The MAPP Room Memory Test: Examining Contextual Memory Using a Novel Computerized Test in Cognitively-Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

Contextual memory, the ability to remember spatial or temporal features related to an event, is affected in Alzheimer's disease (AD). There is a shortfall of tests that measure contextual memory. To evaluate visuospatial contextual memory, we developed a computerized cognitive test, the MAPP Room Memory Test, which requires participants to identify in which visual scene target items were previously presented. We hypothesized that cognitively-unimpaired carriers of an autosomal dominant AD mutation (Presenilin-1 E280A, n=15) would perform more poorly on this test than non-carrier family members (n=31). Compared to non-carriers, the carriers had significantly worse delayed room recognition. The results indicate that the MAPP Room Memory Test may be sensitive to subtle cognitive changes associated with risk of AD. Future studies with larger samples using the MAPP Room Memory Test and biomarkers are needed to examine whether this test may also be sensitive to the earliest pathological changes in preclinical AD.

Memory for Semantically Related Objects Differentiates Cognitively Unimpaired Autosomal Dominant Mutation Carriers from Non-Carrier Family Members.

Early cognitive changes due to Alzheimer's disease (AD) include difficulties in semantic access and working memory. Using a computerized cognitive test developed by our group, called the Memory for Semantically Related Objects test (MESERO), we evaluated if cognitively unimpaired carriers of an autosomal dominant AD (ADAD) mutation performed worse on this test than non-carrier family members. 35 cognitively unimpaired ADAD mutation carriers and 26 non-carrier family members from a Colombian ADAD cohort took the MESERO on a laptop computer. Cognitively unimpaired ADAD carriers had significantly worse MESERO total scores than non-carrier family members, driven by worse performance in semantically-related object sets; group performances did not differ on semantically unrelated object sets. Findings suggest that MESERO performance may be sensitive to subtle cognitive changes associated with AD. Future MESERO research should examine performances between healthy older adults and people at risk for sporadic AD.

Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer's Disease: A Comprehensive Review of the Colombian Kindred.

The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities - such as cortical thinning and hyperactivation in memory networks - as well as differences in biofluid and in vivo measurements of Alzheimer's-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer's disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer's disease to the larger sporadic Alzheimer's disease population.

Sleep in Parkinson's disease: a comparison of actigraphy and subjective measures.

Sleep disturbances are common in Parkinson's disease (PD). Actigraphy has emerged as an alternative to polysomnography to measure sleep, raising the question of its ability to capture sleep quality in PD patients. Our aim was to compare self-report data with actigraphic data. Thirty non-demented individuals with PD and 14 normal control participants (NC) were included. Sleep was measured using 24-h wrist actigraphy over a seven day period, during which time participants kept a sleep diary. Subjective sleep and arousal questionnaires included the Parkinson's Disease Sleep Scale and Epworth Sleepiness Scale. Patients with PD presented with more sleep problems than NC. In NC, none of the actigraphic sleep variables were related to any of the self-report measures of sleep. In PD, scores on subjective sleep measures correlated with actigraphy-derived estimates of sleep quality. Our results suggest that actigraphy is an appropriate method of measuring sleep quality in PD.

Facial frequency manipulation normalizes face discrimination in AD.

People with AD have deficient contrast sensitivity and impaired face discrimination. The authors presented photographs of unfamiliar faces of three different sizes to enhance the low, middle, or high facial frequency information (cycles per face). Patients with AD demonstrated normal discrimination of small faces only, indicating that impaired contrast sensitivity at low facial frequencies contributes to their poor face discrimination.

Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population.

Acquired cerebellar lesions in adults have been shown to produce impairments in higher function as exemplified by the cerebellar cognitive affective syndrome. It is not yet known whether similar findings occur in children with acquired cerebellar lesions, and whether developmental factors influence their presentation. In studies to date, survivors of childhood cerebellar tumours who demonstrate long-term deficits in cognitive functions have undergone surgery as well as cranial irradiation or methotrexate treatment. Investigation of the effects of the cerebellar lesion independent of the known deleterious effects of these agents is important for understanding the role of the cerebellum in cognitive and affective development and for informing treatment and rehabilitation strategies. If the cerebellar contribution to cognition and affect is significant, then damage in childhood may influence a wide range of psychological processes, both as an immediate consequence and as these processes fail to develop normally later on. In this study we evaluated neuropsychological data in 19 children who underwent resection of cerebellar tumours but who received neither cranial irradiation nor methotrexate chemotherapy. Impairments were noted in executive function, including planning and sequencing, and in visual-spatial function, expressive language, verbal memory and modulation of affect. These deficits were common and in some cases could be dissociated from motor deficits. Lesions of the vermis in particular were associated with dysregulation of affect. Behavioural deficits were more apparent in older than younger children. These results reveal that clinically relevant neuropsychological changes may occur following cerebellar tumour resection in children. Age at the time of surgery and the site of the cerebellar lesion influence the neurobehavioural outcome. The results of the present study indicate that the cerebellar cognitive affective syndrome is evident in children as well as in adults, and they provide further clinical evidence that the cerebellum is an essential node in the distributed neural circuitry subserving higher-order behaviours.

Alzheimer-like visual deficits in Down syndrome.

Patients with Alzheimer disease (AD) show visual impairments in color discrimination (blue hues), stereoacuity, and contrast sensitivity. We asked whether the AD-type visual profile occurs in Down syndrome (DS) in light of the fact that AD neuropathology is present in DS by age 40. We tested 22 adults with DS and 18 adults with mental retardation of non-DS etiology (MR). DS subjects made more tritanomalous errors on the test of color vision than predicated by chance (p < 0.05), indicating a deficiency in the discrimination of short wavelengths (blue hues) but not more of other types of hue discrimination errors. DS subjects had higher stereoacuity thresholds than MR subjects (p < 0.01) and reduced contrast sensitivity across the frequency range (p < 0.01). Taken together, the results point to AD-like visual deficits in DS. Like classic AD, DS may be associated with pathological changes in the parastriate and peristriate visual cortex. DS performance was not correlated with age, suggesting that in individual subjects, the AD-like visual deficits may present prior to and independent of age-associated dementia.

Visuospatial dysfunction and problem solving in Parkinson's disease.

Individuals with Parkinson's disease (PD) perform deficiently on Raven's Coloured Progressive Matrices (RCPM), in contrast to their relatively good performance on many other problem-solving tasks. The question is raised as to whether a visuospatial deficit may account for poor RCPM performance in PD. The authors analyzed RCPM results in 50 nondemented participants with PD and 39 age-matched healthy control participants. The PD group made significantly more errors than the control group on all RCPM subtests, including the subtest that mainly assessed visuospatial function (RCPM-A). For the PD group, the composite score of other visuospatial tests, but not the composite scores of tests of executive function or verbal memory, significantly predicted performance on the RCPM-A. Visuospatial impairment in PD may arise from dysfunction of the basal ganglia-thalamocortical circuit that also includes the dorsolateral prefrontal cortex and, importantly, the posterior parietal lobes.

Vision in Alzheimer's disease.

In order to assess vision in Alzheimer's disease (AD) and related disorders, gerontologists must use tests that make minimal cognitive demands on the subject. Using such tests, we have found a pattern of deficits in color discrimination, stereoacuity, contrast sensitivity, and backward masking that differs from that seen in healthy elderly individuals. Impaired vision predicts deficient performance of subjects with AD on numerous tests of cognition, underscoring the importance of understanding visual changes in this population.

Visual dysfunction predicts cognitive deficits in Alzheimer's disease.

Deficits in basic visual capacities are prevalent in Alzheimer's disease (AD), raising the question of their impact on cognitive function. We examined the relation between vision and cognition in 72 patients with AD. Vision tests assessed color discrimination, stereoacuity, contrast sensitivity, and backward pattern masking. For cognitive tests of object recognition, at least 25% (up to 50%) of score variance was predicted by performance on a vision test. For tests of spatial localization, only 2 to 11% of the variance was predicted by performance on a vision test. The results indicated that: (1) visual dysfunction was a significant predictor of cognitive dysfunction in AD, and (2) visual deficits in AD may have a strong functional impact on performance in specific cognitive domains.

Prevalence of visual deficits in Alzheimer's disease.

This study addressed the issue of prevalence and pattern of visual deficits in 77 subjects with Alzheimer's disease (AD) and 111 healthy control subjects. We defined cutoff scores that would be expected from only 1 control subject of 100 (p = 0.01). The percentage of AD subjects who performed at or worse than this level varied across the 16 visual tests from a high of 58% to a low of 0%. The distribution of impairment across tests suggests a high vulnerability in AD of pattern vision, moderate vulnerability of spatial vision, and low vulnerability of motion and flicker perception. We found evidence for heterogeneity in the AD subject group: a subgroup (N = 14) emerged that was characterized by poor performance on the Backward Pattern Masking test, relatively young age, and relatively short duration of AD. Overall, the results indicate that visual dysfunction, especially on Backward Masking, is a common sign of AD.

Impaired problem solving in Parkinson's disease: impact of a set-shifting deficit.

Parkinson's disease (PD) is associated with specific cognitive deficits in the absence of dementia, including the inability to suppress previously learned responses in a changed context. Our goal was to determine whether this set-shifting deficit is sufficient to account for impaired performance on a problem-solving task, or, instead, whether it is necessary to postulate deficits in one or more other cognitive capacities, such as logical deduction. Deductive reasoning and other conceptual abilities were assessed in 15 nondemented subjects with PD who had never been medicated, 15 nondemented subjects with PD who were currently receiving medication, and 15 healthy elderly control subjects. On a deductive reasoning task, Poisoned Food Problems, the PD groups made more errors than the control group. The PD groups' error pattern was characterized by intrusions of information from previous problems. By contrast, the PD groups made appropriate assessments of redundant and irrelevant information that appeared in these problems, and performed normally on other tests of concept formation and problem solving that did not require set shifting, indicating that the capacities for logical deduction and concept formation were intact. The set-shifting deficit, conceptualized as a difficulty in suppressing a prepotent response, appears to be a primary cognitive impairment in PD and presumably arises from dysfunction of the nigrostriatal-dorsolateral prefrontal cortex complex loop.

Incomplete achromatopsia in Alzheimer's disease.

We report that patients with Alzheimer's disease (AD) have a selective deficit in blue hue discrimination, as assessed with three clinical measures of color vision. The Farnsworth D-15 Test, the Lanthony New Color Test, and the City University Color Vision Test were administered to 32 patients with AD (ranging in dementia severity from mild to severe) and 32 age-matched normal control subjects (NCS). Of the AD patients, 11 who were representative of the larger group for age, education level, and dementia severity received a complete neuro-ophthalmological examination that ruled out obvious disorders of the anterior visual structures. AD patients made significantly more tritan (blue) errors than NCS on all three color vision tests but did not make more protan (red) or deutan (green) errors on two of the three tests. The results support the conclusion that there is a deficit in color discrimination in AD that is specific to blue hues, and oppose the hypothesis that AD does not deleteriously affect the color-opponent visual channel. In the absence of obvious damage to anterior visual structures, the likely substrates for the observed deficit are peristriate and inferotemporal visual cortices, which are subject to significant neuropathology in AD.

Category knowledge in Alzheimer's disease: normal organization and a general retrieval deficit.

Three hypotheses that could account for deficits in the retrieval of category information in Alzheimer's disease (AD) were evaluated: abnormal organization, class- or category-specific vulnerability, and limitation by general factors, such as decreased processing speed. Relative to 18 elderly control subjects, 18 patients with AD produced fewer items in a category fluency task and had longer reaction times in a category decision task. The pattern of performance across categories on both tasks was normal in the AD group: The same categories elicited the most (or fastest) responses in both the control group and the AD group. AD patients showed normal performance in ranking of category exemplars by typicality. There was no evidence for differential accessibility by category or by class of information (animate vs. inanimate). The authors conclude that a general factor or factors limit(s) retrievability equally across all categories.

Retinocalcarine function in Alzheimer's disease. A clinical and electrophysiological study.

Impaired visual function in Alzheimer's disease (AD) could result from either precortical or cortical lesions, or both. In a parallel psychophysical study of visual function in AD, we found that contrast sensitivity function, color vision, stereoacuity, and backward masking were impaired relative to the performance of age-matched control subjects, whereas performance on a critical flicker fusion test was normal. The intent of the present study was to determine whether abnormalities of the retinocalcarine pathway contribute to visual dysfunction. We performed neuro-ophthalmological examinations on 38 patients with AD; from this group, 25 received additional psychophysical testing and 13 underwent electrophysiological testing. Clinical neuro-ophthalmological examinations, full-field electroretinograms, focal electroretinograms, and pattern visual evoked potentials were normal in all patients tested. There was no evidence of retinocalcarine abnormality specific to AD. We conclude that the visual impairment experienced by some patients with AD primarily results from involvement of the visual association cortices rather than from precortical damage, at least before the end stage of the disease.

Visual dysfunction in Alzheimer's disease: relation to normal aging.

In patients with Alzheimer's disease (AD), compared with age-matched and young healthy control subjects, visual deficits in the following functions were observed: color, stereoacuity, contrast sensitivity, and backward masking (homogeneous and pattern). Critical flicker fusion thresholds were normal, relative to age-matched healthy subjects. For color, the majority of the errors were tritanomalous (blue axis). Color and stereoacuity deficits were unrelated to severity of dementia, in accordance with models of vision that describe these functions as modular rather than diffuse for cortical localization. Although contrast sensitivity was depressed throughout the frequency range in AD, more patients were impaired at low than at high spatial frequencies, contrasting with the observed normal aging pattern of high-frequency loss. Healthy elderly subjects showed depressed critical flicker fusion thresholds and reduced contrast sensitivity at high frequencies, relative to the young group; differences between these groups were not found for the other vision tests. A subset of the AD group received detailed neuro-ophthalmological examination, and no abnormalities were found. This finding, taken together with normal thresholds for critical flicker fusion, suggests that the widespread visual dysfunction reported here is more likely to be related to known pathological changes in primary visual and association cortex in AD than to changes in the retina or optic nerve.

Visual function in Alzheimer's disease and normal aging.

We examined a wide range of visual behaviors in 59 patients with Alzheimer's disease (AD), 35 elderly control subjects, and 12 young control subjects. A subset of the patients with AD received neuro-ophthalmologic and electrophysiologic examinations in order to evaluate the integrity of the retino-calcarine pathway. Patients with AD showed significant, selective losses in visual function, including color discrimination, stereoacuity, contrast sensitivity, and backward masking, but not in critical flicker fusion. The deficits were not attributable to clinically apparent lesions of the retina or optic nerve. We therefore suggest that AD lesions in primary visual and posterior association cortices underlie the observed behavioral abnormalities.

Abstract reasoning in age-related neurological disease.

Subjects with a variety of neurological disorders including Alzheimer's disease (AD) were tested for abstract reasoning ability with two new tests that do not involve high-order language, memory, or visuospatial skills. All groups performed at the normal level except the patients with AD, who performed poorly on the test of logical reasoning ability, but relatively well on the test of the ability to recognize relationships between common objects. The results suggest that in AD, relational abilities may remain intact well into the disease, whereas generational abilities may be among the cognitive skills that are impaired early in the course of the disease.

Alzheimer's disease: advances in basic research and therapies.

The International Study Group on the Pharmacology of Memory Disorders Associated with Aging met in Zurich, Switzerland in January of 1987 to report and discuss advances in basic research and therapies in regard to Alzheimer's disease. Participants included 121 scientists of 14 nations associated with academic institutions, food and drug companies, granting agencies and the medical community. Approaches to research included those of genetics, neuroimaging, neuropsychology, anatomy and physiology, neurochemistry, neuropathology and experimental animal studies. This report provides an overview of the highlights of the conference.