Prevalence, treatment, and neural correlates of apathy in different forms of dementia: a narrative review.

OBJECTIVES: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD). METHODS: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included. RESULTS: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy. CONCLUSION: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. HIGHLIGHTS: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

Biomarker pathway heterogeneity of amyloid-positive individuals.

INTRODUCTION: In amyloid-positive individuals, disease-related biomarker heterogeneity is understudied. METHODS: We used Subtype and Stage Inference (SuStaIn) to identify data-driven subtypes among cerebrospinal fluid (CSF) amyloid beta (1-42)-positive individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNIGO/2 [n = 376]). Variables included: CSF phosphorylated tau (p-tau181), hippocampal and whole-brain volume, logical memory (LM), composite Trail Making Test score, and white matter hyperintensity (WMH) volumes. CSF amyloid-negative, apolipoprotein E ε4 non-carrier cognitively unimpaired controls (n = 86) were used to calculate z scores. RESULTS: One subtype (n = 145) had early LM changes, with later p-tau and WMH changes. A second subtype (n = 88) had early WMH changes, were older, and more hypertensive. A third subtype (n = 100) had early p-tau changes, and reflected typical Alzheimer's disease. Some amyloid positive (n = 43) individuals were similar to the amyloid-negative group. DISCUSSION: This work identified heterogeneity in individuals who are conventionally considered homogeneous, which is likely driven by co-pathologies including cerebrovascular disease. HIGHLIGHTS: Data-driven modeling identified marker heterogeneity in amyloid-positive individuals. Heterogeneity reflected Alzheimer's disease-like, vascular-like, and mixed pathology presentations. Some amyloid-positive individuals were more similar to amyloid-negative controls. Vascular pathology plays a key role in understanding heterogeneity in those on the amyloid pathway.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

Comorbid cerebral amyloid angiopathy in dementia and prodromal stages-Prevalence and effects on cognition.

OBJECTIVES: To determine the contribution of cerebral amyloid angiopathy to cognitive impairment in MCI and dementia. METHODS: Patients with subjective memory impairment (SMI), amnestic and non-amnestic mild cognitive impairment ((n)aMCI), Alzheimer's disease (AD), mixed and vascular dementia (MD/VD) from our memory clinic were included in this retrospective analysis. Patients underwent neuropsychological testing and cranial magnetic resonance imaging (MRI). Magnetic resonance imaging data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. ANOVAs were used to investigate the contribution of CAA to cognitive impairment within diagnostic groups and to determine whether differences in cognitive test performance between the diagnostic groups are mediated by total CAA burden. RESULTS: 475 patients (222 male, 253 female) with SMI (n = 47), naMCI (n = 41), aMCI (n = 189), early AD (n = 9), AD (n = 114), MD (n = 71) and VD (n = 4) were included. Mean age was 73.2 (9.9) years. CAA prevalence was 14.9% in SMI, 14.6% in naMCI, 24.3% in aMCI, 22.2% in early onset AD, 18.4% in late onset AD, 46.5% in MD and 25% in VD. Patients with possible and probable CAA were older than patients without CAA. In particular, diagnosis of aMCI, early onset AD, MD and VD showed high CAA prevalence. In AD but not in aMCI, CAA diagnosis significantly influenced test performance in the CERAD word list recall (F (1,78) = 4505; p = 0.037; partial eta-square = 0.055). Differences in cognitive test performance between the diagnostic groups of naMCI, aMCI, AD and MD were mediated by total CAA burden within AAT simply nouns subtest (F (2,39) = 4059; p = 0.025; partial eta-square = 0.172) and in CERAD verbal fluency test (F (3,129) = 3533; p = 0.017; partial eta-square = 0.076). CONCLUSION: This retrospective analysis demonstrates high prevalence rates of CAA in cognitive diagnoses. Our data suggest that comorbid CAA independently impacts cognitive test performance in the course of AD with presumably stage-dependent effects. Especially in patients with AD comorbid CAA additionally impairs memory function. Total CAA small vessel disease burden further modulates psychometric differences in cognitive test performance between diagnostic groups regarding word finding and word fluency capabilities.

Initial non-amnestic symptoms relate to faster rate of functional and cognitive decline compared to amnestic symptoms in neuropathologically confirmed dementias.

INTRODUCTION: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials. METHODS: This retrospective longitudinal, autopsy-confirmed, cohort study among 2426 participants in the National Alzheimer's Coordinating Center database included Alzheimer's disease (AD) pathology, n = 1187; Lewy body pathology (LBP), n = 331; and mixed pathology (AD-LBP), n = 904. The predominant initial cognitive symptom was assessed clinically. Linear mixed models evaluated the longitudinal outcome of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. RESULTS: Non-amnestic initial symptoms had a faster rate of decline than amnestic symptoms in all three groups. Language symptoms had a faster rate of decline in all three groups. Executive symptoms had a faster rate of decline than amnestic in AD and AD-LBP. There was a similar trend for visuospatial symptoms in AD-LBP. DISCUSSION: Initial cognitive symptoms, despite varied underlying pathology, are a predictor of longitudinal functional outcomes among dementias. HIGHLIGHTS: Initial non-amnestic symptoms had a faster rate of longitudinal cognitive and functional decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores than amnestic symptoms among Alzheimer's disease, Lewy body pathology, and mixed neuropathology. Given the relative size of CDR-SB changes in Alzheimer's disease clinical trials, clarifying the nature of initial symptoms could be an important variable in ensuring appropriately designed clinical trials.

White matter hyperintensities in Alzheimer's disease: Beyond vascular contribution.

White matter hyperintensities (WMH), frequently seen in older adults, are usually considered vascular lesions, and participate in the vascular contribution to cognitive impairment and dementia. However, emerging evidence highlights the heterogeneity of WMH pathophysiology, suggesting that non-vascular mechanisms could also be involved, notably in Alzheimer's disease (AD). This led to the alternative hypothesis that in AD, part of WMH may be secondary to AD-related processes. The current perspective brings together the arguments from different fields of research, including neuropathology, neuroimaging and fluid biomarkers, and genetics, in favor of this alternative hypothesis. Possible underlying mechanisms leading to AD-related WMH, such as AD-related neurodegeneration or neuroinflammation, are discussed, as well as implications for diagnostic criteria and management of AD. We finally discuss ways to test this hypothesis and remaining challenges. Acknowledging the heterogeneity of WMH and the existence of AD-related WMH may improve personalized diagnosis and care of patients.

Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia.

PURPOSE: This study aimed to evaluate the influence of genetic polymorphisms of drug-metabolizing enzyme genes, transporter gene, pathological gene (APOE), and non-genetic factors on therapeutic outcomes as well as steady-state plasma concentrations (Cpss) of galantamine in Thai patients with mixed dementia. METHODS: Fifty-one Thai patients with mixed dementia who received galantamine for at least 6 months were recruited. CYP2D6, CYP3A5, and ABCB1 polymorphisms were detected by TaqMan® Genotyping Assay. UGT1A1 and APOE polymorphism was detected by direct Sanger sequencing technique and restriction fragment length polymorphism technique. Cpss of galantamine was measured by ultra-performance liquid chromatography. Associations of genetic and non-genetic factors with Cpss and clinical outcomes (change in cognitive function as measured by the Thai Mental State Examination (ΔTMSE) scores) were determined by using univariate and multivariate analysis. RESULTS: The multivariate regression model revealed that patients who carried one or more detrimental allelic variant (CYP2D6, CYP3A5, and UGT1A1) showed a tendency toward a higher galantamine adjusted Cpss (B = 34.559, 95% CI = 0.741-68.377, p value = 0.045). Logistic regression analysis also revealed CYP2D6*10 carriers were significantly associated with higher ΔTMSE (B = 5.227, 95% CI = 2.395-8.060, p value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level can attenuate therapeutic outcomes of galantamine. CONCLUSION: Pharmacokinetic-related genes including CYP2D6*10 and UGT1A1 mutant alleles were significantly associated with galantamine adjusted Cpss and cognitive function. Determination of Cpss and genotype could be an adjunct examination to provide further explanation in interindividual variability of galantamine therapeutic outcome.

The assessment of cognitive and behavioural disturbances in vascular cognitive impairment (VCI) - recommendations of an expert working group.

With newer research-based classification systems, the term Vascular Cognitive Impairment (VCI) is now preferred to vascular dementia. VCI is an umbrella term that includes all forms of cognitive deficits ranging from mild cognitive impairment of vascular origin (VaMCI) to vascular dementia (VaD). The new VCI construct takes into account the fact that in addition to single strategic infarcts, multiple infarcts, and leukoaraiosis, there are other mechanisms of cerebrovascular disease such as chronic hypoperfusion that might account for the pattern of cognitive deficits associated with vascular dementia. The key to defining the spectrum of VCI is neuropsychological testing, bedside or office-based clinical examination, and neuroimaging. The lack of specific cognitive tools that are sufficiently sensitive to detect subtle deficits makes the assessment of cognitive impairment difficult. Prospective cross-sectional and longitudinal studies of VCI from different settings are therefore required. Although there have been few published reports, behavioural and psychological symptoms (BPS) are inherently present in VCI from the onset and during the course of the disease. Besides the type of population (i.e. clinical, community or nursing-home settings), the definition of VCI/VaD and the instruments used, and differences in the prevalence and pattern of BPS between various studies, could be due to other, often unconsidered, factors such as gender, age, education, use of medication and VCI/VaD severity.

Age-stratified longitudinal study of Alzheimer's and vascular dementia patients.

INTRODUCTION: Similar symptoms, comorbidities and suboptimal diagnostic tests make the distinction between different types of dementia difficult, although this is essential for improved work-up and treatment optimization. METHODS: We calculated temporal disease trajectories of earlier multi-morbidities in Alzheimer's disease (AD) dementia and vascular dementia (VaD) patients using the Danish National Patient Registry covering all hospital encounters in Denmark (1994 to 2016). Subsequently, we reduced the comorbidity space dimensionality using a non-linear technique, uniform manifold approximation and projection. RESULTS: We found 49,112 and 24,101 patients that were diagnosed with AD or VaD, respectively. Temporal disease trajectories showed very similar disease patterns before the dementia diagnosis. Stratifying patients by age and reducing the comorbidity space to two dimensions, showed better discrimination between AD and VaD patients in early-onset dementia. DISCUSSION: Similar age-associated comorbidities, the phenomenon of mixed dementia, and misdiagnosis create great challenges in discriminating between classical subtypes of dementia.

Relationship Between Tau, ß Amyloid and α-Synuclein Pathologies.

It is becoming increasing clear that multiple pathological lesions co-exist in the brains of the demented and non-demented elderly, and with putative interactions revealed at the molecular level in addition to the cumulative effects on brain damage, mounting evidence suggests manifestation of multiple protein aggregates will have implications for the clinical course of many neurodegenerative diseases associated with dementia. In this section we will discuss how the presence of multiple pathological lesions can affect the pathological and clinical phenotype of neurodegenerative disorders.

Behavioral Disturbances in Dementia and Beyond: Time for a New Conceptual Frame?

Alzheimer's disease and vascular dementia are estimated to be the most common causes of dementia, although mixed dementia could represent the most prevalent form of dementia in older adults aged more than 80 years. Behavioral disturbances are common in the natural history of dementia. However, so far, there is a paucity of studies that investigated the causal association between behavioral psychological symptoms of dementia and dementia sub-types, due to the high heterogeneity of methodology, study design and type of clinical assessment. To understand the scant evidence on such a relevant clinical issue, it could be hypothesized that a new shifting paradigm could result in a better identification of the relationship between behavioral disturbances and dementia. This narrative review provides an update of evidence on the behavioral patterns associated with different dementia sub-types and offers a potential future perspective as common ground for the development of new translational studies in the field of behavioral disturbances in dementia and the appropriateness of psychoactive treatments.

Clock Drawing Test: A Simple Scoring System for the Accurate Screening of Cognitive Impairment in Patients with Mild Cognitive Impairment and Dementia.

BACKGROUND/AIM: The Clock Drawing Test (CDT) is a valid alternative screening tool to the Mini-Mental State Examination (MMSE) and, crucially, it may be completed faster. The aim of our study was to standardize and simplify the CDT scoring system for screening in three common conditions: mild cognitive impairment (MCI), Alzheimer's disease (AD) and mixed dementia (MD). METHODS: We included 188 subjects (43 healthy volunteers, 49 patients with MCI, 54 patients with AD, and 42 patients with MD), who performed the MMSE and CDT. The CDT was evaluated using a modified 4-point scoring system. RESULTS: The healthy subjects had the highest median values for the MMSE and CDT, followed by patients with MCI, AD and MD. The optimal cut-off for all patients and each patient group separately was 3 out of 4 points. Sensitivity was 89% for AD, 93% for MD and 83% for all patients, while specificity was 91%. The MMSE produced similar results. In comparison to the MMSE, sensitivity for MCI was significantly higher using the CDT (20 vs. 69%, respectively). CONCLUSION: A simple, 4-point scoring system may be used as a screening method for fast and accurate detection of cognitive impairment in patients with MCI, AD and MD.

Physical aggression among patients with dementia, neuropathologically confirmed post-mortem.

OBJECTIVE: To investigate the prevalence of physical aggression among patients with dementia of different types and to analyze potential differences in clinical traits, in terms of singular or repetitive behavior and occurrence in early or late stage of the disease. We also aimed at examining against whom the physical aggression was exerted. METHODS: We included 281 cases with a neuropathological dementia diagnosis from the brain bank at the Department of Pathology, Lund University, for this retrospective medical records review. The study covers cases with a post-mortem examination performed between 1967 and 2013. RESULTS: Of the 281 patients studied, 97 (35%) patients had a history of exerting physical aggression during the course of their disease. The patients with frontotemporal dementia exerted physical aggression earlier in the course of their disease than Alzheimer's disease patients. The most frequent victims of the patients' physical aggression were health staff and other patients. The aggression also affected family members as well as (to the demented patient) unknown people. The frequency of the physical aggression differed among the different diagnostic groups; frontotemporal dementia patients exhibiting a higher physical aggression frequency score than did Alzheimer's disease patients. CONCLUSIONS: The patterns of manifested physical aggression thus differ between the frontotemporal dementia and Alzheimer's disease patient groups in this study. Knowledge about such differences may be of value in decision making in patient care.

Concomitant vascular and neurodegenerative pathologies double the risk of dementia.

INTRODUCTION: The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. METHODS: We systematically searched for population-based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. RESULTS: We identified 10 studies comprising 2856 subjects. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%-86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer-type pathology. DISCUSSION: Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component.

Reduced Efficacy of Anti-Aß Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity.

UNLABELLED: Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aß immunotherapy, which uses antibodies against Aß to clear it from the brain. While successful in clearing Aß and improving cognition in mice, anti-Aß immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aß immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aß levels, there was no cognitive benefit of the anti-Aß immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aß immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes. SIGNIFICANCE STATEMENT: Despite significant mouse model data demonstrating both pathological and cognitive efficacy of anti-Aß immunotherapy for the treatment of Alzheimer's disease, clinical trial outcomes have been underwhelming, failing to meet any primary endpoints. We show here that vascular cognitive impairment and dementia (VCID) comorbidity eliminates cognitive efficacy of anti-Aß immunotherapy, despite amyloid clearance. Further, cerebrovascular adverse events of the anti-Aß immunotherapy are significantly exacerbated by the VCID comorbidity. These data suggest that VCID comorbidity with Alzheimer's disease may mute the response to anti-Aß immunotherapy.

Impact of multiple pathologies on the threshold for clinically overt dementia.

Longitudinal clinical-pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) as important factors in the development of Alzheimer's disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical-pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.

Leukocyte telomere length is linked to vascular risk factors not to Alzheimer's disease in the VITA study.

Association of telomere shortening with overall dementia or Alzheimer's disease is described controversially and the pathophysiologic relevance is unclear. Whether patients, suffering from pure probable Alzheimer's disease or pure vascular dementia, have shorter leukocyte telomeres than cognitively healthy controls was determined. Leukocyte telomere lengths (LTLs) of 597 participants of the VITA study (longitudinal community-based age-cohort [mean 75.7 (±0.45) years] study: 243 male; 578 non-demented at baseline) were compared with different aspects of cognition, risk factors of dementia and survival. LTLs of 264 persons cognitively healthy at baseline (mild cognitive impaired excluded) and all follow-ups (mean = 5643 bp, SD = 736) did not show any difference to LTLs of 43 incident pure possible (mean = 5548 bp; SD = 666) or 34 incident pure probable Alzheimer's diseases (mean = 5712 bp; SD = 695; post hoc Dunnett test: MD = -95; SE = 119; p = 0.67 and MD =+68.3; SE = 132; p = 0.84, res.). 264 stably cognitively healthy showed a trend to longer telomeres than 6 incident vascular dementias (mean = 5643 bp, SD = 736 vs mean = 5101 bp, SD = 510; t test: T = 1.8; df = 268; p = 0.07). Males (n = 243; mean = 5470 bp; SD = 684) had significantly shorter telomeres than females (n = 354; mean = 5686 bp; SD = 714; t test: T = -3.7; df = 595; p = 0.0001) and died significantly earlier (113.7 vs 130.1 months: Log Rank Chi square = 12.2; p = 0.0001). Shorter telomeres were associated with prevalence of more than one vascular risk factor (n = 587; mean = 5728; SD = 723 vs mean = 5533; SD = 691; t test: T = 3.1; df = 576; p = 0.002) and, as a trend, with poorer survival (Cox Regression: Wald = 4.9; p = 0.026; OR = 0.98; 95% CI 0.96-0.99). In 75.7 years old persons, no association of LTL with incident pure Alzheimer's disease was found. Significantly shorter telomeres were associated with sum of vascular risk factors, males and early mortality in males. Exclusion of mixed dementias may improve the search for risk factors more specific for Alzheimer's disease.

N-Terminal Prosomatostatin and Risk of Vascular Dementia.

BACKGROUND: Increased somatostatin plasma concentration has been found in patients with vascular dementia. However, it is unknown whether or not somatostatin levels may predict dementia development in the general population. To this end, we sought to assess the association of circulating N-terminal prosomatostatin (NT-proSST) with incident dementia among community-dwelling older adults. METHODS: In the prospective population-based Malmö Preventive Project, 5,347 study participants (mean age: 69 ± 6years; 70% men) provided plasma for the determination of NT-proSST concentration. Of these, 373 participants (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) during a follow-up period of 4.6 ± 1.3 years. The association of NT-proSST with the risk of dementia and its subtypes was studied using multivariable-adjusted Cox regression models controlling for age, gender, body mass index, systolic blood pressure, antihypertensive treatment, smoking, diabetes, lipid levels and prevalent stroke. RESULTS: Higher levels of NT-proSST were significantly associated with an increased risk of vascular dementia (hazard ratio [HR] per 1 SD: 1.29; 95% CI 1.05-1.59; p = 0.016), whereas no association was observed with Alzheimer's disease (HR per 1 SD: 0.99; 95% CI 0.81-1.20; p = 0.91), all-cause dementia (HR per 1 SD: 1.04; 95% CI 0.94-1.16; p = 0.44), and mixed dementia (HR per 1 SD: 0.98; 95% CI 0.79-1.21; p = 0.84). Levels of NT-proSST above 563 pmol/L (highest quartile) conferred distinctly increased risk of vascular dementia (HR 1.66; 95% CI 1.05-2.63; p = 0.029) compared with lower values. CONCLUSIONS: Higher levels of circulating N-terminal-prosomatostatin are associated with increased incidence of vascular dementia. Our findings might be of importance for the understanding of dementia development in older adults.

Factors associated with mixed dementia vs Alzheimer disease in elderly Mexican adults. / Factores asociados a la demencia mixta en comparación con demencia tipo Alzheimer en adultos mayores mexicanos.

INTRODUCTION: Mixed dementia (DMix) refers to dementia resulting from Alzheimer disease in addition to cerebrovascular disease. The study objectives were to determine the clinical and imaging factors associated with Dmix and compare them to those associated with Alzheimer disease. MATERIAL AND METHODS: Cross-sectional study including 225 subjects aged 65 years and over from a memory clinic in a tertiary hospital in Mexico City. All patients underwent clinical, neuropsychological, and brain imaging studies. We included patients diagnosed with DMix or Alzheimer disease (AD). A multivariate analysis was used to determine factors associated with DMix. RESULTS: We studied 137 subjects diagnosed with Dmix. Compared to patients with AD, Dmix patients were older and more likely to present diabetes, hypertension, dyslipidaemia, and history of cerebrovascular disease (P<.05). The multivariate analysis showed that hypertension (OR 1.92, CI 1.62-28.82; P=.009), white matter disease (OR 3.61, CI 8.55-159.80; P<.001), and lacunar infarcts (OR 3.35, CI 1.97-412.34; P=.014) were associated with Dmix, whereas a history of successfully treated depression showed an inverse association (OR 0.11, CI 0.02-0-47; P=.004) CONCLUSIONS: DMix may be more frequent than AD. Risk factors such as advanced age and other potentially modifiable factors were associated with this type of dementia. Clinicians should understand and be able to define Dmix.