Genetic Counseling for Early-onset Familial Alzheimer Disease in Large Aboriginal Kindred from a Remote Community in British Columbia: Unique Challenges and Possible Solutions

A novel, pathogenic presenilin 1 (PS1) mutation has recently been identified in a large Aboriginal kindred living in dispersed communities throughout British Columbia, Canada. Disseminating genetic information and ensuring that appropriate genetic counseling services are provided to all concerned relatives have posed several unique challenges. These challenges include knowledge exchange and continuity of care in a geographically remote and culturally distinct community. To our knowledge, this is the first time a specific genetic counseling approach has been needed for early-onset familial Alzheimer disease (EOFAD) in a North American Aboriginal community.     

Case Report: Depression vs. Early-Onset Alzheimer Disease: The Genetic Counselor's Role

Awareness of depression in the differential diagnosis of Alzheimer disease is essential for genetic counselors seeing patients at risk for early-onset familial Alzheimer disease (EOFAD). The genetic counselor is in a unique position to recognize depression as the cause of symptoms mimicking early-onset Alzheimer disease. While generating a family medical history, the counselor can evoke significant emotional history as well. Based on this information, appropriate referrals can be given for neurological and psychological evaluation. The counselor also serves to explain EOFAD and the benefits and limitations of genetic testing for each individual patient. Whether or not patients choose testing, they can benefit from correct diagnosis of troublesome, or even debilitating, symptoms that imitate symptoms of the feared hereditary disease.     

阿尔茨海默病发病机制的研究进展

阿尔茨海默病是一种起病隐匿,进行性发展的神经系统退行性疾病。临床上以记忆障碍、失语、失用、失认、视空间损害、执行功能障碍以及人格和行为改变等全面性痴呆表现为特征,病因迄今未明,发病机制复杂。本文对可能的发病机制：遗传因素（包括ApoE基因、早老素-1和早老素-2基因,APP基因、α2巨球蛋白基因、TOMM40基因、COL25A1基因）;Aβ代谢（合成、分解、转运）;神经递质学说;自由基与氧化应激学说;金属离子学说等进行综述。     

Neuropsychological indicators of preclinical Alzheimer’s disease among depressed older adults

Older adults with major depressive disorder (MDD) may also have preclinical Alzheimer’s disease (AD). Differential diagnosis is quite challenging due to the overlapping symptoms of MDD and AD. In the current study, we predicted that impaired long-term memory (an area most affected in early AD), but not executive function (an area affected in MDD and AD), would distinguish older depressed patients who developed AD from those who did not. Patients (N = 120) assessed as having MDD but not dementia at baseline were administered tests of cognitive function and followed longitudinally for subsequent diagnosis of AD. Using structural equation modeling we found a latent construct of long-term memory to be associated with AD to a greater extent than executive functioning. Additional analyses to enhance clinical utility of findings indicated that individual tests of episodic memory were most predictive of AD status. Tests of long-term memory can be utilized by the clinician when assessing for preclinical AD among depressed elderly.     

Functional Brain Connectivity Using fMRI in Aging and Alzheimer’s Disease

Normal aging and Alzheimer’s disease (AD) cause profound changes in the brain’s structure and function. AD in particular is accompanied by widespread cortical neuronal loss, and loss of connections between brain systems. This degeneration of neural pathways disrupts the functional coherence of brain activation. Recent innovations in brain imaging have detected characteristic disruptions in functional networks. Here we review studies examining changes in functional connectivity, measured through fMRI (functional magnetic resonance imaging), starting with healthy aging and then Alzheimer’s disease. We cover studies that employ the three primary methods to analyze functional connectivity—seed-based, ICA (independent components analysis), and graph theory. At the end we include a brief discussion of other methodologies, such as EEG (electroencephalography), MEG (magnetoencephalography), and PET (positron emission tomography). We also describe multi-modal studies that combine rsfMRI (resting state fMRI) with PET imaging, as well as studies examining the effects of medications. Overall, connectivity and network integrity appear to decrease in healthy aging, but this decrease is accelerated in AD, with specific systems hit hardest, such as the default mode network (DMN). Functional connectivity is a relatively new topic of research, but it holds great promise in revealing how brain network dynamics change across the lifespan and in disease.     

Association rule learning in neuropsychological data analysis for Alzheimer’s disease

Efficient methods of analysis readily available for clinicians continue to be limited within neuropsychological assessment at the raw data level. Here, a novel approach for generating predictive response patterns and analysing neuropsychological raw data is offered. In order to assess the usefulness of association rule learning as an analysis tool for neuropsychological raw data, Frequent Pattern Growth (FP-Growth) was used to mine patterns from the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB) database. Complete assessment data for 84 post-mortem confirmed Alzheimer’s disease (AD) cases and 294 age, race, and education matched controls were analysed across baseline and one-year follow-up using FP-Growth, for the purpose of assessing the clinical utility of a finer analysis at the raw data level and the feasibility of predicting response patterns for clinical/control groups. Output from FP-Growth, in terms of the number of frequent itemsets retained across both evaluation timepoints, was discernable between controls, mild, and moderate to severe Alzheimer’s disease cases (p < .001, and η² = .488). Patterns within raw data scores, both in terms of frequent itemsets and predictive association rules, appear to be differentiable across groups within neuropsychological analysis, which indicates that FP-Growth is applicable as a supplementary analysis tool for neuropsychological assessment by means of offering an additional level of data analysis, predictive item response capabilities, and aiding in clinical decision making.     

Very Early Decline in Recognition Memory for Odors in Alzheimer’s Disease

When in the progression of Alzheimer’s disease (AD) a decline in detection sensitivity and recognition memory for odors begins, and whether a fast progression in dementia is related to a fast loss in odor sensitivity, was determined by studying 78 patients with probable AD, categorized as very mild, mild, or moderate in degree of dementia, and 78 controls. Taste and vision were studied for comparison. Whereas the earliest decline in odor sensitivity and visual memory was found in mild patients, a decline in odor memory was found in the very mild patients. Similar taste thresholds in the four groups suggest that the poor odor detectability in AD was not related to task demands in threshold testing. A fast progression in dementia was also found to be related to a fast loss in odor sensitivity. The findings imply that memory-based olfactory tests may contribute to early diagnosis of AD.     

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.     

Predictive Genetic Testing in Children: Constitutional Mismatch Repair Deficiency Cancer Predisposing Syndrome

Biallelic germline mutations in mismatch repair genes predispose to constitutional mismatch repair deficiency syndrome (CMMR-D). The condition is characterized by a broad spectrum of early-onset tumors, including hematological, brain and bowel and is frequently associated with features of Neurofibromatosis type 1. Few definitive screening recommendations have been suggested and no published reports have described predictive testing. We report on the first case of predictive testing for CMMR-D following the identification of two non-consanguineous parents, with the same heterozygous mutation in MLH1: c.1528C > T. The genetic counseling offered to the family, for their two at-risk daughters, is discussed with a focus on the ethical considerations of testing children for known cancer-causing variants. The challenges that are encountered when reporting on heterozygosity in a child younger than 18 years (disclosure of carrier status and risk for Lynch syndrome), when discovered during testing for homozygosity, are addressed. In addition, the identification of CMMR-D in a three year old, and the recommended clinical surveillance that was proposed for this individual is discussed. Despite predictive testing and presymptomatic screening, the sudden death of the child with CMMR-D syndrome occurred 6 months after her last surveillance MRI. This report further highlights the difficulty of developing guidelines, as a result of the rarity of cases and diversity of presentation.     

Normal McCollough effect in Alzheimer’s disease and global amnesia

The McCollough effect (ME), a long-lasting, pattern-contingent aftereffect in normal human vision, was examined in persons with known deficits in memory. We induced MEs in 11 subjects, 5 patients with various severities of Alzheimer’s disease (AD), H.M. (a patient who has global amnesia due to bilateral medial temporal lobectomy and who has been studied for 35 years since his operation), and 5 control subjects. H.M. and the AD patients showed MEs of strength and duration comparable to those of the control subjects. These results demonstrate a dissociation between learning mechanisms that mediate recall and recognition versus mechanisms that mediate the ME. Furthermore, knowledge about the sites of neuropathology in H.M. and in AD are consistent with other sources of evidence implicating early visual areas, especially V1, as a critical locus of the ME.     

Speech rhythm alterations in Spanish-speaking individuals with Alzheimer’s disease

Rhythm is the speech property related to the temporal organization of sounds. Considerable evidence is now available for suggesting that dementia of Alzheimer’s type is associated with impairments in speech rhythm. The aim of this study is to assess the use of an automatic computerized system for measuring speech rhythm characteristics in an oral reading task performed by 45 patients with Alzheimer’s disease (AD) compared with those same characteristics among 82 healthy older adults without a diagnosis of dementia, and matched by age, sex and cultural background. Ranges of rhythmic-metric and clinical measurements were applied. The results show rhythmic differences between the groups, with higher variability of syllabic intervals in AD patients. Signal processing algorithms applied to oral reading recordings prove to be capable of differentiating between AD patients and older adults without dementia with an accuracy of 87% (specificity 81.7%, sensitivity 82.2%), based on the standard deviation of the duration of syllabic intervals. Experimental results show that the syllabic variability measurements extracted from the speech signal can be used to distinguish between older adults without a diagnosis of dementia and those with AD, and may be useful as a tool for the objective study and quantification of speech deficits in AD.     

Differences Between African American and White Research Volunteers in Their Attitudes,Beliefs and Knowledge Regarding Genetic Testing for Alzheimer’s Disease

Genetic susceptibility testing for common diseases is expanding, but little is known about race group differences in test perceptions. The purpose of this study was to examine differences between African Americans and Whites in knowledge, attitudes, and motivations regarding genetic susceptibility testing for Alzheimer’s disease (AD). Before enrolling in an AD genetic testing research trial, 313 first-degree relatives of AD patients (20% African American; 71% female; mean age = 58 years) were surveyed regarding: (1) knowledge about genetics and AD risk; (2) concerns about developing AD; and (3) reasons for seeking testing. In comparison to Whites, African Americans were less knowledgeable about genetics and AD risk (p < .01) and less concerned about developing AD (p < .05), with lower levels of perceived disease risk (p = .04). The results suggest that African Americans and Whites differ notably in their knowledge, beliefs, and attitudes regarding genetic testing for AD. Additional research with more representative samples is needed to better understand these differences.     

Object decision test (BORB): normative data for the adult Quebec population and performance in Alzheimer’s disease and the semantic variant of primary progressive aphasia

Object decision (OD) test is one subtest of the Birmingham Object Recognition Battery (BORB). It is useful for differential diagnosis among several neurodegenerative diseases. However, normative data provided with this battery count on very few subjects and do not control for the effect of age, which limits interpretability. The purpose of Study 1 was to provide normative data for the OD test of the BORB (version A—hard). The objectives of Study 2 were to establish the diagnostic validity of this task and predictive validity of the normative data in the case of the semantic variant of primary progressive aphasia (svPPA) and Alzheimer’s disease (AD).Based on multiple linear regressions, equations to calculate Z-scores corrected for age were provided for 130 participants aged from 47 to 89 years. Performance of 20 healthy participants was compared to that of 14 individuals with svPPA and 18 with AD. After controlling for confounders, participants with svPPA had a lower total score than controls and AD participants. AD participants had a poorer performance than controls only when chimeric objects were considered. Among those with a deficit on the total score of the test, 94% (17/18, including 12 with svPPA) were correctly identified as having a pathological condition (svPPA or AD). This test could help refine differential diagnosis between svPPA and AD patients, especially before the deficits of episodic memory show up.     

Recognition of familiar and unfamiliar melodies in normal aging and Alzheimer’s disease

We tested normal young and elderly adults and elderly Alzheimer’s disease (AD) patients on recognition memory for tunes. In Experiment 1, AD patients and age-matched controls received a study list and an old/new recognition test of highly familiar, traditional tunes, followed by a study list and test of novel tunes. The controls performed better than did the AD patients. The controls showed the “mirror effect” of increased hits and reduced false alarms for traditional versus novel tunes, whereas the patients false-alarmed as often to traditional tunes as to novel tunes. Experiment 2 compared young adults and healthy elderly persons using a similar design. Performance was lower in the elderly group, but both younger and older subjects showed the mirror effect. Experiment 3 produced confusion between preexperimental familiarity and intraexperimental familiarity by mixing traditional and novel tunes in the study lists and tests. Here, the subjects in both age groups resembled the patients of Experiment 1 in failing to show the mirror effect. Older subjects again performed more poorly, and they differed qualitatively from younger subjects in setting stricter criteria for more nameable tunes. Distinguishing different sources of global familiarity is a factor in tune recognition, and the data suggest that this type of source monitoring is impaired in AD and involves different strategies in younger and older adults.     

Diagnostic Accuracy of Memory Measures in Alzheimer’s Dementia and Mild Cognitive Impairment: a Systematic Review and Meta-Analysis

With an increasing focus on biomarkers in dementia research, illustrating the role of neuropsychological assessment in detecting mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) is important. This systematic review and meta-analysis, conducted in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) standards, summarizes the sensitivity and specificity of memory measures in individuals with MCI and AD. Both meta-analytic and qualitative examination of AD versus healthy control (HC) studies (n = 47) revealed generally high sensitivity and specificity (≥ 80% for AD comparisons) for measures of immediate (sensitivity = 87%, specificity = 88%) and delayed memory (sensitivity = 89%, specificity = 89%), especially those involving word-list recall. Examination of MCI versus HC studies (n = 38) revealed generally lower diagnostic accuracy for both immediate (sensitivity = 72%, specificity = 81%) and delayed memory (sensitivity = 75%, specificity = 81%). Measures that differentiated AD from other conditions (n = 10 studies) yielded mixed results, with generally high sensitivity in the context of low or variable specificity. Results confirm that memory measures have high diagnostic accuracy for identification of AD, are promising but require further refinement for identification of MCI, and provide support for ongoing investigation of neuropsychological assessment as a cognitive biomarker of preclinical AD. Emphasizing diagnostic test accuracy statistics over null hypothesis testing in future studies will promote the ongoing use of neuropsychological tests as Alzheimer’s disease research and clinical criteria increasingly rely upon cerebrospinal fluid (CSF) and neuroimaging biomarkers.     

Examining the reliability of ADAS-Cog change scores

The purpose of this study was to estimate and examine ways to improve the reliability of change scores on the Alzheimer’s Disease Assessment Scale, Cognitive Subtest (ADAS-Cog). The sample, provided by the Alzheimer’s Disease Neuroimaging Initiative, included individuals with Alzheimer’s disease (AD) (n = 153) and individuals with mild cognitive impairment (MCI) (n = 352). All participants were administered the ADAS-Cog at baseline and 1 year, and change scores were calculated as the difference in scores over the 1-year period. Three types of change score reliabilities were estimated using multivariate generalizability. Two methods to increase change score reliability were evaluated: reweighting the subtests of the scale and adding more subtests. Reliability of ADAS-Cog change scores over 1 year was low for both the AD sample (ranging from .53 to .64) and the MCI sample (.39 to .61). Reweighting the change scores from the AD sample improved reliability (.68 to .76), but lengthening provided no useful improvement for either sample. The MCI change scores had low reliability, even with reweighting and adding additional subtests. The ADAS-Cog scores had low reliability for measuring change. Researchers using the ADAS-Cog should estimate and report reliability for their use of the change scores. The ADAS-Cog change scores are not recommended for assessment of meaningful clinical change.     

Bilingualism Is Associated with a Delayed Onset of Dementia but Not with a Lower Risk of Developing it: a Systematic Review with Meta-Analyses

Neuropsychology Review - Some studies have linked bilingualism with a later onset of dementia, Alzheimer’s disease (AD), and mild cognitive impairment (MCI). Not all studies have observed...     

Neuropsychological Measures that Predict Progression from Mild Cognitive Impairment to Alzheimer's type dementia in Older Adults: a Systematic Review and Meta-Analysis

This study aimed to determine the extent to which cognitive measures can predict progression from mild cognitive impairment (MCI) to Alzheimer’s type dementia (AD), assess the predictive accuracy of different cognitive domain categories, and determine whether accuracy varies as a function of age and length of follow-up. We systematically reviewed and meta-analyzed data from longitudinal studies reporting sensitivity and specificity values for neuropsychological tests to identify individuals with MCI who will develop AD. We searched articles in Medline, Cochrane, EMBASE, PsycINFO, and the Web of Science. Methodological quality was assessed using the STARDem and QUADAS standards. Twenty-eight studies met the eligibility criteria (2365 participants) and reported predictive values from 61 neuropsychological tests with a 31-month mean follow-up. Values were pooled to provide combined accuracy for 14 cognitive domains. Many domains showed very good predictive accuracy with high sensitivity and specificity values (≥ 0.7). Verbal memory measures and many language tests yielded very high predictive accuracy. Other domains (e.g., executive functions, visual memory) showed better specificity than sensitivity. Predictive accuracy was highest when combining memory measures with a small set of other domains or when relying on broad cognitive batteries. Cognitive tests are excellent at predicting MCI individuals who will progress to dementia and should be a critical component of any toolkit intended to identify AD at the pre-dementia stage. Some tasks are remarkable as early indicators, whereas others might be used to suggest imminent progression.     

Enhanced cognitive activity--over and above social or physical activity--is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity

Although social, physical, and cognitive activities have each been suggested to reduce the risk of Alzheimer's disease (AD), epidemiologic studies cannot determine which activity or combination of activities is most important. To address this question, mutant APP transgenic AD mice were reared long-term in one of four housing conditions (impoverished, social, social+physical, or complete enrichment) from 1(1/2) through 9 months of age. Thus, a stepwise layering of social, physical, and enhanced cognitive activity was created. Behavioral evaluation in a full battery of sensorimotor, anxiety, and cognitive tasks was carried out during the final 5 weeks of housing. Only AD mice raised in complete enrichment (i.e., enhanced cognitive activity) showed: (1) protection against cognitive impairment, (2) decreased brain beta-amyloid deposition, and (3) increased hippocampal synaptic immunoreactivity. The protection provided by enhanced cognitive activity spanned multiple cognitive domains (working memory, reference learning, and recognition/identification). Cognitive and neurohistologic benefits of complete enrichment occurred without any changes in blood cytokine or corticosterone levels, suggesting that enrichment-dependent mechanisms do not involve changes in the inflammatory response or stress levels, respectively. These results indicate that the enhanced cognitive activity of complete enrichment is required for cognitive and neurologic benefit to AD mice-physical and/or social activity are insufficient. Thus, our data suggest that humans who emphasize a high lifelong level of cognitive activity (over and above social and physical activities) will attain the maximal environmental protection against AD.     

Investigating secondary‐distinctiveness‐based effects in aging and Alzheimer's disease patients

The aim of the present study was 2‐fold. First, two experiments were devised to further investigate secondary distinctiveness‐based effects in relation to aging. By using a repeated study‐test procedure, it aimed at restoring the bizarreness effect (Experiment 1) or at amplifying the orthographic distinctiveness (OD) effect in older adults (Experiment 2). Second, by including Alzheimer's disease patients (AD patients) in both experiments, it also aimed at instigating research on secondary distinctiveness‐based effects in relation to Alzheimer disease. The results of Experiment 1 revealed that a repeated study‐test procedure may to some extent facilitate the free recalling of bizarre images in older adults. However, the benefit of such procedure does not seem to be durable in older adults (no bizarreness effect for the last study‐test cycle) and is inefficient in AD patients. Surprisingly, for both older adults and AD patients, results of Experiment 2 revealed a similar OD effect across all study‐test cycles. The findings of both experiments were related to previous work suggesting that the bizarreness effect and the OD effect are mediated by different processing.