Identifying dementia in Down syndrome with the Severe Impairment Battery, Brief Praxis Test and Dementia Scale for People with Learning Disabilities.

BACKGROUND: Individuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer's disease. However, many measures regularly used for the detection of dementia in the general population are not suitable for individuals with DS due in part to floor effects. Some measures, including the Severe Impairment Battery (SIB), Brief Praxis Test (BPT) and Dementia Scale for People with Learning Disabilities (DLD), have been used in clinical trials and other research with this population. Validity research is limited, particularly regarding the use of such tools for detection of prodromal dementia in the DS population. The current project presents baseline cross-sectional SIB, BPT and DLD performance in order to characterise their predictive utility in discriminating normal cognition, possible dementia and probable dementia in adult DS. METHOD: Baseline SIB, BPT and DLD performances from 100 individuals (no dementia = 68, possible dementia = 16 & probable dementia = 16) were examined from a longitudinal cohort of aging individuals with DS. Receiver operating characteristic curves investigated the accuracy of these measures in relation to consensus dementia diagnoses, diagnoses which demonstrated high percent agreement with the examining neurologist's independent diagnostic impression. RESULTS: The SIB and BPT exhibited fair discrimination ability for differentiating no/possible versus probable dementia [area under the curve (AUC) = 0.61 and 0.66, respectively]. The DLD exhibited good discrimination ability for differentiating no versus possible/probable dementia (AUC = 0.75) and further demonstrated better performance of the DLD Cognitive subscale compared with the DLD Social subscale (AUC = 0.77 and 0.67, respectively). CONCLUSIONS: Results suggest that the SIB, BPT and DLD are able to reasonably discriminate consensus dementia diagnoses in individuals with DS, supporting their continued use in the clinical assessment of dementia in DS. The general performance of these measures suggests that further work in the area of test development is needed to improve on the AUCs for dementia status discrimination in this unique population. At present, however, the current findings suggest that the DLD may be the best option for reliable identification of prodromal dementia in this population, reinforcing the importance of including informant behaviour ratings in assessment of cognition for adults with DS.

A preliminary study of cerebral blood flow, aging and dementia in people with Down syndrome.

BACKGROUND: People with Down syndrome (DS) develop Alzheimer's disease (AD) at an earlier age of onset than those with sporadic AD. AD neuropathology is typically present in DS by 40 years of age with an onset of dementia approximately 10 years later. This early onset is due to the overexpression of amyloid precursor protein from the third copy of chromosome 21. Cerebrovascular neuropathology is thought to contribute in 40-60% of cases sporadic AD. However, the vascular contribution to dementia in people with DS has been relatively unexplored. We hypothesised that vascular perfusion is compromised in older adults with DS relative to younger individuals and is further exacerbated in those with dementia. METHOD: Cerebral blood flow (CBF) was measured using pulsed arterial spin labelling in 35 cognitively characterised adults with DS (26-65 years). DS participants were also compared with 15 control subjects without DS or dementia (26-65 years). Linear regression evaluated the difference in CBF across groups and diagnosis along with assessing the association between CBF and cognitive measures within the DS cohort. RESULTS: Cerebral blood flow was significantly lower among DS participants with probable AD compared with controls (P = 0.02) and DS participants with no dementia (P = 0.01). Within the DS cohort, CBF was significantly associated with the Severe Impairment Battery (SIB) measure and the Dementia Questionnaire for People with Learning Disabilities (DLD) rating (F3,25  = 5.13; P = 0.007). Both the SIB (ß = 0.74; t = 2.71; P = 0.01) and DLD (ß = -0.96; t = -3.87; P < 0.001) indicated greater impairment as global CBF decreased. Age was significantly associated with CBF among participants with DS. There was a non-linear effect of age, whereby CBF declined more rapidly after 45 years of age. CONCLUSIONS: This preliminary study of CBF in DS indicates that cerebrovascular pathology may be a significant contributor to dementia in DS. CBF was associated with diagnosis, cognition and age. Notably, CBF decreases at a greater rate after age 45 and may represent a significant prodromal event in AD progression.

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases.

According to the WHO, the proportion of people over 60 years is increasing and expected to reach 22% of total world's population in 2050. In parallel, recent animal demographic studies have shown that the life expectancy of pet dogs and cats is increasing. Brain aging is associated not only with molecular and morphological changes but also leads to different degrees of behavioral and cognitive dysfunction. Common age-related brain lesions in humans include brain atrophy, neuronal loss, amyloid plaques, cerebrovascular amyloid angiopathy, vascular mineralization, neurofibrillary tangles, meningeal osseous metaplasia, and accumulation of lipofuscin. In aging humans, the most common neurodegenerative disorder is Alzheimer's disease (AD), which progressively impairs cognition, behavior, and quality of life. Pathologic changes comparable to the lesions of AD are described in several other animal species, although their clinical significance and effect on cognitive function are poorly documented. This review describes the commonly reported age-associated neurologic lesions in domestic and laboratory animals and the relationship of these lesions to cognitive dysfunction. Also described are the comparative interspecies similarities and differences to AD and other human neurodegenerative diseases including Parkinson's disease and progressive supranuclear palsy, and the spontaneous and transgenic animal models of these diseases.

Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention.

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.

Cognitive dysfunction and the neurobiology of ageing in cats.

With improvements in nutrition and veterinary medicine the life expectancy of pet cats is increasing. Accompanying this growing geriatric population there are increasing numbers of cats with signs of apparent senility. A recent study suggests that 28 per cent of pet cats aged 11 to 14 years develop at least one geriatric onset behavioural problem, and this increases to over 50 per cent for cats of 15 years of age or older. While behavioural changes may result from systemic illness, organic brain disease or true behavioural problems, the possibility of age-related cognitive dysfunction is often overlooked. Studies have revealed a number of changes in the brains of geriatric cats that showed signs of cognitive dysfunction, and potential causes include vascular insufficiency leading to hypoxia, increased free radical damage and the deposition of beta-amyloid plaques and/or the modification of other proteins. By recognising the importance of behavioural changes in old cats, investigating them fully for potentially treatable medical conditions, and instigating dietary and environmental modifications to meet their changing needs, we can make the lives of our geriatric cats much more comfortable and rewarding.

(1)H-MRS metabolites in adults with Down syndrome: Effects of dementia.

To determine if proton magnetic resonance spectroscopy ((1)H-MRS) detect differences in dementia status in adults with Down syndrome (DS), we used (1)H-MRS to measure neuronal and glial metabolites in the posterior cingulate cortex in 22 adults with DS and in 15 age- and gender-matched healthy controls. We evaluated associations between (1)H-MRS results and cognition among DS participants. Neuronal biomarkers, including N-acetylaspartate (NAA) and glutamate-glutamine complex (Glx), were significantly lower in DS patients with Alzheimer's should probably be changed to Alzheimer (without ' or s) through ms as per the new naming standard disease (DSAD) when compared to non-demented DS (DS) and healthy controls (CTL). Neuronal biomarkers therefore appear to reflect dementia status in DS. In contrast, all DS participants had significantly higher myo-inositol (MI), a putative glial biomarker, compared to CTL. Our data indicate that there may be an overall higher glial inflammatory component in DS compared to CTL prior to and possibly independent of developing dementia. When computing the NAA to MI ratio, we found that presence or absence of dementia could be distinguished in DS. NAA, Glx, and NAA/MI in all DS participants were correlated with scores from the Brief Praxis Test and the Severe Impairment Battery. (1)H-MRS may be a useful diagnostic tool in future longitudinal studies to measure AD progression in persons with DS. In particular, NAA and the NAA/MI ratio is sensitive to the functional status of adults with DS, including prior to dementia.

Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study.

The effectiveness of two interventions, dietary fortification with antioxidants and a program of behavioral enrichment, was assessed in a longitudinal study of cognitive aging in beagle dogs. A baseline protocol of cognitive testing was used to select four cognitively equivalent groups: control food-control experience (C-C), control food-enriched experience (C-E), antioxidant fortified food-control experience (A-C), and antioxidant fortified food-enriched experience(A-E). We also included two groups of young behaviorally enriched dogs, one receiving the control food and the other the fortified food. Discrimination learning and reversal was assessed after one year of treatment with a size discrimination task, and again after two years with a black/white discrimination task. The four aged groups were comparable at baseline. At one and two years, the aged combined treatment group showed more accurate learning than the other aged groups. Discrimination learning was significantly improved by behavioral enrichment. Reversal learning was improved by both behavioral enrichment and dietary fortification. By contrast, the fortified food had no effect on the young dogs. These results suggest that behavioral enrichment or dietary fortification with antioxidants over a long-duration can slow age-dependent cognitive decline, and that the two treatments together are more effective than either alone in older dogs.

Beta-amyloid deposition and tau phosphorylation in clinically characterized aged cats.

The current study describes both Abeta and tau abnormalities that accumulate in the brains of aged (16-21 years), but not young (<4 years) clinically characterized cats. Diffuse plaques that were morphologically different from what is typically observed in the human brain could be detected with 4G8 (Abeta17-24) or an Abeta1-42-specific antibody but not with N-terminal Abeta or an Abeta1-40-specific antibody. SELDI-TOF mass spectrometry experiments indicated that cat brain Abeta consisted almost entirely of Abeta1-42. Markers of tau hyperphosphorylation (AT8 and PHF-1) labeled a subset of neurons in two aged animals. In the hilus of the hippocampus, a subset of AT8 positive neurons showed a sprouting morphology similar to that observed in human brain. Western blot analysis with antibodies against hyperphosphorylated tau indicated that tau is hyperphosphorylated in the aged cat and contains many of the same epitopes found in Alzheimer's disease (AD) brain. Thus, the aged cat brain develops AD-related lesions with important morphological and biochemical differences compared to human brain.

Parallel compensatory and pathological events associated with tau pathology in middle aged individuals with Down syndrome.

Aged individuals with Down syndrome (DS) develop senile plaques and neurofibrillary tangles consistent with Alzheimer disease (AD). Prior to or in parallel with AD pathology, compensatory growth responses may occur. Immunohistochemistry and confocal microscopy studies in the hippocampus from 15 individuals ranging in age from 5 months to 67 years compared markers of normal and abnormal tau accumulation (phosphorylated tau [AT8, MC-1], tau-1, N-terminal tau) with the extent and location of neuronal growth marker immunoreactivity (BDNF, GAP-43, MAP-2). In middle age (30-40 years), prior to entorhinal neuron loss, the earliest tau accumulation occurred in the outer molecular layer (OML), which was consistent with both pathological and compensatory fetal tau expression. These events were followed at a later age, associated with entorhinal neuron loss, by an increase in GAP-43. Hilar neurons exhibiting a sprouting morphology were also noted. Age-dependent observations in the DS brain in the current study parallel hippocampal compensatory responses described in entorhinal cortex lesion studies in rodents. Thus, compensatory growth responses may occur in DS prior to extensive AD pathology and may be one mechanism underlying observations in PET studies of hypermetabolism in the entorhinal cortex of individuals with DS.

Landmark discrimination learning in the dog: effects of age, an antioxidant fortified food, and cognitive strategy.

The landmark discrimination learning test can be used to assess the ability to utilize allocentric spatial information to locate targets. The present experiments examined the role of various factors on performance of a landmark discrimination learning task in beagle dogs. Experiments 1 and 2 looked at the effects of age and food composition. Experiments 3 and 4 were aimed at characterizing the cognitive strategies used in performance on this task and in long-term retention. Cognitively equivalent groups of old and young dogs were placed into either a test group maintained on food enriched with a broad-spectrum of antioxidants and mitochondrial cofactors, or a control group maintained on a complete and balanced food formulated for adult dogs. Following a wash-in period, the dogs were tested on a series of problems, in which reward was obtained when the animal responded selectively to the object closest to a thin wooden block, which served as a landmark. In Experiment 1, dogs were first trained to respond to a landmark placed directly on top of coaster, landmark 0 (L0). In the next phase of testing, the landmark was moved at successively greater distances (1, 4 or 10 cm) away from the reward object. Learning varied as a function of age group, food group, and task. The young dogs learned all of the tasks more quickly than the old dogs. The aged dogs on the enriched food learned L0 significantly more rapidly than aged dogs on control food. A higher proportion of dogs on the enriched food learned the task, when the distance was increased to 1cm. Experiment 2 showed that accuracy decreased with increased distance between the reward object and landmark, and this effect was greater in old animals. Experiment 3 showed stability of performance, despite using a novel landmark, and new locations, indicating that dogs learned the landmark concept. Experiment 4 found age impaired long-term retention of the landmark task. These results indicate that allocentric spatial learning is impaired in an age-dependent manner in dogs, and that age also affects performance when the distance between the landmark and target is increased. In addition, these results both support a role of oxidative damage in the development of age-associated cognitive dysfunction and indicate that short-term administration of a food enriched with supplemental antioxidants and mitochondrial cofactors can partially reverse the deleterious effects of aging on cognition.

Region-specific age at onset of beta-amyloid in dogs.

Cortical patterns of beta-amyloid (Abeta) deposition were evaluated in 40 beagle dogs ranging in age from 2 to 18 years. Abeta deposition in the prefrontal, occipital, parietal and entorhinal cortices was visualized by using an antibody against Abeta1-42. A logistic regression was used to estimate differences in age-at-onset and rate of deposition of Abeta as a function of brain region. The earliest and most consistent site of Abeta deposition with age was in the prefrontal cortex. Entorhinal Abeta deposition was not consistently observed until the age of 14 years, but was present in a subset of dogs under the age of 14 years. These regional vulnerabilities to Abeta accumulation are similar to those seen in the aging human. By using parameters derived from regression analyses, it may be possible to predict the presence of Abeta within specific brain regions in individual dogs. We propose that these models will be a useful tool to evaluate interventions that delay the age of onset or slow the rate of accumulation of Abeta in the dog.

Visual-discrimination learning ability and beta-amyloid accumulation in the dog.

Young, middle-aged, and old beagle dogs were tested on several visual-discrimination tasks: reward- and object-approach learning, object discrimination and reversal, long-term retention of a reversal problem, and a size-discrimination task. Beta-amyloid accumulation in the entorhinal, prefrontal, parietal, and occipital cortices was quantified using immunohistochemical and imaging techniques at the conclusion of cognitive testing. Middle-aged and old dogs were impaired in size-discrimination learning. In each task, a subset of aged dogs was impaired relative to age-matched peers. Beta-amyloid accumulation was age-dependent. However, not all middle-aged and old dogs showed beta-amyloid accumulation in the entorhinal cortex. The error scores from dogs tested with a nonpreferred object during visual discrimination learning and from reversal learning were correlated with beta-amyloid in the prefrontal but not entorhinal cortex. Size-discrimination and reward and object-approach learning error scores were correlated with beta-amyloid accumulation in the entorhinal but not prefrontal cortex. The results of these studies support an association between cognitive test and the location and extent of beta-amyloid pathology.

The canine as an animal model of human aging and dementia.

The aged canine displays many features that make it an excellent model for studying the progression of pathology in brain aging and linking these findings to learning, memory and other cognitive functions. Canines develop extensive beta-amyloid deposition within neurons and their synaptic fields, which appears to give rise to senile plaques. These plaques are primarily of the early diffuse subtype. Aged canines also exhibit accumulations of lipofuscin, cerebral vascular changes, dilation of the ventricles, and cytoskeletal changes. Neurofibrillary tangles (NFTs) are not present in the aged canine. Thus, the aged canine brain provides a suitable model for studying early degeneration normally considered to be pre-Alzheimer's. This supposition is also supported by behavioral data. We have found that the extent of beta-amyloid deposition correlates with a decline in select measures of cognitive function. These data provide the first evidence of a correlation between beta-amyloid accumulation and cognitive decline in the absence of NFTs. We summarize four lines of evidence that support using the aged canine as a model of human aging: (a) Aged canines develop aspects of neuropathology similar to that observed in aged humans; (b) Veterinarians have observed that many canines exhibit a clinical syndrome of age-related cognitive dysfunction; (c) Aged canines are deficient on a variety of neuropsychological tests of cognitive function; (d) The level of beta-amyloid accumulation correlates with cognitive dysfunction in the canine. These data indicate that the aged canine is a particularly useful model for studying age-related cognitive dysfunction (ARCD), early neuronal changes associated with aging, and the initial stages of senile plaque formation.

Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging.

Dogs exhibit both neuroanatomical and cognitive changes as a function of age that parallel those seen in aging humans. This study describes in vivo changes in neuroanatomical and cerebrovascular characteristics of the canine brain as a function of age in a group of dogs ranging from 4 to 15 years old. Dynamic contrast-enhanced magnetic resonance imaging (MRI) was used to measure the kinetics of contrast agents in the brain. Measures of vascular volume and blood-brain barrier (BBB) permeability were derived from a pharmacokinetic analysis. Cortical atrophy and ventricular enlargement were characteristic features of the aged canine brain. Vascular volume did not vary as a function of age and BBB permeability exhibited a nonsignificant increasing trend with age. However, BBB dysfunction was detected in one middle-aged dog that in addition to having unusually large ventricles, demonstrated an early onset of diffuse senile plaques at postmortem. These findings indicate that BBB dysfunction detected by magnetic resonance imaging may be useful for predicting and potentially diagnosing early pathological conditions.

Dietary enrichment counteracts age-associated cognitive dysfunction in canines.

Advanced age is accompanied by cognitive decline indicative of central nervous system dysfunction. One possibly critical causal factor is oxidative stress. Accordingly, we studied the effects of dietary antioxidants and age in a canine model of aging that parallels the key features of cognitive decline and neuropathology in humans. Old and young animals were placed on either a standard control food, or a food enriched with a broad spectrum of antioxidants and mitochondrial enzymatic cofactors. After 6 months of treatment, the animals were tested on four increasingly difficult oddity discrimination learning problems. The old animals learned more slowly than the young, making significantly more errors. However, this age-associated decline was reduced in the animals fed the enriched food, particularly on the more difficult tasks. These results indicate that maintenance on foods fortified with complex mixtures of antioxidants can partially counteract the deleterious effects of aging on cognition.

Diffuse plaques contain C-terminal A beta 42 and not A beta 40: evidence from cats and dogs.

Recent reports have suggested that beta-amyloid (A beta) species of variable length C-termini are differentially deposited within early and late-stage plaques and the cerebrovasculature. Specifically, longer C-terminal length A beta 42/3 fragments (i.e., A beta forms extending to residues 42 and/or 43) are thought to be predominant within diffuse plaques while both A beta 42/3 and A beta 40 (A beta forms terminating at residue 40) are present within a subset of neuritic plaques and cerebrovascular deposits. We sought to clarify the issue of differential A beta deposition using aged canines, a partial animal model of Alzheimer's disease that exhibits extensive diffuse plaques and frequent vascular amyloid, but does not contain neuritic plaques or neurofibrillary tangles. We examined the brains of 20 aged canines, 3 aged felines, and 17 humans for the presence of A beta immunoreactive plaques, using antibodies to A beta 1(-17), A beta 17(-24), A beta 1(-28), A beta 40, and A beta 42. We report that plaques within the canine and feline brain are immunopositive for A beta 42 but not A beta 40. This is the first observation of nascent AD pathology in the aged feline brain. Canine plaques also contained epitopes within A beta 1(-17), A beta 17(-24), and A beta 1(-28). In all species examined, vascular deposits were immunopositive for both A beta 40 and A beta 42. In the human brain, diffuse plaques were preferentially A beta 42 immunopositive, while neuritic plaques and vascular deposits were both A beta 40 and A beta 42 immunopositive. However, not all neuritic plaques contain A beta 40 epitopes.

Clinical and pathological evidence for a frontal variant of Alzheimer disease.

OBJECTIVE: To evaluate the clinical and pathological features of a subgroup of patients with Alzheimer disease (AD) who exhibited early and disproportionately severe impairments on tests of frontal lobe functioning. We hypothesized that these patients would exhibit a greater degree of either neurofibrillary tangle (NFT) or senile plaque pathology in the frontal lobes than would patients with typical AD. DESIGN AND OUTCOME MEASURES: We examined the neuropsychological profiles and senile plaque and NFT accumulation in the frontal, entorhinal, temporal, and parietal cortices in 3 patients with AD who exhibited disproportionate frontal impairments during early stages of dementia (frontal AD) and 3 matched patients with typical AD (typical AD). RESULTS: Compared with the typical AD group, the frontal AD group performed significantly worse on 2 tests of frontal lobe functioning and on the Wechsler Adult Intelligence Scale-Revised Block Design test. No significant group differences were found on other tests. Analysis of brain tissue samples demonstrated that, despite comparable entorhinal, temporal, and parietal NFT loads, the frontal AD group showed a significantly higher NFT load in the frontal cortex than the typical AD group. Senile plaque pathology in the frontal and entorhinal cortices did not differentiate the 2 groups. CONCLUSIONS: We identified a subgroup of patients with pathologically confirmed AD who presented in the early stages of dementia with disproportionate impairments on tests of frontal lobe functioning and had a greater-than-expected degree of NFT pathology in the frontal lobes, suggesting the existence of a frontal variant of AD that has distinctive clinical and pathological features.

Identification of neuronal plasma membrane microdomains that colocalize beta-amyloid and presenilin: implications for beta-amyloid precursor protein processing.

Alzheimer's disease (AD) is associated with the accumulation of extracellular deposits of the beta-amyloid protein (Abeta). Abeta is a result of misprocessing of the beta-amyloid precursor protein (APP). Gamma-secretase is involved in APP misprocessing and one hypothesis holds that this secretase is identical to PS1. We tested this hypothesis by determining whether PS is co-localised with Abeta in situ. Using confocal analyses and a sensitive immunogold procedure we show that PS and Abeta are co-localised within discrete microdomains of neuronal plasma membranes in AD patients and in aged dogs, an established model of human brain aging. Our data indicate that APP misprocessing occurs in discrete plasma membrane domains of neurons and provide evidence that PS1 is critically involved in Abeta formation.

Ultrastructural evidence of fibrillar beta-amyloid associated with neuronal membranes in behaviorally characterized aged dog brains.

The aged dog brain accumulates beta-amyloid in the form of diffuse senile plaques, which provides a potentially useful in vivo model system for studying the events surrounding the deposition of beta-amyloid. We used postembedding immunocytochemistry at the electron microscopic level to determine the subcellular distribution of beta-amyloid 1-40 and beta-amyloid 1-42 peptides in the prefrontal and parietal cortex of behaviorally characterized dogs ranging in age from one to 17 years. Immunogold particles signaling beta-amyloid 1-42 occurred over intracellular and extracellular fibrils that were approximately 8 nm in width. Intracellular beta-amyloid 1-42 fibrils were found in close proximity to glial fibrillary acidic protein fibers within astrocytes, but only in cells with signs of plasma membrane disruption. Neuronal labeling of beta-amyloid 1-42 appears to be associated with the plasma membrane. Membrane-bound beta-amyloid 1-42 occurs in the form of fine fibrils that are embedded in the dendritic membrane and appear to project into the extracellular space as determined by quantitative analysis of the immunogold particle distribution. Bundles of beta-amyloid 1-42 were also closely associated and/or integrated with degenerating myelin sheaths of axons. In one dog that was impaired on several cognitive tasks, extensive beta-amyloid 1-42 deposition was associated with microvacuolar changes and vascular pathology. The present findings suggest that beta-amyloid 1-42 may be generated at the dendritic plasma membrane as well as in intracellular compartments. The close association between beta-amyloid 1-42 and destroyed myelin suggests one possible new mechanism by which beta-amyloid 1-42 induces neurodegeneration.