephalus (iNPH) and (2) amyloid-β (Aβ) plaques in cortical brain biopsies of presumed NPH patients with and without a final clinical diagnosis of Alzheimer9s disease (AD). Methods 202 patients with presumed NPH were evaluated by intraventricular pressure monitoring and frontal cortical biopsy immunostained against Aβ (134 semiquantified by Aβ plaques/mm 2 ). The 202 patients and 687 cognitively healthy individuals were genotyped for APOE . The final clinical diagnoses in a median follow-up of 3.9 years were: 113 iNPH (94 shunt responsive, 16 shunt non-responsive, three not shunted); 36 AD (12 mixed iNPH + AD); 53 others. Results The APOE genotypes distributed similarly in the 94 shunt responsive and 16 non-responsive iNPH patients and healthy controls. In multivariate analysis, the APOE4 allele correlated independently with Aβ plaques in the cortical biopsies (OR 8.7, 95% CI 3.6 to 20, p APOE4 allele in presumed NPH predicted later AD as follows: sensitivity 61%; specificity 77%; positive predictive value 37%; negative predictive value 90%. Conclusion In presumed NPH patients, APOE4 associates independently with the presence of Aβ plaques in the frontal cortical biopsy. APOE4 is not a risk factor for iNPH and does not predict the response to shunt. Our data further support the view that the iNPH syndrome is a distinct dementing disease. Trial registration number Kuopio NPH Registry (http://www.uef.fi/nph)

Background/Aim: Alzheimer’s disease (AD) causes impairment in memory and other cognitive functions as well as neuropsychiatric symptoms and limitations in the activities of daily living (ADL). The aim of this study was to examine whether demographic variables, dementia severity, ADL and neuropsychiatric symptoms are associated with cognition in very mild or mild AD. Methods: We analyzed the baseline data of 236 patients with very mild or mild AD participating in a prospective AD follow-up study (ALSOVA). The Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery total score was used in the evaluation of the global cognitive performance. Results: Cognition was associated with dementia severity and ADL but not with neuropsychiatric symptoms. ADL functions were associated with both cognitive performance and neuropsychiatric symptoms. Conclusion: Even patients with very mild or mild AD may exhibit neuropsychiatric symptoms not related to cognitive impairment. The results of this study emphasize the importance of taking a multidimensional approach to the diagnostic and prognostic evaluation of AD patients already in the early stages of the disease.

V. Leinonen, A. M. Koivisto, S. Savolainen, J. Rummukainen, A. Sutela, R. Vanninen, J. E. Jaaskelainen, H. Soininen and I. Alafuzoff (2012) Neuropathology and Applied Neurobiology38, 72–86 Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature Aims: Neuropathological features of idiopathic normal-pressure hydrocephalus (iNPH) are poorly characterized. Brain biopsy during life may help in the differential diagnosis of dementia, but post-mortem validation of biopsy findings is scarce. Here we review and report brain biopsy and post-mortem neuropathological findings in patients with presumed NPH. Methods: We evaluated 10 patients initially investigated by intraventricular pressure monitoring and a frontal cortical biopsy for histological and immunohistochemical assessment as a diagnostic procedure for presumed NPH. Results: Out of the 10 patients, eight were shunted and seven benefited. Until death, six had developed severe and two mild cognitive impairment. One was cognitively unimpaired, and one was mentally retarded. Three subjects displayed amyloid-β (Aβ) aggregates in their frontal cortical biopsy obtained at the initial procedure. One of these patients developed Alzheimer's disease during a follow-up time of nearly 10 years. One patient with cognitive impairment and NPH suffered from corticobasal degeneration. In six patients various vascular lesions were seen at the final neuropathological investigation. Five of them were cognitively impaired, and in four vascular lesions were seen sufficient in extent to be considered as causative regarding their symptoms. Conclusions: The frequent finding of vascular pathology in NPH is intriguing, suggesting that vascular alterations might be causative of cognitive impairment in a notable number of patients with NPH and dementia. Brain biopsy can be used to detect Aβ aggregates, but neuropathological characteristics of iNPH as a distinct disease still need to be discovered.

Normal pressure hydrocephalus (NPH) can be alleviated by cerebrospinal fluid shunting but the differential diagnosis and patient selection are challenging. Intraventricular intracranial pressure monitoring as part of the diagnostic workup as well as shunting enable to obtain cortical brain biopsies to detect amyloid-β (Aβ) and hyperphosphorylated tau (HPτ), the hallmark lesions of Alzheimer’s disease (AD). In possible NPH, Aβ alone indicates an increased risk of AD and when present with HPτ probable AD, but the effect of those brain lesions on survival is not known. The aim of this study was to evaluate the predictive value of brain biopsy for the long-term outcome of possible NPH. Between 1991 and 2006, the Neurosurgery Department of the Kuopio University Hospital evaluated 468 patients for possible NPH by intraventricular intracranial pressure monitoring and frontal cortical brain biopsy immunostained against Aβ and HPτ. All patients were followed up until the end of 2008 (n = 201) or death (n = 267) with a median follow-up of 4.6 years (range 0–17). Logistic regression analysis with Cox models was applied. Out of the 468 cases, Aβ was detected in 197 (42%) cortical biopsies, and together with HPτ in 44 (9%). Aβ alone indicated increased risk of AD and with HPτ probable AD, but it did not affect survival. Vascular aetiology was the most frequent cause of death. Cortical biopsy findings indicate that NPH is at present a heterogeneous syndrome and has notable overlapping with AD. Brain biopsy did not predict survival but may open a novel research window to study the pathobiology of neurodegeneration.

Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells through a post-translational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered β-secretase activity. We also discovered that the overexpression of a specific Alzheimer's-disease-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates β-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.

Persons with Alzheimer’s disease (AD) may be particularly susceptible to the adverse drug reactions associated with anti-epileptic drugs (AEDs). The objective of this study was to investigate the national pattern of AED use among communitydwelling persons with and without AD in Finland. All persons (n = 28,093) with a diagnosis of AD in 2005 were identified by the Social Insurance Institution of Finland (SII). The SII also identified comparison persons without AD individually matched in terms of age (±one year), gender, and region. Records of all reimbursed drug purchases in 2005 were extracted from the Finnish National Prescription Register. Conditional logistic regression was used to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for reimbursed AED use. Persons with and without AD were aged 42 to 101 (mean 80.0) years, with men comprising 32.2% (n = 9,048) of persons. Epilepsy was diagnosed for 2.1% of persons with AD compared to 1.3% of persons without AD (OR 1.66; 95% CI, 1.45 to 1.89). AEDs were used by 5.0% (n = 1417) of persons with AD compared to 3.4% (n = 955) persons without AD (adjusted OR 1.33; 95% CI, 1.21 to 1.46). The annual prevalence of phenytoin, clonazepam, valproic acid, and oxcarbazepine use was higher among persons with AD. In contrast, pregabalin use was lower among persons with AD (adjusted OR 0.83; 95% CI, 0.70 to 0.99). Use of older AEDs is more prevalent among persons with AD, despite persons with AD being particularly vulnerable to adverse drug reactions associated with many older AEDs. Refereed/Peer-reviewed

Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF amyloid-β (Aβ)(42), tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ(42), highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ(42) level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease.

Objective: Amyloid-beta(A beta) aggregates are presumed to be found in the brain at an early stage of Alzheimer's disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients. Methods: Between 1991 and 2006 we evaluated 468 patients with suspected normal pressure hydrocephalus with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for A beta and hyperphosphorylated tau (HP tau). Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether A beta and/or HP tau in the biopsy samples obtained during life predicted development of cognitive impairment, in particular, AD. Results: Of the 433 frontal cortical samples, 42 (10%) displayed both A beta and HP tau, 144 (33%) A beta only, and 247 (57%) neither A beta nor HP tau. In a median follow-up time of 4.4 years, 94 patients (22%) developed clinical AD. The presence of both A beta and HP tau was strongly associated (odds ratio [OR], 68.2; 95% confidence interval [Cl], 22.1-210) and A beta alone significantly associated (OR, 10.8; 95% Cl, 4.9-23.8) with the clinical diagnosis of AD. Interpretation: This is the largest follow-up study of patients assessed for the presence of A beta and HP tau in frontal cortical brain biopsy samples. 1) The presence of A beta and HP tau spoke strongly for the presence or later development of clinical AD; 2) A beta alone was suggestive of AD; and 3) the absence of A beta and HP tau spoke against a later clinical diagnosis of AD.

Alzheimer's disease (AD) is a genetically complex disorde r encompassing several individual susceptibility genes with low risk effects. To assess the risk gene effects in a cohort c onsisting of �1300 Finnish AD patients and controls, 21 candidate gene polymorphisms were selected for genotyping on the basis of the meta-analyses retrieved from the AlzGene database. A significant genotype and allele association with AD was obse rved with rs1800629 in the tumor necrosis factor � (TNF). Risk analysis revealed a protective effect for the minor allele c arriers of rs1800629. This suggests that genetic alteratio n in TNF gene may play a role in AD.

Single nucleotide polymorphisms (SNPs) in diabetes related peroxisome proliferator-activated receptor gamma (PPARG) gene were investigated with a case-control approach. To examine the genetic association of this gene with Alzheimer's disease (AD) risk, we used the TaqMan technique to genotype eight SNP sites for PPARG gene, in 538 Finnish AD cases and 672 controls and conducted a single allele and genotypic distribution comparison as well as estimated haplotype frequencies between cases and controls. No significant differences in AD risk were found in single SNP and haplotype analyses for PPARG gene between the study groups. We conclude that PPARG gene does not play a major role in the genetic predisposition to AD in the Finnish population.

Single nucleotide polymorphisms (SNPs) in three diabetes-related genes (SIRT1, PPARD, PGC-1alpha) were investigated with a case-control approach. To examine the genetic association of those genes with Alzheimer's disease (AD) risk, we used the TaqMan technique to genotype five SNP sites for SIRT1, six for PPARD and eight for the PGC-1alpha gene, in 326 Finnish AD cases and 463 controls and conducted a single allele and genotypic distribution comparison as well as estimated haplotype frequencies between cases and controls. No significant differences in AD risk were found in single SNP and haplotype analyses for any of the three genes between 326 cases and 463 controls. However, in a subgroup of women older than 65 years, the frequencies of three SNPs in the SIRT1 gene were significantly different between AD and controls. We conclude that there is no real association with SNPs available in the present study between SIRT1, PPARD or PGC-1alpha genes and AD risk in the Finnish population.

Objective: To explore family caregiver (FC) long-term psychological distress after Alzheimer disease (AD) diagnosis in a family member. Methods: FC (n = 236) and patients with AD were prospectively followed up to 36 months after AD diagnosis. FC psychological distress was evaluated using the General Health Questionnaire (GHQ). Furthermore, caregiver depressive symptoms and sense of coherence, along with AD patient measurements, were measured at baseline and annually. Generalized estimating equation models were applied to study associations of these baseline factors to caregiver GHQ. Results: After 36 months of follow-up, spousal caregivers (SCs) GHQ was significantly higher ( P < .001) than in the nonspousal caregivers (NSCs). The difference in GHQ scores was associated by depressive symptoms ( P < .001) at baseline, and the depressed SCs have more severe distress than NSCs over the observation period. Conclusion: During longitudinal caregiving, spousal and depressed caregivers of patients with AD report higher and increasing psychological stress than nonspousal and nondepressed caregivers. Spousal relationship, caregivers’ depressive symptoms, and the severity of patients’ neuropsychological symptoms at the time of AD diagnosis predict the trajectory of psychological distress. The current study highlights the need for evaluating AD caregiver mental health and level of coping.

Background: Amyloid-beta (A beta(1-42)), total tau (T-tau), and phosphorylated tau (P-tau(181)) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble A beta decreases with increasing age and advanced A beta pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. A beta(1-42) and P-tau(181) remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while A beta(1-42) levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau(181) (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF A beta(1-42) levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF A beta and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.

Objective To examine and compare self-rated and caregiver-rated measures of quality of life (QoL) in relation to disease progression in patients with very mild or mild Alzheimer disease (AD) and at what disease stage patient's ability to respond to QoL questionnaires with or without assistance begins to diminish. Methods 236 patients with very mild or mild AD and their family caregivers from three Finnish hospital districts participated in this prospective, longitudinal study with 5 years of follow-up. Three patient-reported instruments were used to assess QoL (the generic 15D, the Quality of Life in Alzheimer Disease [QoL-AD] questionnaire, and a visual analogue scale) as well as one caregiver-rated assessment of patient QoL (QoL-AD). AD severity was evaluated with the Clinical Dementia Rating Scale − Sum of Boxes (CDR-SOB). Results All self- and caregiver-rated QoL estimates correlated with AD severity. The self- and caregiver-rated QoL scores began to diverge even with very mild cognitive impairment after CDR-SOB reached 4, the value that corresponds with a Mini-Mental State Examination (MMSE) score of 25–30. Patients also began to need assistance in responding to questionnaires at very early stages of AD (CDR-SOB score: 4–6). Furthermore, their ability to respond to QoL questionnaires with or without assistance declined after CDR-SOB reached 11 points, a value that correlates with an early moderate stage of AD and MMSE score of 11–20. Conclusions AD patients' self-rated QoL ratings are much more insensitive to disease progression than caregiver ratings.

Neuropsychiatric symptoms of Alzheimer's disease (AD) such as depression may be associated with pain, which according to the literature may be inadequately recognized and managed in this population. This study aimed to identify the factors associated with analgesic use in persons with AD; in particular, how AD severity, functional status, neuropsychiatric symptoms of AD, co-morbidities and somatic symptoms are associated with analgesic use. 236 community-dwelling persons with very mild or mild AD at baseline, and their caregivers, were interviewed over five years as part of the prospective ALSOVA study. Generalized Estimating Equations (GEEs) were used to estimate unadjusted and adjusted odds ratios (ORs) for the factors associated with analgesic use over a five year follow-up. The proportion of persons with AD using any analgesic was low (13.6%) at baseline and remained relatively constant during the follow-up (15.3% at Year 5). Over time, the most prevalent analgesic changed from non-steroidal anti-inflammatories (8.1% of persons with AD at Year 1) to acetaminophen (11.1% at Year 5). Depressive symptoms (measured by the Beck Depression Inventory, BDI) were independently associated with analgesic use, after effects of age, gender, education, AD severity, comorbidities and somatic symptoms were taken into account. For every one unit increase in BDI, the odds of analgesic use increased by 4% (OR = 1.04, 95% confidence interval CI = 1.02-1.07). Caregiver depressive symptoms were not statistically significantly associated with analgesic use of the person with AD. Depressive symptoms were significantly associated with analgesic use during the five year follow-up period. Possible explanations warranting investigation are that persons with AD may express depressive symptoms as painful somatic complaints, or untreated pain may cause depressive symptoms. Greater awareness of the association between depressive symptoms and analgesic use may lead to safer and more effective prescribing for these conditions.

Early diagnosis, initiation of Alzheimer's disease (AD) therapy and programs that support care of persons with AD at home are recommended. The objective of this study was to assess the effect of early psychosocial intervention on delaying the institutionalization of persons with AD. We also assessed the influence of intervention on AD progression, behavioral symptoms, and health-related quality of life (HRQoL) in persons with AD and caregivers.Kuopio ALSOVA study, a prospective, randomized intervention study with a 3-year follow-up, was carried out at memory clinics. Home-dwelling persons with very mild or mild AD (n = 236) and AD-targeted therapy and their family caregivers (n = 236) were randomized to the intervention or control group (1:2). Psychosocial intervention including education, counseling, and social support was given during the first 2 years (16 days). The primary outcome was the cumulative risk (controlled for death) of institutionalization over 36 months. Secondary outcomes were adjusted mean changes from baseline in disease severity, cognition, daily activities, behavior, and HRQoL for persons with AD; and change in psychological distress, depression, and HRQoL for caregivers.No differences were found in nursing home placement after the 36-month follow-up between intervention and control groups. No beneficial effects of the intervention were found on the secondary outcomes.The psychosocial intervention did not delay nursing home placement in persons with AD and had no effect on patient well-being, disease progression, or AD-related symptoms or caregiver well-being. Instead of automatically providing psychosocial intervention courses, individualized support programs may be more effective.