Neurological And Communicative Disorders And Stroke And The Alzheimer's Disease And Related Disorders Association Research Articles

Interrater agreement in dementia diagnosis: A systematic review and meta-analysis.

Dementia remains a clinical diagnosis with a degree of subjective assessment and potential for interrater disagreement. We described interrater agreement of clinical dementia diagnosis for various diagnostic criteria. We conducted a PROSPERO-registered (CRD42020168245) systematic review and meta-analysis. We searched multiple cross-disciplinary databases from inception until April 2020 for relevant papers, extracted data and described study quality in duplicate. Study quality was assessed using the Guidelines for Reporting Reliability and Agreement Studies. We used random-effects models to obtain summary estimates of interrater agreement using kappa and, where possible, Gwet's AC1/2 coefficients. We found 7577 titles and 22 eligible studies. Meta-analysis was possible for all-cause dementia using the Diagnostic and Statistical Manual of Mental Disorders third edition revised (DSM-III-R) criteria (kappa=0.66, 95% CI=[0.53,0.78]), Alzheimer's disease using the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria (kappa=0.71, 95% CI=[0.65,0.77] for presence/absence and AC2=0.61, 95% CI=[0.53,0.70] when distinguishing probable/possible cases), and vascular dementia using the International Classification of Diseases version 10 (ICD-10) criteria kappa=0.79 (95% CI=[0.70,0.87]). Data was more limited for other criteria and dementia types. AC1/2 coefficients generally indicated higher agreement. One study was rated as high quality. Diagnostic criteria for clinical dementia may have good but imperfect agreement. This has important implications for clinical practice and research studies, which frequently assume these criteria are perfect tests, such as diagnostic test accuracy studies frequently conducted for biomarkers and neuropsychological tests, and for trials where incident dementia is the outcome.

Alzheimer's Disease Diagnosis: Discrepancy between Clinical, Neuroimaging, and Cerebrospinal Fluid Biomarkers Criteria in an Italian Cohort of Geriatric Outpatients: A Retrospective Cross-sectional Study.

The role of cerebrospinal fluid (CSF) biomarkers, and neuroimaging in the diagnostic process of Alzheimer's disease (AD) is not clear, in particular in the older patients. The aim of this study was to compare the clinical diagnosis of AD with CSF biomarkers and with cerebrovascular damage at neuroimaging in a cohort of geriatric patients. Retrospective analysis of medical records of ≥65-year-old patients with cognitive impairment referred to an Italian geriatric outpatient clinic, for whom the CSF concentration of amyloid-β (Aβ), total Tau (Tau), and phosphorylated Tau (p-Tau) was available. Clinical diagnosis (no dementia, possible and probable AD) was based on the following two sets of criteria: (1) the Diagnostic Statistical Manual of Mental Disorders (DSM-IV) plus the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and (2) the National Institute on Aging-Alzheimer's Association (NIA-AA). The Fazekas visual scale was applied when a magnetic resonance imaging scan was available. We included 94 patients, mean age 77.7 years, mean Mini Mental State Examination score 23.9. The concordance (kappa coefficient) between the two sets of clinical criteria was 70%. The mean CSF concentration (pg/ml) (±SD) of biomarkers was as follows: Aβ 687 (±318), Tau 492 (±515), and p-Tau 63 (±56). There was a trend for lower Aβ and higher Tau levels from the no dementia to the probable AD group. The percentage of abnormal liquor according to the local cutoffs was still 15 and 21% in patients without AD based on the DSM-IV plus NINCDS-ADRDA or the NIA-AA criteria, respectively. The exclusion of patient in whom normotensive hydrocephalus was suspected did not change these findings. A total of 80% of patients had the neuroimaging report describing chronic cerebrovascular damage, while the Fazekas scale was positive in 45% of patients overall, in 1/2 of no dementia or possible AD patients, and in about 1/3 of probable AD patients, with no difference across ages. We confirmed the expected discrepancy between different approaches to the diagnosis of AD in a geriatric cohort of patients with cognitive impairment. Further research is needed to understand how to interpret this discrepancy and provide clinicians with practical guidelines.

18F PET with flutemetamol for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

18F-flutemetamol uptake by brain tissue, measured by positron emission tomography (PET), is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer's pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer's Association (NIA-AA) revised the diagnostic criteria for Alzheimer's disease and the confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using some amyloid biomarkers tests like 18F-flutemetamol. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-flutemetamol to predict the progression from MCI to Alzheimer's disease dementia (ADD) or other dementias has not yet been systematically evaluated. To determine the DTA of the 18F-flutemetamol PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD) or any form of dementia at follow-up. The most recent search for this review was performed in May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to the electronic searches. We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of 18F-flutemetamol scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis, for example, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies. Progression from MCI to ADD was evaluated in 243 participants from two studies. The studies reported data on 19 participants with two years of follow-up and on 224 participants with three years of follow-up. Nine (47.4%) participants converted at two years follow-up and 81 (36.2%) converted at three years of follow-up.There were concerns about participant selection and sampling in both studies. The index test domain in one study was considered unclear and in the second study it was considered at low risk of bias. For the reference standard domain, one study was considered at low risk and the second study was considered to have an unclear risk of bias. Regarding the domains of flow and timing, both studies were considered at high risk of bias. MCI to ADD;Progression from MCI to ADD at two years of follow-up had a sensitivity of 89% (95% CI 52 to 100) and a specificity of 80% (95% CI 44 to 97) by quantitative assessment by SUVR (n = 19, 1 study).Progression from MCI to ADD at three years of follow-up had a sensitivity of 64% (95% CI 53 to 75) and a specificity of 69% (95% CI 60 to 76) by visual assessment (n = 224, 1 study).There was no information regarding the other two objectives in this systematic review (SR): progression from MCI to other forms of dementia and progression to any form of dementia at follow-up. Due to the varying sensitivity and specificity for predicting the progression from MCI to ADD and the limited data available, we cannot recommend routine use of 18F-flutemetamol in clinical practice. 18F-flutemetamol has high financial costs; therefore, clearly demonstrating its DTA and standardising the process of the 18F-flutemetamol modality is important prior to its wider use.

18F PET with florbetaben for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

18F PET with florbetaben for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

Treatment effects in multiple cognitive domains in Alzheimer's disease: a two-year cohort study.

IntroductionDespite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort.MethodsA cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated = 65, untreated = 65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE).ResultsAt one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function.ConclusionsThe present study offers two important contributions to knowledge of the effectiveness of cholinesterase inhibitor treatment in patients with mild-moderate AD: 1) that second-generation cholinesterase inhibitors demonstrate long-term effectiveness for reducing global cognitive decline over one to two years of follow-up, and 2) that decline in function for cognitive domains, including executive function, memory, and visuospatial skill that are primarily mediated by frontal networks and by the cholinergic system, rather than memory, may be slowed by treatment targeting the cholinergic system.

P02-237 - A study of the relationship between weight loss and behavioral symptoms in patients with severe alzheimer's disease

IntroductionAlzheimer's disease (AD) is often accompanied and worsened by malnutrition.AimsThe aim of this study is to investigate the relationship between weight loss and behavioral symptoms in institutionalized severe AD patients.MethodsAll subjects were recruited from Asahi Hospital, a long-term care facility.The diagnosis of AD was made in accordance with the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The inclusion criteria were (1) an MMSE score of 12 or less, (2) stable physical condition for at least three months. Exclusion criteria were (1) presence of acute disorders such as infection, heart failure, or requiring special treatment and intensive care. Weight was measured monthly. At baseline, 12 weeks, and 24 weeks, each patient received the Mini-Mental State Examination (MMSE), the Barthel Index, and Neuropsychiatric Inventory (NPI).ResultsWe included 48 patients who were judged appropriate for the study. At baseline, the mean age was 83.3 ± 6.2, the mean weight was 41.8 ± 7.9, the mean body mass index (BMI) was 18.7 ± 3.5. During the 24 weeks of follow-up, 16 patients lost at least 3 kg of body weight, 20 patients remained stable, and 12 patients gained at least 3 kg of body weight. The mean NPI scores was significantly higher in the weight-loss group than in the weight-gain and weight-stable groups.ConclusionThese preliminary results suggest that behavioral disturbances play a role in low body weight and weight loss in AD patients.

Jealous Delusions and Dysfunction of the Right Parietal Lobe in Early-Onset Alzheimer's Disease

Jealous Delusions and Dysfunction of the Right Parietal Lobe in Early-Onset Alzheimer's Disease

Psychotic Symptoms in a Population-Based Sample of 85-Year-Old Individuals With Dementia

Psychotic symptoms are common in elderly persons with dementia. These symptoms affect a person's ability to function in daily life and put strain on the caregiver. Most studies focus on psychotic symptoms in clinical samples with Alzheimer disease (AD). Thus, their prevalence and relation with dementia subtype and severity in very old populations is unclear. We assessed a representative sample of 85-year-old individuals living in Gothenburg, Sweden (n = 494) using neuropsychiatric examinations, key informant interviews, and medical record reviews; 147 had dementia. Dementia and its severity were diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders (Third Edition, Revision [DSM-III-R]) criteria. Alzheimer disease according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria was diagnosed in 64 persons and vascular dementia (VaD) according to Erkinjuntti criteria was observed in 69. Fourteen had dementia due to other causes. Psychotic symptoms were classified according to DSM-III-R. The prevalence of psychotic symptoms in this very old population was 36% among AD cases compared to 54% in VaD cases (P = .04). Proportions with psychotic symptoms increased with increasing dementia severity in individuals with AD. No such association could be shown in those with VaD. This finding of a high proportion of psychotic symptoms also in individuals with mild severity of VaD should alert health professionals to evaluate dementia in very old patients who present with hallucinations or delusions.

Disturbances in Everyday Life Activities and Sequence Disabilities in Tool use for Alzheimer Disease and Vascular Dementia

To determine whether everyday life activities are affected by general cognitive impairment or tool using disabilities in Alzheimer disease (AD) and vascular dementia (VaD). Thirty AD the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and 30 VaD the state of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) patients and 10 normal controls (NC) were studied. Everyday activities in the community were assessed with the Social Activities Questionnaire (SAQ), and tool uses were evaluated with the single-tool and the multiple-tool sequence tasks. The SAQ scores of the AD and VaD groups were significantly lower than that of the NC group. For the single tool tasks, the AD and VaD groups exhibited lower scores than the NC group. The sequence score of the VaD group was lower than that of the AD group. The multiple regression analysis disclosed that the SAQ of the AD group was explained by the Mini-Mental State Examination and sequence scores. However, that of the VaD group was mainly explained by the sequence scores. Disturbances in everyday life activities of AD are associated with general cognitive impairment and sequence disabilities. By contrast, those of VaD may be based only on sequence disabilities.

P3-209: Genetic variation in the alpha 7 nicotinic acetylcholine receptor is associated with delusional symptoms in Alzheimer's disease

Psychotic symptoms, such as delusions and hallucinations, are among the most common and distressing neuropsychiatric symptoms in Alzheimer's disease (AD). AD with psychosis has been proposed as a distinct endophenotype, associated with more severe cognitive deficits and faster cognitive decline. The aetiology of these symptoms is unclear but they may be attributed to genetic risk factors revealed during neurodegeneration. CHRNA7, the gene for the alpha 7 nicotinic acetylcholine receptor, has been associated with schizophrenia in linkage and association studies. Objective: To investigate genetic variation in CHRNA7 in relation to AD with psychosis. The study group consisted of 409 Northern Irish patients with a diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Patients were assessed for the presence of psychotic symptoms using the Neuropsychiatric Inventory (NPI). Fourteen highly polymorphic intronic single nucleotide polymorphisms (SNPs) across CHRNA7 were selected and genotyped using Taqman technology and PCR-RFLP. Haploview was used to define linkage disequilibrium. Genotype and haplotype frequencies were compared using chi-squared analysis. Following correction for multiple testing, a significant association between delusions and the T allele of rs6494223 (p = 0.014, OR = 1.63, CI = 1.22–2.17) was found. Haplotype analysis revealed four blocks of high linkage disequilibrium across CHRNA7 but there were no associations between haplotypes and AD with psychosis. This novel finding suggests that the alpha 7 nicotinic acetylcholine receptor may be a suitable target in the treatment of AD with psychosis but further work in this area is required.

Vagus Nerve Stimulation in Patients With Alzheimer's Disease

Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported. All patients (N = 17) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Responder rates for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) were measured as improvement or absence of decline from baseline. Global change, depressive symptoms, and quality of life were also assessed. Cerebrospinal fluid (CSF) levels for total tau, tau phosphorylated at Thr181 (phosphotau), and Abeta42 were measured by standardized enzyme-linked immunosorbent assay (ELISA). VNS was well tolerated. After 1 year, 7 (41.2%) of 17 patients and 12 (70.6%) of 17 patients improved or did not decline from baseline on the ADAS-cog and MMSE, respectively. Twelve of 17 patients were rated as having no change or some improvement from baseline on the Clinician Interview-Based Impression of Change (CIBIC+). No significant decline in mood, behavior, or quality of life occurred during 1 year of treatment. The median change in CSF tau at 1 year was a reduction of 4.8% (p = .057), with a 5.0% increase in phosphotau (p = .040; N = 14). The results of this study support long-term tolerability of VNS among patients with AD and warrant further investigation.

Genetic epidemiology of Alzheimer disease.

Dementia is a major health problem in the elderly. Following an extended period of loss of personality and cognition, the disease results in a state of complete dependency. By far the most common cause of dementia is Alzheimer disease, which is clinically characterized by a gradual, progressive decline in intellectual functions (1). Psychosis, depression, agitation, and anxiety are common manifestations (2). The most frequently used diagnostic criteria for Alzheimer disease are described by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (3). The diagnosis of Alzheimer disease is considered to be probable when alternative causes of dementia are excluded (3, 4). According to the NINCDS-ADRDA criteria, a definite diagnosis is made when a probable diagnosis of Alzheimer disease is confirmed at autopsy (3). The neuropathologic characteristics of Alzheimer disease are senile plaques, neurofibrillary tangles, amyloid angiopathy, neuronal loss, as well as decreased activity of the enzyme choline acetyltransferase (5). Senile plaques are extracellular deposits of predominantly /3-amyloid. Neurofibrillary tangles are intraneuronal inclusions, which are, in part, composed of abnormally phosphorylated tau protein. The prevalence of Alzheimer disease increases with advancing age. It affects less than 1 percent of individuals aged 60-64 years, and up to 40 percent of those over age 85 years (6). Also, the incidence increases with aging, and is estimated to be 1 per 1,000

Progression of Cognitive Impairment in Alzheimer's Disease

Change in cognitive function was assessed over 12 months in 110 patients over the age of 65 satisfying National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for "probable" Alzheimer's Disease. A highly significant deterioration in cognitive function was observed. Decline in cognitive scores was relatively normally distributed. Patients who died during the follow-up had more apraxia at entry to the study than survivors. A greater rate of decline was seen in patients whose parents suffered from dementia (but not in those where a sibling or other relative was affected), in subjects who had moderate dementia, and those who had been ill for less than 24 months. Age, age of onset, and the presence or absence of aphasia or apraxia had no influence on rate of progression. A cluster analysis revealed three patterns of decline.