Cholesterol modulates the membrane-disordering effects of beta-amyloid peptides in the hippocampus: specific changes in Alzheimer's disease

Cholesterol represents an important determinant of the physical state of biological membranes. In Alzheimer's disease (AD) brains, specific changes in the distribution of cholesterol and its membrane-ordering effects take place. In the present study, membrane fluidity was investigated at the level of the hydrocarbon core and of the heads of the phospholipid bilayers using two different fluorescent probes. Hippocampal membranes of AD brains showed a reduced fluidity in the hydrocarbon core region only. Fluidity was correlated with the cholesterol content in AD and control membranes. Aggregated beta-amyloid peptides (Abeta) disrupted brain membrane structure in AD patients and controls in the same fashion. However, this effect was correlated with the cholesterol content in AD membranes only. It is suggested that in AD the brain becomes specifically sensitive for the modulation by membrane-bound cholesterol of the membrane-disturbing and ultimately neurotoxic properties of Abeta.     

The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old

Neurofibrillary pathology as found in Alzheimer’s disease (AD) is also found in the normal elderly, suggesting that these changes may be part of the aging process. In this study, we assessed the densities and distribution of structures recognized by the monoclonal antibody (mAb) to phosphorylated tau (AT8) in the hippocampal formation and medial temporal isocortex of 19 centenarians. Of these, 4 cases were demented and 15 non-demented. AT8 immunoreactivity correlated with the global deterioration scale (GDS). The density of both intraneuronal neurofibrillary tangles (I-NFTs) and neuritic clusters (NCs) significantly correlated with the GDS in the layer II of the entorhinal cortex (r = 0.66, P = 0.005 and r = 0.611, P = 0.01, respectively). Density of I-NFTs in the subiculum (r = 0.491; P = 0.034) also correlated significantly. No other area was found to be statistically significant. Importantly, no correlation was found when demented and non-demented centenarian cases were analyzed separately, suggesting that the difference marks a fundamental shift between AD and non-demented individuals. This assertion is supported by the significantly higher densities of I-NFTs and NCs in the transentorhinal (P = 0.043 and P = 0.011, respectively) and layer II of the entorhinal cortex (P = 0.02 and P = 0.007, respectively), and I-NFTs in the subiculum (P < 0.001) and CA1 (P = 0.011) in the demented group when compared with the non-demented cases. Granular diffuse deposits, an early stage parameter of the neurofibrillary pathology involving accumulation of non-fibrillar abnormally phosphorylated tau protein did not correlate with the GDS or between the two groups studied. This study, combining morphometric and confocal analyses, not only provides further evidence that, in the brains of patients with AD, the perforant pathway is highly sensitive to tau pathology but also that involvement is distinct from the changes of normal aging, even of the oldest old. Received: 23 April 1999 / Revised: 27 July 1999, 11 October 1999 / Accepted: 12 October 1999     

Increased skin temperature in Alzheimer’s disease is associated with sleepiness

The 24-h rhythms in sleep and temperature both change in Alzheimer's disease (AD). Characteristic changes consist of a more fragmented diurnal sleep profile with frequent nocturnal awakenings and daytime sleepiness, as well as a reduction in the amplitude of the 24-h rhythm in core body temperature (CBT). Although the 24-h rhythm in CBT is to a large extent the result of a 24-h rhythm in heat loss from the skin caused by pronounced changes in skin blood flow and consequently skin temperature (Ts), changes in the diurnal skin temperature profile in AD as compared to normal aging have remained unexplored. Because recent work indicates a causal contribution of fluctuations in skin temperature to daytime sleepiness and nocturnal sleep depth, the present study aimed to investigate the skin temperature rhythm in AD and its association with daytime sleepiness and nocturnal sleep. Ambulatory recorders were used to estimate sleep and 24-h rhythms in skin temperature in 55 AD patients and 26 matched non-demented elderly controls. Subjective sleep and daytime sleepiness were obtained using questionnaires. The results indicate that AD patients had a significantly higher daytime proximal skin temperature (PST) than elderly controls. In both AD patients and elderly controls, an elevated daytime PST was associated with more daytime sleepiness. The findings suggest a deficient downregulation of daytime proximal skin blood flow that might contribute to daytime sleepiness. Because daytime sleepiness contributes to cognitive dysfunction in AD, further research into the underlying mechanisms and possible reversibility is warranted.     

Immediate causes of death of demented and non-demented elderly

Objective – To investigate the immediate causes of death, in autopsied demented and non-demented elderly. Design – Retrospective clinicopathologic correlations. Setting – Acute and intermediate care geriatric hospital. Participants – 342 hospitalized demented and non-demented elderly (mean age 84.94±6.9 years) who underwent consecutive post-mortem examinations: 120 demented patients with either vascular dementia (VaD, n =34), mixed dementia (MD, n =65) or Alzheimer's disease (AD, n =21) neuropathologically confirmed and 222 non-demented elderly. Results – Primary causes of death were similar in both demented and non-demented patients; the commonest were cardiovascular disease and bronchopneumonia. Cardiac causes of death and especially cardiac failure were more frequent in VaD than in AD or MD (respectively P =0.027 and 0.005). Dementia was an underlying but never a primary cause of death. Conclusions – Immediate causes of death are similar in elderly demented and non-demented patients.     

Blood-brain barrier in Alzheimer dementia and in non-demented elderly

Summary Peroxidase-antiperoxidase staining of formalin-fixed brain was employed to compare the blood-brain barrier (BBB) function in five patients with Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) and three patients with AD/SDAT combined with multi-infarct dementia (MID/SDAT) with that of six non-demented aged controls. The diffusion of serum proteins through the BBB was visualized with antisera to albumin, prealbumin, immunoglobulin, C1q, C3c and to fibrinogen. A similar patterns of diffusion was seen in AD/SDAT and non-demented aged individuals. Neuron and glial cells were stained with different antisera in the vicinity of the diffusion. Senile (neuritic) plaques were occasionally visualized with antisera to IgG, C1q and C3c but not with antisera to albumin, prealbumin and fibrinogen in both demented and non-demented aged individuals. Neurofibrillary tangles were not labelled with any of the antisera studied. These results indicate that the BBB is compromised equally in AD/SDAT and in the non-demented elderly.Supported by grants from the Swedish Medical Research Council, King Gustaf V. and Queen Victoria's Foundation, Osterman's, Pfannestill's, Mångberg's and Thuring's foundations and NIH grants NS 18105 and NS 17487     

The apolipoprotein E ε4 allele is not a significant risk factor for frontotemporal dementia

Frontotemporal dementia (FTD) is the most common early-onset non-Alzheimer's dementia (non-AD). Although the role of the ε4 allele of apolipoprotein E (ApoE) has been well established in AD, studies of ApoE allele distribution in patients with FTD have produced variable results. We studied 33 rigorously diagnosed FTD patients, including several who wre pathologically confirmed, and compared the fequency of the ε4 allele in patients with FTD with the frequency in those with early-onset AD (EOAD), in those with late-onset AD (LOAD), and in non-demented elderly controls. The frequency of ApoE ε4 was 21% in patients with FTD, significantly less than the ApoE ε4 frequency in those patients with EOAD (38%) and those with LOAD (40%), but not significantly different from the ApoE ε4 frequency in elderly controls (13%).     

Elevated levels of fragmented DNA nucleosomes in native and activated lymphocytes indicate an enhanced sensitivity to apoptosis in sporadic Alzheimer's disease. Specific differences to vascular dementia

Apoptotic cell death is thought to be the most likely mechanism of cell death contributing to neurodegeneration in Alzheimer's disease (AD). Here, we provide evidence that in sporadic AD cases the vulnerability of peripheral cells to undergo apoptosis is increased compared to non-demented elderly controls and, very importantly, to patients with subcortical vascular encephalopathy (SVE) as another, but demented control group. Quiescent 'native' and 'activated' lymphocytes from AD patients that were predisposed to commit apoptotic cell death by priming the cells with interleukin-2, are shown to accumulate apoptosing cells to a significantly higher extent in spontaneous and in oxidative stress-induced in vitro apoptosis. Our results demonstrate robust differences in cell death sensitivity between AD and vascular dementia. In none of the conditions investigated, lymphocytes from SVE patients were significantly different from non-demented controls. The comparable findings of a higher extent of apoptotic features in neurons and in peripheral blood cells of AD patients are remarkable and may suggest a rather general modulation of apoptotic mechanisms by the disease, which even can be picked up at the level of peripheral lymphocytes under specific in vitro conditions.     

Eosinophilic bodies in the cerebral cortex of Alzheimer’s disease cases

The light microscopical, immunohistochemical and ultrastructural aspects of eosinophilic bodies in the cerebral cortex from patients with Alzheimer’s disease (AD) are described, based on a study of 16 cases of AD, 5 elderly non-demented controls and, as disease controls, 5 cases of Pick’s disease, 9 with progressive supranuclear palsy, 5 with Creutzfeldt-Jakob disease and 1 with Binswanger’s disease. At the light microscopy level, the bodies were clearly separated from the surrounding tissues and were mostly round or elliptic with a diameter of 5–30 μm and a central, intensely eosinophilic core. Ultrastructurally, they consisted of a central homogeneous electron-dense body (HDB), and filamentous structures (resembling either neurofilaments or paired helical filaments) or other small organelles in the periphery. Immunohistochemically, some of these bodies exhibited ring-shaped rims which were positive with antibodies against paired helical filaments, tau-2, phosphorylated neurofilaments and ubiquitin. The bodies were widely distributed throughout the cerebral cortex, but were not observed in the white matter. These bodies were thought to be compatible with one type of axonal dystrophy in the gracile nucleus (termed ‘old’ spheroid by Jellinger), and are here referred to as the HDB-type spheroid based on their ultrastructure. In this study HDB-type spheroids were found in high incidence in the AD cases, but only two HDB-type spheroids were seen in one case of Pick’s disease, and none in any of the other cases of neurodegenerative diseases or in the elderly non-demented controls. It seems plausible that the incidence of HDB-type spheroids in the cerebral cortex might be related to a pathological process and not to a physiological ageing phenomenon, and might be characteristic of, but not unique to, AD. Received: 4 March 1996 / Revised, accepted: 3 June 1996     

The neuropsychological profiles of mild Alzheimer's disease and questionable dementia as compared to age-related cognitive decline.

Test scores from a comprehensive neuropsychological battery administered to 1602 subjects consisting of 1347 subjects with probable Alzheimer's disease (AD), 100 subjects with questionable dementia (QD) and 155 non-demented elderly control subjects were cross-sectionally analyzed. Subjects with probable AD were categorized as mild (n = 244), moderate (n = 480), severe (n = 376), and very severe (n = 247) according to modified mini mental status exam (mMMSE) scores. Mean scores on individual neuropsychological tests are provided for each group of subjects. Stratified random sampling was performed to select a sample of mild AD subjects who were matched in age and education to non-demented elderly controls, and analyses focused on the performance of QD subjects and mild AD subjects, whose scores were compared to those of the elderly control subjects. Selected scores were organized by cognitive domain and logistic regressions were used to determine the domains and individual tests within each that were most predictive of group status. Results suggested a profile of scores associated with QD and mild AD including impaired recall of verbal information for both groups. Areas of lower functioning in QD subjects as compared to elderly controls included category fluency and visuospatial ability.     

Ideomotor and ideational apraxia in alzheimer's disease

Ideomotor apraxia (IMA) and ideational apraxia (IA) were studied in 32 Alzheimer's disease (AD) patients and in 30 non-demented elderly controls using a standardized apraxia battery. AD patients performed significantly worse than controls on all apraxia tests, and were more impaired when pantomiming movements than when imitating movements. IMA and IA scores correlated with severity of dementia as measured by the Mini-Mental State Examination. Analysis of individual performances revealed dissociated apraxic disorders in four patients, which may be interpreted as a manifestation of focal damage to left hemisphere cortical systems involved in praxis. Furthermore, these results suggest a greater ideational than ideomotor defect in apraxic AD patients.     

Increased cAMP immunostaining in cerebral vessels in Alzheimer’s disease

Increasing evidence suggests that up-regulation of the cAMP-second messenger system is implicated in Alzheimer’s disease neurodegeneration. Since previous studies reported an increased level of cAMP in microvessels of Alzheimer’s patients compared with those from non-demented elderly controls, we have carried out an immunohistochemical study to compare cAMP immunostaining in brain vessels from patients with dementia and neuropathological criteria of Alzheimer’s disease (n=5) with those of age-matched patients (n=10). We have also included a control group of adult patients (n=5) to evaluate the role of aging separate from the effects of dementia. Our results demonstrated an increased cAMP immunostaining in cerebral cortical and meningeal vessels from Alzheimer’s patients compared to nondemented elderly and adult controls. Vascular cAMP immunostaining was mainly observed in frontal and temporal cortex, the hippocampus being the region that showed the more intense and widespread vascular cAMP immunostaining. We also observed a conspicuous vascular beta-amyloid immunostaining specifically in those vessels that showed the highest cAMP immunostaining. We suggest that increased vascular cAMP immunostaining is mainly localised in the selectively vulnerable targets of neurodegeneration that characterise AD. Moreover, the co-immunolocalisation of cAMP and β-amyloid protein in cerebral vessels of patients with AD suggests a possible role of cAMP up-regulation in the accumulation of those amyloidogenic peptides.     

Cause of death in demented and non-demented elderly inpatients; an autopsy study of 308 cases

Few studies evaluated cause of death (COD) in elderly demented and non-demented people, the majority based on death certificates alone. The present study is based on autopsy reports with neuropathological examination of 308 inpatients (58.1% female) over age 60 years (mean: 83.5, SD: +/-8.6). CODs were classified into seven groups. The most common were bronchopneumonia (n=117; 38%) and cardiovascular disease (n=116, 37.7%). In 176 patients (57.1%) neuropathology was indicative for dementia: 76.7% Alzheimer disease (AD), 4.5% vascular dementia, 4.0% mixed type dementia (AD + vascular dementia), and 14.8% other dementias. Main COD significantly differed in demented and non-demented patients: bronchopneumonia (45.5% in demented versus 28.0% in non-demented), cardiovascular disease (46.2% in non-demented versus 31.3% in demented). Whereas there were significant differences in COD between AD patients and non-demented ones (bronchopneumonia versus cardiovascular disease), no differences were seen between the latter and patients with other types of dementia than AD. Our data emphasize the high incidence of bronchopneumonia as a COD in patients suffering from AD.     

Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) and Alzheimer’s disease (AD) share clinical, neuropathological, and pathogenetic features. To investigate eventual mutual influences, we screened prominently affected neocortex from 110 neuropathologically proven CJD patients for Alzheimer-type pathology with anti-β/A4, Bielschowsky and anti-tau (immuno)stains. The neuropathological classification of Alzheimer-type pathology was made according to the CERAD criteria. Results were controlled by comparison with Alzheimer-type changes in sections from the same cortical areas in 110 sex- and age-matched non-demented control patients. For comparison, the control patients were also classified according to the CERAD neuropathology criteria as if they had been demented. Alzheimer-type tissue changes as in definite and probable CERAD AD occur in 10.9% of the CJD patients and 19.1% of control patients (P = 0.11). The median age of CJD and control patients with CERAD AD is 72 and 68 years, respectively, which differs significantly from the median ages of 64 and 63 years, respectively, in the non-AD/CJD and non-AD control patients. Since CERAD criteria include “presence of other neuropathological lesions likely to cause dementia”, an AD diagnosis in CJD patients (all of whom are demented) is solely based on densities of neuritic plaques. Similar Alzheimer-type changes in even higher frequency, however, are also present in elderly non-demented controls. Thus, the coexistence of Alzheimer-type pathology in CJD most likely represents an age-related change. Deposits of prion protein (PrP) frequently accumulate at the periphery of β/A4 plaques. The presence of β/A4 amyloid in the brain may influence PrP morphogenesis. Received: 18 November 1997 / Revised, accepted: 11 February 1998     

Smell identification test as an indicator for cognitive impairment in Alzheimer's disease

OBJECTIVES: The aim of the present study was to assess olfactory dysfunction in patients with Alzheimer's disease (AD) and to compare utility of the olfactory tests as possible clinical markers. METHODS: Two olfactory identification tests (The Cross-Cultural Smell Identification Test [CC-SIT] and the Picture-based Smell Identification Test [P-SIT]) and the Mini Mental State Examination (MMSE) were administered to patients with AD and age-matched controls. Apolipoprotein E (Apo E) genotypes of patients with AD were identified. RESULTS: Patients with AD had significantly lower olfactory identification scores than age-matched non-demented elderly subjects in both olfactory assessments. In the AD group, the coefficient of correlation between the MMSE scores and the P-SIT scores was higher than that between the MMSE scores and the CC-SIT scores. Receiver operating curve (ROC) analyses for both tests indicated that the P-SIT discriminated AD patients from controls more reliably than did the CC-SIT. Within AD patients, those who were carrying one or two ApoE epsilon4 alleles had a higher coefficient of correlation between the MMSE scores and the P-SIT scores than patients without the ApoE epsilon4 allele. CONCLUSIONS: The results suggest that a short and simple non-lexical olfactory identification test can be useful as a clinical marker of AD appropriate for Japanese elderly population.     

A high incidence of apolipoprotein E ε4 allele in middle-aged non-demented subjects with cerebral amyloid β protein deposits

We examined the apolipoprotein E (ApoE) genotypes of 19 middle-aged non-demented subjects with cerebral amyloid β protein (Aβ) deposits, and compared the results with those of 16 patients with sporadic Alzheimer’s disease (AD) and those of 34 age-matched controls. The frequency of the ApoE ɛ4 allele was higher (P = 0.0256) in these 19 subjects (0.211) than in controls (0.059), and was close to that in AD patients (0.281). This result suggests that middle-aged non-demented subjects with cerebral Aβ deposits are at high risk of developing AD, and that the diffuse Aβ deposits in these cases represent an early stage of AD pathology. We speculate that in the majority of late-onset sporadic AD patients, cerebral Aβ deposition commences when these patients are in their forties or fifties, and that the pathological process progresses gradually, taking 20 to 30 years for clinical manifestation of dementia. Received: 16 March 1998 / Revised, accepted: 29 June 1998     

Community care for patients with Alzheimer's disease and non-demented elderly people: use and satisfaction with services and unmet needs in family caregivers

OBJECTIVE: This study measures and compares use of and satisfaction with medical and social services in addition to subjectively perceived needs of family supporters of patients with probable or possible Alzheimer's disease (AD) and family supporters of non-demented elderly people. Differences in judgement of services within the subpopulation of families of AD patients are also assessed by gender and burden level.METHODS: The main family supporters of 60 community-dwelling elderly (aged over 65) with Alzheimer's disease and of 60 age- and sex-matched controls were tested with a detailed questionnaire on use and satisfaction with services, any unmet needs and kinds of intervention perceived to be helpful.RESULTS: Supporters of elderly people with AD were significantly more involved in providing care than supporters of non-demented people. Judgement on the health, social relations and financial status of their families was significantly worse in AD supporters than in supporters of non-demented elderly people. Although the former made more use of available health and social services than the control population, they did appear to make little use of such services, not only because of lack of information but also for logistic reasons or because they would prefer a service with more specifically trained operators or more tailored intervention. AD family supporters would like to receive more information and support from their general practitioner, which confirms the importance of this figure in management of this pathology. They were less satisfied with the care provided than the control population, particularly those with a moderate-high burden. Irrespective of burden level, they also expressed a need for financial and psychological support and adequate intervention schemes, especially within the home. These should be provided by specially trained personnel and be tailored to specifically manage the individual patient's problems, especially in relation to behavioural disorders. This would help alleviate caregiver burden and allow patients to continue to be managed at home.     

Relationship between CSF neurotransmitter metabolites and aggressive behavior in Alzheimer's disease

To assess neurochemical correlates of aggressive behavior in Alzheimer's disease (AD) we examined concentrations of homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in lumbar cerebrospinal fluid (CSF) of 11 clinically diagnosed Alzheimer's disease (AD) patients and 12 non-demented age-equivalent controls. There were no significant differences between AD patients and controls in CSF HVA concentrations. However, the CSF 5-HIAA content was significantly lower in AD patients compared to controls. Patients without aggressive behavior had significantly lower concentrations of HVA and 5-HIAA than those with aggression, in whom concentrations were preserved compared to non-demented controls.     

Weight loss,nutritional status and physical activity in patients with Alzheimer’s Disease

The etiology of weight loss in Alzheimer's disease (AD) patients is still uncertain. This study was designed to investigate the possible factors that might contribute to weight change of AD patients. From July 1999 to June 2001, we recruited 51 AD patients and 27 non-demented controls. Demographic data, neuropsychological tests, Geriatric Depression Scale-Short Form, eating behavior questionnaire, dietary and physical activity diaries, anthropometric and laboratory measures of nutritional status were assessed. More than half of our AD patients developed body weight loss, and overall, the AD patients were significantly thinner than the non-demented subjects. Anthropometric and laboratory measures suggested a poorer nutritional status in the AD patients. The AD patients had fewer daily physical activities. More AD patients had the problem of poor appetite. However, daily calorie intake was not significantly different between the two groups. The AD patients, especially those who presented with body weight loss, even consumed more calories per body weight kilogram (kg) per day. In the food composition analysis, AD patients took more carbohydrate than controls. Multivariate regression analysis showed the existence of AD and poor appetite were the main risk factors of weight loss. We suggest that the pathophysiological process in AD gives rise to the changes of appetite and metabolic state in AD patients, and that these changes contribute to the weight loss.     

Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population

The mitochondrial α-ketoglutarate dehydrogenase complex (KGDHC) is deficient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrolipoyl succinyltransferase (DLST) component of KGDHC, and recent reports indicate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and the DLST and apolipoprotein E (APOE) genes in elderly (89 ± 7 years) AD patients, in whom the ε4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APOE4 with AD was found only in patients homozygous for the G,C allele of DLST. Similar relationships occurred in the “very elderly” (≥85 years, n = 302) subgroup of this series, and also in an autopsy series (n = 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DLST locus in the pathogenesis of AD in very elderly subjects. Ann Neurol 1999;45:48–53     

Decreased phospholipase A2 activity in the brain and in platelets of patients with Alzheimer's disease

Phospholipase A₂ (PLA₂) is a key enzyme in the metabolism of membrane phospholipids. PLA₂ influences the processing and secretion of the amyloid precursor protein, which give rise to the -amyloid peptide, the major component of the amyloid plaque in Alzheimer's disease (AD). We investigated the PLA₂ activity in two samples: in post-mortem brains from 23 patients with AD and 20 non-demented elderly controls, and platelets from 16 patients with a diagnosis of probable AD, 13 healthy controls and 14 elderly patients with a major depression. In AD brains PLA₂ activity was significantly decreased in the parietal, and to a lesser degree in the frontal, cortex. Lower PLA₂ activity correlated significantly with an earlier onset of the disease, an earlier age at death and higher counts of neurofibrillary tangles and senile plaques. In platelets PLA₂ activity was also significantly reduced in the AD group as compared with healthy and depressed controls. The reduction of the enzyme activity in platelets correlated with an early disease onset and with the severity of cognitive impairment, indicating a relationship between abnormally low PLA₂ activity and a more severe form of the illness. The present results provide new evidence for a disordered phospholipid metabolism in AD brains and suggest that reduced PLA₂ activity may contribute to the production of amyloidogenic peptides in the disease. Further studies are needed to examine whether PLA₂ activity in platelets may be useful as a peripheral marker for a subgroup of patients with AD.