Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer''s dementia.

Concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) from control subjects and patients of both presenile and senile age with histologically verified Alzheimer's dementia. CSF HVA increased with age in control but not in Alzheimer patients. HVA and 5-HIAA in the CSF of presenile Alzheimer patients was lower than that of age matched control subjects.     

Monoamine metabolites in cerebrospinal fluid and behavioral ratings in patients with early and late onset of Alzheimer dementia

Patients with Alzheimer disease (AD, onset less than 65 years of age, n = 13) and senile dementia of the Alzheimer type (SDAT, onset greater than or equal to 65 years of age, n = 28) were investigated for cerebrospinal fluid (CSF) content of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) and compared with a group of controls (n = 26). A geriatric rating scale, the Gottfries-Br?ne-Steen scale, was used to assess impairment of motor performance, intellectual and emotional functioning, and symptoms common in dementia disorders. The HVA levels in CSF were significantly lower in the AD group than in the SDAT group and controls. MHPG was slightly but significantly increased in the SDAT group when compared with the controls. The HVA and 5-HIAA concentrations were correlated negatively with impairment of motor performance in the SDAT group; 5-HIAA correlated positively with impaired performance in the AD group; and 5-HIAA/HVA ratios were correlated positively with the performance variables. HVA correlated significantly and negatively with "impaired wakefulness" and "inability to increase tempo" in the SDAT group. 5-HIAA and the ratio 5-HIAA/HVA correlated significantly and positively with some items measuring intellectual and emotional impairment. In the AD group, "anxiety" and "fear-panic" correlated positively with 5-HIAA and "restlessness" with MHPG. The data indicate qualitative differences in the CSF monoamine pattern between AD and SDAT.     

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type

The possibility of disturbed dopamine and serotonin metabolism in senile dementia of Alzheimer type was studied. The basal concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were studied in 28 patients with senile dementia of Alzheimer type and in 13 controls of similar age with no neurological disease. The concentrations of HVA were significantly reduced in the dementia patients compared to the concentrations of the controls. The values of HVA were also significantly reduced in the most severely demented patients compared to the less severely demented ones. There was a slight but statistically significant decrease in the 5-HIAA levels in the dementia patients compared to the levels of the controls. The 5-HIAA levels were reduced in the most severely demented patients compared to the controls but not when compared with the less severely demented patients.
It is concluded that in severe forms of senile dementia of Alzheimer type, there is a decrease in the levels of HVA and 5-HIAA in CSF which may reflect a decreased turnover of dopamine and serotonin. Patients diagnosed as senile dementia of Alzheimer type, but with less severe symptoms, had levels of HVA and 5-HIAA similar to controls.     

Alzheimer''s disease and senile dementia of Alzheimer type

Clinical and neuropsychological findings, EEG, and several blood and CSF parameters were investigated in 36 patients with Alzheimer's disease (AD) and 35 patients with senile dementia of Alzheimer type (SDAT). There were more women among senile patients and more familial cases among presenile patients. The average duration of the symptoms was longer in presenile patients (6.1 years) than in senile patients (3.9 years). This could be due to the lower resistance to the disease process in the senile group.
Extrapyramidal signs, especially rigidity, were found in over 60 % of all patients and in practically all patients with advanced dementia. Tremor was found in three patients only. Four presenile (11 %) and two senile (6 %) patients had epileptic seizures. All patients had abnormal EEG recordings, mainly in form of diffuse slowing. A positive correlation was found between the EEG abnormality and the severity of dementia in AD but not in SDAT. However, the difference between the correlation coefficients in AD and SDAT was insignificant. Between EEG and the duration of the disease there was no correlation. EEG was not more abnormal in very severe dementia than in severe dementia. Other findings were similar in AD and SDAT.
It is concluded that it is artificial to separate AD and SDAT at the age of 65 and that they clinically compose a single entity. This entity could well be called Alzheimer's disease.     

Low B12 levels related to high activity of platelet MAO in patients with dementia disorders. A retrospective study

In 35 patients with Alzheimer's presenile disease (AD), 56 patients with senile dementia of the Alzheimer type (SDAT), 54 patients with vascular dementia (VD) and 10 patients with confusional states, age, vitamin B12 in serum, P-folate, B-folate and B-Hb were investigated. Platelet monoamine oxidase (MAO) and cerebrospinal fluid (CSF) levels of homovanillic acid (HVA), 5-hydroxyin-doleacetic acid and 3-methoxy-4-hydroxyphenylglycol were measured. Group differences showed that vitamin B12 levels were reduced in the group of patients with confusional states and SDAT. Five out of ten and 13 out of 56 (respectively) had vitamin B12 concentrations below the lower limit of the reference value (130 pmol/l). A negative correlation was found between B12 levels and platelet MAO activity. The findings indicate that there is a subgroup of patients with late-onset dementia that has low vitamin B12 blood concentrations. HVA levels in CSF, usually found to be reduced in AD patients, were normal in this subgroup.     

Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis

In the past, 'Alzheimer disease' (AD) referred to pathologic AD with clinical onset of dementia in the presenium, while 'senile dementia of the Alzheimer type' (SDAT) referred to senile onset AD. Because AD appears clinically homogeneous regardless of age of onset, the two subtypes in more recent years have not been distinguished. Pathologic differences have been noted, but synapse loss has not previously been compared between the two groups. Hypothesizing that synapse loss would be greater in presenile onset than senile onset AD, we compared synapse loss, as well as Alzheimer pathology in presenile and senile onset AD, using an ELISA method to quantify synaptophysin. Synaptophysin was significantly lower in presenile than senile AD in right frontal and bilateral parietal lobes. Neuritic plaque counts were significantly higher in presenile than senile AD in bilateral frontal and parietal lobes. Semi-quantitative evaluation of neurofibrillary tangles revealed significantly more tangles in bilateral frontal and parietal lobes in presenile than senile AD. Brain weight was significantly lower in presenile than senile AD. The differences in synapse loss and Alzheimer-type pathology in presenile and senile onset AD support the hypothesis that 'cognitive reserve' protects the human brain from neurodegenerative disease.     

Brain electrical activity in patients with presenile and senile dementia of the Alzheimer type

Neurophysiological and behavioral data obtained from 9 patients with presenile dementia and 10 with senile dementia of the Alzheimer type were compared with similar data from 25 age- and sex-equivalent controls. Compared with the healthy controls, both patient groups demonstrated increased background electroencephalographic slowing with a reduction in fast activity (synchronization). Topographic analyses of data from electroencephalographic and evoked potential studie indicate that areas of maximal group differences between the presenile patients and their controls include the right posterior temporal and, to a lesser extent, left midtemporal to anterior temporal areas, whereas the maximal differences between the senile patient group and their controls involve the midfrontal and anterior frontal lobes, bilaterally. Moreover, right-sided numerical features derived from topographic maps proved most useful in differentiating the presenile patients and their age-matched controls, whereas bilateral features were more useful in separating senile patients from their controls. These topographic dissimilarities between patient groups suggest that an age-disease interaction exists between patients with presenile and senile dementia of the Alzheimer type. Correlational analyses between neuropsychological test scores and neurophysiological features indicate that increased slowing and decreased fast activity were associated with poorer test performance.     

What is ‘early onset dementia’?

There are two types of dementia with early onset: (i) presenile dementias; and (ii) senile dementias with early onset. Most patients who develop dementia before 65 years of age have Alzheimer's disease (AD). The remainder are likely to have vascular dementia (VaD), frontotemporal dementia, head injury, alcohol intoxication, or metabolic disorder. Presenile dementias, caused by frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration, usually occur in patients of presenile and are rarely seen in patients of senile age. Although the factors responsible for the accelarted onset of the illness are not fully known, genetic abnormalities appear to be important in some types of presenile dementia, such as frontotemporal dementia with parkinsonism linked to chromosome 17. Conversely, senile dementias such as sporadic AD and VaD commonly occur in patients of senile age. These disorders may also occur in patients of presenile age, although less frequently. Alzheimer's disease was originally classified as a ‘presenile dementia’. Since the 1980s, ‘senile dementia of Alzheimer type’ (SDAT) and ‘Alzheimer's disease’ have been considered to belong to the same pathological entity and both are now known as ‘dementia of Alzheimer's type (DAT)’ or merely ‘Alzheimer's disease’. Rapid progression of cognitive impairment with neuropsychological syndromes and neurological symptoms has been considered a characteristic of early onset AD. However, recently, neurological symptoms such as spastic paraparesis, seizures, and myoclonic convulsions have been reported to occur infrequently in early onset AD, although language problems and visuospatial dysfunctions are common. There are at least three dominant genes that have been identified in cases of familial Alzheimer's disease with early onset, namely the amyloid precursor gene (APP), and the genes encoding presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Therefore, genetic abnormalities are important factors contributing to the earlier onset of the illness. It is also important to investigate the pathophysiological mechanism in relation to genetic abnormalities, environmental factors, physical illnesses, and metabolic disturbances to understand the processes underlying the development of dementia with early onset.     

Neuropsychological patterns of presenile and senile dementia of the Alzheimer type

Thirty-seven patients with a presumptive diagnosis of dementia of the Alzheimer type were divided into presenile and senile groups according to the age at which they first received a clinical diagnosis. Although there were no differences in mental status, dementia rating, or chronicity of disease, multivariate analyses of WAIS subtests revealed the presenile subjects to be relatively impaired on Performance subtests. Univariate tests of Verbal, Performance, and Full Scale IQ measures were significantly lower in the presenile group. There was no group effect detected for Digits forward, adjusted for age differences based upon performance of 40 age-matched controls, while the presenile group performed significantly more poorly on backward span. Further, significant differences were detected for an embedded figure task, as well as graphomotor speed. These data suggest that patients who develop a degenerative dementia during the presenile period are more impaired than their senile counterparts on age-adjusted measures of sustained concentration and mental tracking.     

Platelet MAO-B activity and vitamin B12 in old age dementias

Platelet MAO-B activity, serum vitamin B₁₂ levels, and plasma folate were measured in patients suffering from presenile (AD) and senile (SDAT) dementia of Alzheimer-type, and vascular dementia (VD). MAO-B was higher in the SDAT group than in AD and controls. An inverse relationship between MAO-B activity and vit. B₁₂ levels was documented in the whole group and in each category studied; furthermore, MAO-B was positively related to age. All the patients were then divided into two groups, according to vit. B₁₂ levels (Group I: <200 pg/mL; Group II: ≥200 pg/mL); Group I showed a significantly higher MAO-B activity with respect to Group II. The results indicate the existence of a negative association between platelet MAO-B activity and serum levels of vitamin B₁₂ and confirm the existence of biological differences between presenile and senile dementia of Alzheimer type.     

CSF alpha-MSH in dementia of the Alzheimer type

We measured CSF alpha-melanocyte stimulating hormone-like immunoreactivity (alpha-MSH-LI) in 35 patients with dementia of the Alzheimer type (DAT) and in 27 healthy control subjects. Mean alpha-MSH-LI concentration was significantly decreased in DAT patients as compared with age-matched controls. However, when the DAT patients were analyzed according to age at onset of dementia or presence of extrapyramidal signs, alpha-MSH-LI concentrations remained significantly lower than in controls only in DAT patients with late onset of dementia (greater than 65 years of age). No correlation was found between alpha-MSH levels and degree of mental impairment. A significant negative correlation was found between CSF concentrations of alpha-MSH and homovanillic acid in the group of all DAT patients (p less than 0.001). These results suggest that hypothalamic neurons which produce pro-opiomelanocortin-related peptides may be involved in Alzheimer's disease.     

血及脑脊液β-淀粉样蛋白对老年期痴呆鉴别诊断的意义

目的:探讨血及脑脊液中β-淀粉样蛋白(β-AP)对老年期痴呆主要包括老年性痴呆(AD)、血管性痴呆(VD)及其他原因所致的痴呆(OD)的鉴别诊断意义。方法:采用平衡饱和竞争放射免疫分析法对55例不同类型的痴呆患者及30例正常对照者血清及脑脊液(CSF)中β-AP进行测定。结果:在正常对照组,随着观察者年龄的增长,血清β-AP含量缓慢增高,CSF中β-AP含量缓慢下降(r分别为0.56,0.52,均P<0.01)。不同病因痴呆患者血清β-AP含量均高于对照组,其中AD组最明显;CSF中β-AP含量在AD组最低,明显低于对照组(P<0.01),在VD组最高,接近对照组(P>0.05)。AD组中的重度痴呆患者,其β-AP含量在血清中升高最明显,同时在CSF中降低也最显著。结论:血清及CSF中β-AP含量变化的测定,可能有助于各型痴呆的鉴别诊断及AD患者病情轻重的判断,但这种变化具重叠性。     

Cholinesterase activity in plasma, erythrocytes, and cerebrospinal fluid of patients with dementia of the Alzheimer type

Cholinesterases, including pseudocholinesterase (BChE) of human plasma and acetylcholinesterase (AChE) of erythrocytes and cerebrospinal fluid (CSF), have been considered as possible markers in dementia of the Alzheimer type (DAT). Reported data, however, are widely varied, and no significant pattern emerges when total enzyme activity is assayed. In the present studies, we have reexamined the relationship of ChE activities in DAT and control patients. ChE activity was measured in plasma, erythrocytes, and CSF from DAT patients and compared with normal controls as well as with samples from patients with a diagnosis other than DAT. Early age onset (presenile) and late age onset (senile) DAT were also compared. No significant differences in total enzyme activity were found in any of the comparisons. Calculations of AChE/BChE ratios in CSF also provided no significant indication of any changes in ChE activities in DAT. It is suggested that measurements of total AChE or BChE activity in these biological materials do not provide a useful index of alterations in central cholinergic function in patients with DAT.     

ALZHEIMER''S PRESENILE DEMENTIA, SENILE DEMENTIA OF ALZHEIMER TYPE AND DOWN''S SYNDROME IN MIDDLE AGE FORM AN AGE RELATED CONTINUUM OF PATHOLOGICAL CHANGES

A loss of nerve cells from the nucleus basalis of Meynert and the locus caeruleus together with a reduction in nucleolar volume in surviving cells was measured in twenty-two patients with Alzheimer's disease who ranged in age from 48-92 years, and in six patients over 50 years of age with Down's syndrome who also showed extensive formation of senile plaques and neurofibrillary tangles within their cerebral cortex. When compared with age matched controls the severity of these changes was greatest in the younger patients with Alzheimer's disease, but this fell with age such that by 90 years the level of change in Alzheimer's disease approached that in old age alone. There were only slight differences in the extent of these pathological changes in those patients with Down's syndrome when compared with others of similar age with Alzheimer's disease. It is concluded that the presenile dementia of Alzheimer's disease, the senile dementia of Alzheimer type and Down's syndrome in middle age all form an age-related continuum of pathological change.     

Gray-matter degeneration in presenile Alzheimer's disease

Previous comparisons between presenile Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT) did not control for disease severity and duration. In the current study, 18 patients with each diagnosis were matched for disease duration, cognitive dysfunction, and behavioral symptoms (using the modified Mini-Mental Status [mMMS] examination and the Blessed Dementia Rating Scale [BDRS] ). Regional cerebral blood flow (rCBF) was quantified by the 133xenon inhalation technique, and several indices of tissue perfusion were examined. The two variables of primary interest were relative gray-matter relative weight (35% in presenile patients versus 39% in senile patients and healthy control subjects, p = 0.006), with neither perfusion nor disease severity differences between the two dementia samples. This loss of gray matter was significantly related to both severity and duration of disease in the patients with presenile AD, but not in patients with SDAT. These findings lend support ot previous suggestions of greater degenerative process in presenile AD and confirm the need to examine and control age of onset in future investigations of AD. Further, correlation analysis suggests greater proportion of common variance among clinical and physiological indices in presenile AD.     

Insulin-like growth factors and somatomedin B in the cerebrospinal fluid of patients with dementia of the Alzheimer type

Cerebrospinal fluid levels of radioreceptor assayable insulin-like growth factors (RRA-IGFs) and immunoreactive somatomedin B (SMB) (RIA-B) were determined in apparently healthy individuals and in patients with dementia of the Alzheimer type (AD). The CSF levels of RIA-B and RRA-IGFs did not alter from the healthy controls. After being acidified, the CSF from the controls and from the presenile ADs were separated over a G-50 fine Sephadex . The RRA-IGFs activity eluted in three peaks. The results indicate that the major constituent of CSF RRA in both AD patients and controls is an IGF binding protein. The two minor peaks eluted at approximately 9 K and 6 K, corresponding to the elution positions of "big" IGF-2 and IGF-2.     

CSF cholinesterase in early-onset and lateonset Alzheimer's disease and multi-infarct dementia of Chinese patients

Using Ellman spectrophotometric method we measured the total cholinesterase (ChE) activity in lumbar cerebrospinal fluid (CSF) of 13 persons without neurological disorder, 10 non-demented patients with cerebral infarcts, 17 patients with dementia of Alzheimer's type (DAT) (11 presenile, 6 senile cases), 10 patients with multi-infarct dementia (MID), 1 patient with Parkinson's disease associated with dementia. The ChE activity in CSF was significantly lower in the DAT group compared with age-matched control subjects (p<0.001). This paper also analyses the possibility of using CSF ChE activity as a marker of DAT, and the relationships between its level of activity and the age of the patient at onset, stage of illness and severity of dementia as well as discrepancies in the data published so far. Previous work has shown that ChE activity in the brain tissue and CSF of MID is normal: therefore, if low ChE activity is found in the CSF of MID patients, as was obtained in 8 out of 10 cases in our series, the diagnosis of mixed dementia should be considered.     

Aging brain and dementias: changes in central opioids

We evaluated the CSF levels of beta-lipotropin (beta-LPH), beta-endorphin (beta-EP) and ACTH, which are three neuropeptides expressed by the same gene encoding for pro-opiomelanocortin, in various groups of demented patients including degenerative (presenile and senile Alzheimer-type dementia, ATD) and vascular (MID) forms. Twelve sex- and age-matched subjects were taken as controls. Our data indicate that ACTH levels are significantly reduced both in ATD and MID patients, while beta-EP and beta-LPH are significantly reduced only in ATD. The low CSF ACTH levels can be considered typical of all demented processes (both degenerative and vascular), while the reduction of beta-EP and beta-LPH in CSF could be due to a degenerative process of CNS.     

Blood-brain-barrier in a geriatric population: barrier function in degenerative and vascular dementias

ABSTRACT Albumin and IgG were determined in serum and cerebrospinal fluid (CSF) of patients with early-onset Alzheimer's disease (AD, n. 13), senile dementia of Alzheimer type (SDAT, n. 33), vascular dementia divided into multi-infarct (MID, n. 9) and probable vascular (PVD, n. 11) dementia. Albumin and IgG ratio and IgG index were calculated. CSF albumin and albumin ratio were significantly higher in MID patients indicating an increased BBB permeability. IgG ratio and IgG index did not show any significant difference among groups. These results do not provide evidence for BBB damage in AD/SDAT, while in MID the increase of CSF albumin and albumin ratio is suggestive of BBB dysfunction.