Occipital atrophy is associated with visual hallucinations in Alzheimer's disease

In this study of patients with Alzheimer's disease (AD), patients with visual hallucinations were compared with patients who did not have visual hallucinations to determine if selective occipital lobe atrophy is associated with visual hallucinations. Seven AD patients with visual hallucinations were matched by cognitive score to 7 AD patients without visual hallucinations and 3-D MRI images obtained. A ratio of measured occipital volumes to whole brain volumes was compared between the two groups. AD patients with visual hallucinations had a significantly smaller occipital/whole brain ratio than AD patients without visual hallucinations. These results suggest visual hallucinations in AD may be associated with neuropathology of the occipital lobe.     

Prion protein is reduced in aging and in sporadic but not in familial Alzheimer's disease

The cellular form of the prion protein (PrPC) has been shown to inhibit the production of amyloid-β which is critically involved in the pathogenesis of Alzheimer's disease (AD). We examined the expression of PrPC by immunoblot analysis in the hippocampus and temporal cortex in sporadic AD, familial AD, and appropriate age-matched controls, and in an aging series (age 20 to 88 years) of brains. PrPC was reduced by 53% (p=0.032) in the hippocampus in sporadic AD as compared to the age-matched controls. No such reduction in PrPC was seen in familial AD. PrPC was reduced in the hippocampus with aging (rs=0.03). The reduction in PrPC in sporadic but not familial AD suggests that reduced PrPC expression reflects a primary mechanism of disease and is not merely a secondary consequence of other AD-associated changes. The reduction of PrPC in the brain with aging suggests that age-related decreases in PrPC may contribute to the increased incidence of AD in older people.     

Basal forebrain atrophy is a presymptomatic marker for Alzheimer's disease

BackgroundAlzheimer's disease (AD) is the most common degenerative neurologic disorder. The onset of symptoms is insidious and follows a long period of progression of an asymptomatic pathology that proceeds in a precise anatomic and temporal sequence. Recent studies with quantitative magnetic resonance imaging techniques have shown the localization of the in vivo pathology of AD and its antecedent, mild cognitive impairment. The objective of the present study was to determine whether a sensitive and reliable marker for the presymptomatic phase of the disorder could be identified by longitudinal analysis of an initially asymptomatic, community-based population.MethodsOne hundred forty-eight healthy, cognitively normal participants in the Cardiovascular Health Study–Cognition Study had detailed clinical examinations and magnetic resonance imaging scans in 1998–1999 and 2002–2003. Modulated voxel-based morphometry was used to compare regional brain volumes in subjects who remained cognitively normal after 5 to 6 years of follow-up (n = 127) with those who developed probable AD during the same period (n = 21).ResultsAmong normal subjects destined to develop AD, there was significant atrophy in the basal forebrain area as long as 4.5 years before the development of clinical symptoms. When the left hippocampus was also atrophic, the onset of dementia typically occurred earlier than in cases in which the atrophy was confined to basal forebrain.ConclusionsAtrophy in the basal forebrain precedes the development of AD in subjects with cognition judged to be normal by neuropsychological testing. The time required to develop dementia appears to be shortened if hippocampal atrophy is also present. These data indicate that atrophy restricted to medial basal forebrain is a biomarker that predicts development of probable AD in asymptomatic elderly subjects.     

Asymmetrical cerebral atrophy in Alzheimer's disease

In most Alzheimer patients brain atrophy seems to be symmetrical. Recent neuropsychological and brain imaging investigations suggest, however, that in some patients one hemisphere is more severely affected from the onset of symptoms. We have observed four Alzheimer patients with grossly asymmetrical cerebral atrophy at autopsy, in whom the topography of the most severe atrophy was consistent with the earliest clinical signs of focal brain damage. In the three patients who at onset had relevant language disorders, atrophy of the brain was more severe in the association areas surrounding the left sylvian fissure. In the fourth patient, who first complained of visuospatial troubles, the right, nondominant hemisphere was more affected. These clinical and pathological findings suggest that association areas of one hemisphere were involved quite early in the evolution of the disease, conceivably at the same time as the hippocampus and related limbic structures. In these patients, a morphometric analysis of cortical changes in homologous areas of the cortex (area 22) was carried out in order to investigate the effect of the evolution of the disease upon cortical changes. This analysis showed that the numerical densities of nerve cells and tangle-bearing neurons were lower on the more atrophied side and suggested that the severity of cortical atrophy might have affected the size, but not the density, of senile plaques.     

Corpus callosum size correlates with asymmetric performance on a dichotic listening task in healthy aging but not in Alzheimer's disease

Alzheimer's disease (AD) involves not only gray matter but also white matter pathology, as reflected by atrophy of the corpus callosum (CC). Since decreased CC size may indicate reduced functional interhemispheric connectivity, differences in callosal size may have cognitive consequences that may become specifically apparent in neuropsychological tasks that tap hemispheric laterality. In the present study, we examined callosal functioning with a dichotic listening task in 25 Alzheimer patients, 20 healthy elderly and 20 healthy elderly with subjective memory complaints. We found decreased performance, increased ear asymmetry, and decreased callosal size in the AD group compared to healthy elderly. As expected, in the healthy elderly, we found significant negative correlations between ear asymmetry and callosal size, specifically in the anterior and posterior callosal subareas. While the association with the posterior subareas (isthmus and splenium) points at involvement of temporal areas mediating language processing, the association with the anterior subarea (the rostrum and genu) points at involvement of frontal areas mediating attention and executive functions. Remarkably however, in contrast to the healthy elderly, callosal size was not related to ear asymmetry in the AD group. The absence of an association between callosal atrophy and ear asymmetry implies that other pathological processes, next to reduced callosal functioning, attribute to ear asymmetry in AD. Difficulties to attend specifically to the left ear during dichotic listening in some of the AD patients, points at decreased attention and executive functions and suggests that pathology of specifically the frontal areas is involved.     

Association between cerebrospinal fluid tau and brain atrophy is not related to clinical severity in the Alzheimer's disease continuum

We aimed to assess the association between core cerebrospinal fluid (CSF) biomarkers, regional brain atrophy and clinical severity in the Alzheimer's disease (AD) continuum, as well as to investigate how cognitive reserve (CR) may modulate these putative associations. Forty-nine subjects (11 controls, 10 patients with subjective memory complaints, 19 with mild cognitive impairment and 9 mild AD) underwent lumbar puncture and high-resolution magnetic resonance imaging (MRI). CSF amyloid-β_1-42 (Aβ_1-42), total tau (t-tau) and phosphorylated tau (p-tau₁₈₁) were determined. Voxel-based morphometry (VBM) was applied and multiple regression analyses for the whole sample were carried out. Clinical severity was adjusted using the Clinical Dementia Rating Sum of Boxes score (CDR-SB). A negative correlation between t-tau levels and grey matter (GM) volume in temporo-parietal regions was found, regardless of CDR-SB score. In contrast, the negative correlation between p-tau₁₈₁ and GM volume was largely explained by clinical severity, except in the posterior cingulate cortex. CR did not significantly modify these correlations. Aβ_1-42 levels were not related to GM volume but were related to clinical severity, an association that was attenuated when CR was considered. In conclusion, the present findings reflect that t-tau CSF concentrations are associated with GM atrophy in neuropathologically relevant areas across the AD continuum, whereas the p-tau₁₈₁ association is largely dependent on the degree of clinical severity. The relationship between CSF Aβ_1-42 and clinical severity seems to be modulated by CR, suggesting that there may be subjects with pathological levels of Aβ_1-42 and high CR estimates who remain clinically asymptomatic.     

Saitohin gene is not associated with Alzheimer's disease

BACKGROUND: The deposition of tau protein in neurofibrillary tangles constitutes an important feature of many neurodegenerative disorders, including Alzheimer's disease. A polymorphic gene, saitohin (STH), nested within the tau gene (microtubule associated protein tau, MAPT), was recently identified and an association of a non-synonymous polymorphism in STH with increased risk for Alzheimer's disease was suggested. Objective and methods: To test the above hypothesis in a case-control association study of two independent white populations within Switzerland and Greece, comparing genotype and allele frequencies from 225 Alzheimer's disease patients and 144 healthy control subjects. RESULTS: No differences in allelic or genotypic distributions between Alzheimer's disease patients and controls was found in the individual samples (Swiss/Greek) or in the combined sample. Stratification for the presence of apolipoprotein E (APOE) epsilon 4 allele, sex, or age did not show significant effects in the populations studied, nor was there an effect on the age of onset. CONCLUSIONS: No evidence was found for an association of the non-synonymous polymorphism (Q7R) in STH and Alzheimer's disease. This finding is in line with earlier studies showing no association between MAPT and Alzheimer's disease.     

Association between cerebrospinal fluid tau and brain atrophy is not related to clinical severity in the Alzheimer's disease continuum

We aimed to assess the association between core cerebrospinal fluid (CSF) biomarkers, regional brain atrophy and clinical severity in the Alzheimer's disease (AD) continuum, as well as to investigate how cognitive reserve (CR) may modulate these putative associations. Forty-nine subjects (11 controls, 10 patients with subjective memory complaints, 19 with mild cognitive impairment and 9 mild AD) underwent lumbar puncture and high-resolution magnetic resonance imaging (MRI). CSF amyloid-β(1-42) (Aβ(1-42)), total tau (t-tau) and phosphorylated tau (p-tau(181)) were determined. Voxel-based morphometry (VBM) was applied and multiple regression analyses for the whole sample were carried out. Clinical severity was adjusted using the Clinical Dementia Rating Sum of Boxes score (CDR-SB). A negative correlation between t-tau levels and grey matter (GM) volume in temporo-parietal regions was found, regardless of CDR-SB score. In contrast, the negative correlation between p-tau(181) and GM volume was largely explained by clinical severity, except in the posterior cingulate cortex. CR did not significantly modify these correlations. Aβ(1-42) levels were not related to GM volume but were related to clinical severity, an association that was attenuated when CR was considered. In conclusion, the present findings reflect that t-tau CSF concentrations are associated with GM atrophy in neuropathologically relevant areas across the AD continuum, whereas the p-tau(181) association is largely dependent on the degree of clinical severity. The relationship between CSF Aβ(1-42) and clinical severity seems to be modulated by CR, suggesting that there may be subjects with pathological levels of Aβ(1-42) and high CR estimates who remain clinically asymptomatic.     

Apolipoprotein D is a component of compact but not diffuse amyloid-beta plaques in Alzheimer's disease temporal cortex

Apolipoprotein D (apoD) is elevated in Alzheimer's disease (AD) cortex, localizing to cells, blood vessels, and neuropil deposits (plaques). The role of apoD in AD pathology and the extent of its co-distribution with diffuse (amorphous) and compact (dense fibrillar) amyloid-beta (Abeta) plaques are currently unclear. To address this issue, we combined apoD and Abeta immunohistochemistry with ThioS/X-34 staining of the beta-pleated sheet protein conformation in temporal cortex from 36 AD patients and 12 non-demented controls. ApoD-immunoreactive, Abeta-immunoreactive, and ThioS/X-34-stained plaques were detected exclusively in AD tissue. Dual-immunolabeling showed that 63% of Abeta plaques co-localized apoD. All apoD plaques contained Abeta protein and ThioS/X-34 fluorescence. Compared to controls, AD cases showed elevated vascular and intracellular apoD immunostaining which localized primarily to cells clustered within plaques and around large blood vessels. ApoD-immunoreactive cells within plaques morphologically matched MHC-II- and CD-68-immunoreactive microglia, and did not contain the astrocytic marker GFAP, which labeled a subset of apoD-immunoreactive cells surrounding plaques. These data suggest that neuropil deposits of apoD localize only to a subset of Abeta plaques, which contain compact aggregates of fibrillar Abeta. Elevated apoD in AD brain may influence Abeta aggregation, or facilitate phagocytosis and transport of Abeta fibrils from plaques to cerebral vasculature.     

Uric acid is associated with the prevalence but not disease progression of multiple system atrophy in Chinese population

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Uric acid has an antioxidative effect. Our aim is to clarify the correlations between serum uric acid and MSA in Chinese population. A total of 234 patients with probable MSA and 240 age- and gender- matched healthy controls were included in the study. The serum uric acid levels of all the patients and controls were evaluated. The Unified MSA Rating Scale (UMSARS) was used to assess the severity and the mean rate of annualized changes of UMSARS to assess the progression of MSA. The mean age of MSA patients was 58.90 ± 9.00 years and the mean disease duration was 2.60 ± 1.75 years. The serum uric acid levels of MSA patients were significantly lower than that of controls in males (p = 0.0001). The occurrence of MSA was increased in the lowest uric acid quartiles compared with the highest uric acid quartiles (p = 0.005). In a gender-specific analysis, increased occurrence was found in the lowest quartiles and second quartiles compared with the highest quartiles in males (p = 0.001 and p = 0.0001 respectively), but not in females. No correlation was found between the mean rate of annualized changes and serum levels of uric acid, as well as other independent factors, such as age, BMI, gender, subtype (C-type or P-type) and disease duration at the initial visit in 107 followed-up patients. MSA patients have lower levels of serum uric acid than controls. High levels of serum uric acid may be associated with a lower prevalence of MSA in the Chinese population, especially in males. However, serum uric acid does not deteriorate or ameliorate the progression of MSA.     

Anosognosia in very mild Alzheimer's disease but not in mild cognitive impairment

OBJECTIVE: To study awareness of cognitive dysfunction in patients with very mild Alzheimer's disease (AD) and subjects with mild cognitive impairment (MCI). METHODS: A complaint interview covering 13 cognitive domains was administered to 82 AD and 79 MCI patients and their caregivers. The patient groups were comparable according to age and education, and Mini Mental State Examination (MMSE) scores were > or =24 in all cases. The discrepancy between the patients' and caregivers' estimations of impairments was taken as a measure of anosognosia. RESULTS: Self-reports of cognitive difficulties were comparable for AD and MCI patients. However, while in comparison to caregivers MCI patients reported significantly more cognitive impairment (p < 0.05), AD patients complained significantly less cognitive dysfunctions (p < 0.001). CONCLUSIONS: While most MCI patients tend to overestimate cognitive deficits when compared to their caregiver's assessment, AD patients in early stages of disease underestimate cognitive dysfunctions. Anosognosia can thus be regarded as a characteristic symptom at a stage of very mild AD (MMSE > or =24) but not MCI. Accordingly, medical history even in mildly affected patients should always include information from both patient and caregiver.     

Alzheimer's disease with asymmetric atrophy of the cerebral hemispheres: morphometric analysis of four cases

To examine the clinicopathological correlations in rare Alzheimer's disease patients with asymmetric cerebral atrophy and to compare their pattern of cortical involvement by senile lesions with that observed in other cases with atypical Alzheimer's disease, we performed an extensive neuropathological analysis of the cerebral cortex in four such cases. Three patients presented with severe language impairment but relatively good preservation of praxis and gnosis even after several years of clinical evolution. Cerebral autopsies of these cases revealed a predominant left hemisphere atrophy. Conversely, in one case with marked right hemisphere atrophy, all of the cognitive functions were involved early in the course of dementia. Neurofibrillary tangles and senile plaques were preferentially localized in the prefrontal, temporal and posterior parietal cortex in both hemispheres, whereas the hippocampal formation displayed lower lesion densities than neocortical areas. Significantly higher neurofibrillary tangle and senile plaque densities were found in the more atrophic side in most of the areas studied. The ratio of neurofibrillary tangle and senile plaque densities between the two hemispheres was not correlated with the number of these lesions in the cerebral cortex. These results indicate that the degenerative process in demented cases with interhemispheric asymmetric cerebral atrophy is characterized by a widespread involvement of the neocortex by senile lesions and lacks clear regional topography of neurofibrillary tangle and senile plaque distribution. Moreover, the relative sparing of the hippocampus, comparable to that found in cases with focal progressive dementia, suggests that the dementing process may involve different cortical structures in cases with asymmetric cerebral atrophy than in typical Alzheimer's disease cases.Supported in part by grants from the NIH (AG05138) and the Brookdale Foundation (to P.R.H.)     

Alzheimer's disease is not associated with altered concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine in cerebrospinal fluid

Summary. Nitric oxide (NO) may play a role in the pathophysiology of Alzheimer's disease (AD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is involved in regulation of NO production. Recently it has been reported that dimethylarginine dimethylaminohydrolase, an enzyme that hydrolyses ADMA into citrulline and dimethylamine, is specifically elevated in neurons displaying cytoskeletal abnormalities and oxidative stress in AD. We hypothesized that this could lead to altered CSF concentrations of ADMA in AD. Measurement of ADMA and dimethylamine in CSF revealed no significant differences between AD patients (n = 20) and age-matched control subjects (n = 20). Our results suggest that in early stages of AD overall regulation of NO production by ADMA is not aberrant. Received March 14, 2002; accepted May 21, 2002 Published online July 26, 2002     

BAG1 is a protective factor for sporadic frontotemporal lobar degeneration but not for Alzheimer's disease

BCL2-associated athanogene 1 (BAG1) is an anti-apoptotic factor that interacts with tau and regulates its proteasomal degradation. A significant increase of the BAG-1M isoform was found in Alzheimer's disease (AD) brains, and the protein co-localized with tau and amyloid. We carried out an association study of BAG1 in a population of 291 patients clinically diagnosed with frontotemporal lobar degeneration (FTLD), none of whom was a carrier of mutations in progranulin or microtubule associated protein tau genes and 374 with AD as compared with 314 age- and gender-matched controls. In addition, another candidate named Chromatin-modifying protein 5 (CHMP5) and located in the same linkage disequilibrium block, has been included in this study. The distribution of the two single nucleotide polymorphism (SNPs), rs844239 in CHMP5 and rs706118 in BAG1, covering 100% gene variability, were determined. A statistically significant decreased allelic frequency of the BAG-1 rs706118 SNP was observed in patients with FTLD as compared with controls (16.7 versus 23.9%; p = 0.007, OR: 0.35, CI: 0.25-0.50), whereas allelic frequency of the SNP in patients with AD was similar to controls (24.3%, p > 0.05). Conversely, no significant association was found as regards CHMP5 rs844239. Stratifying according to gender, no differences were observed. BAG-1 rs706118 SNP likely acts as protective factor for sporadic FTLD, but not for AD, suggesting its specific role in a pathogenic event in FTLD. Nevertheless, a replication study would be needed to confirm these preliminary results.