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Serum immunoglobulins and circulating antinuclear antibodies were assayed in 91 elderly female in-patients with dementia. Clinical criteria were used to distinguish a group with multi-infarct dementia from those with senile dementia of Alzheimer type and the results were compared with those of 19 age-matched controls. Dementia patients aged 85 and over had a higher prevalence of antinuclear antibodies (P less than 0.05) and those aged 90-95 had higher levels of IgA than younger age groups (P less than 0.025). IgG levels were higher than controls in the 'multi-infarct' group (P less than 0.025).

Four patients with recurrent stroke and multi-infarct dementia are presented in whom the dementia was progressive and severe. Three of the patients developed the dementia during the course of an illness which was punctuated by repeated episodes of cerebral infarction demonstrated by computed tomographic (CT) scans. The fourth patient presented with an illness dominated by progressive and deteriorating higher mental functions, which culminated in a major stroke 18 months later. Three patients fulfilled the American Rheumatism Association (ARA) criteria for the classification of systemic lupus erythematosus, the fourth had a 'lupus-like' disease. All had livedo reticularis, severe migraines, and also demonstrated antibodies to phospholipids. All four patients suffered deep vein thromboses.

Sections of formaldehyde-fixed paraffin-embedded cortical and hippocampal brain tissue from five cases with senile dementia of Alzheimer type (SDAT) and five cases with Pick's disease (PD) were immunostained with the monoclonal antibodies (mabs) 147, RT 97, BF 10 and 8D8 with and without pretreatment with alkaline phosphatase (AP) or trypsin (Tr). The mabs 147, RT 97 and BF 10 had previously been demonstrated to bind exclusively to phosphorylated epitopes of neurofilament proteins, while mab 8D8 is shown in this report to bind mainly, but not exclusively, to phosphorylated neurofilament epitopes. The mabs RT 97, BF 10 and 8D8, but not 147 stain most, if not all, Pick bodies (PB) and Alzheimer neurofibrillary tangles (NFT). When sections are pretreated with AP or Tr the immunostaining with mab BF 10 is very resistent in both PB and NFT. This resistance of PB and NFT is in contrast to the reduced staining of axons and of swollen cells in PD by the same enzymatic pretreatment. Immunostaining with mab RT 97 of PB and NFT is reduced moderately by AP and considerably by Tr. Only when stained with mab 8D8 is there a discrepancy between PB and NFT in their reaction to the pretreatment with AP: NFT staining with mab 8D8 is not affected, while that of PB is abolished. Thus, in spite of their different ultrastructure, PB and NFT are very similar immunocytochemically and in the accessibility of their phosphorylated epitopes to enzymatic treatment.

To identify HLA antigen associations with geriatric depression, the authors typed 36 elderly patients with major depression and, for comparison, 36 patients with Alzheimer-type dementia and 29 nondemented elderly controls. The frequency for antigen Aw32 was significantly higher in the group of patients with major depression (14%) than in the demented (0%) and control (3%) groups. The frequencies for antigens Aw32 (22%) and Bw51 (22%) were significantly higher in the subgroup of 23 patients with endogenous depression than in the demented (Aw32 = 0%; Bw51 = 11%) and the control (Aw32 = 3%; Bw51 = 0%) groups. Although these results were derived from a relatively small sample (n = 101) and become nonsignificant when corrected for multiple comparisons, they suggest that HLA antigen associations may be present for only certain depressive subtypes in geriatric depression.

Immunoperoxidase techniques were used to obtain information about the possible presence of serum factors in senile plaques. We found only in plaques consisting of an amyloid core surrounded by a corona of degenerating neurites small amounts of IgG and light chains (kappa and lambda). These immunoglobulins were principally localized in the corona and not in the central amyloid core. Further it was found that all plaques contain the complement factors C1q, C3b, C3c, C3d and C4. Senile plaques lacked C5, C3 pro-activator and properdin. The possible significance of these findings in the genesis of the senile plaques and amyloid formation is discussed.

Serum antibody titres to eight neurotropic viruses were measured by enzyme immunoassay in 450 psychiatric in-patients and 143 controls. A seasonal variation in schizophrenic births was observed, with a peak incidence between March and April. Both herpes simplex virus and cytomegalovirus antibody titres correlated with age and, when this was controlled for, no significant differences emerged between any patient group and the controls. Mumps antibody titres were significantly lower in patients with mental subnormal and neurosis or personality disorder; measles and rubella antibody titres were lower in male but not female mentally handicapped patients; males had lower antibody titres to mumps, cytomegalovirus and Epstein-Barr virus than females in all groups. A decrease in mumps antibody titres was also found in schizophrenics if the medication factor was excluded. These low antibody titres may indicate an impaired immune response. Thus perinatal or childhood subclinical viral infections of the central nervous system, particularly of mumps, might lead to a range of possible psychiatric outcomes in later life.

The molecular nature of neurofibrillary tangles of senile dementia of the Alzheimer type (SDAT) was studied by immunoperoxidase and immunofluorescence techniques. Five antiserums, including anti-humanbrain-2-cycle-purified-microtubule-fractions (2 x MT), anti-calf-brain-2 x MT, anti-sea-urchin-egg-tubulin, antibeef-brain-tubulin, and anti-human-brain-neurofilament(NF)-210-kilodalton(kd)-protein were tested for their binding to neurofibrillary tangles. The antihuman-2 x MT serum stained structures resembling neurofibrillary tangles, neurites of neuritic plaques, and microglialike cells in SDAT brains, but no such staining pattern was detected in normal brain sections. In neurons isolated from SDAT brains, about 40% of the tangles were labeled by the anti-human-2xMT serum with an identical pattern. Other antiserums tested did not preferentially bind tanglelike structures in tissue sections and bound to less than 5% of the tangles in isolated neurons. These results suggest that the antigenic sites of tubulin and NF proteins are not shared by neurofibrillary tangles. Different from the calf preparation, the human-2 x MT fractions contained a prominent protein band that was identical to ferritin in molecular weight and cross-reacted with anti-human-2 x MT and anti-human-ferritin serums. However, antiserums to this ferritinlike protein, or anti-ferritin, did not stain neurofibrillary tangles. Although neither the calf 2 x MT nor two other human MT fractions failed to elicit an antiserum that stained tangles, these fractions were able to remove the antihuman-2 x MT serum activity that binds to tangles. The data suggest that the protein (or proteins) that makes up neurofibrillary tangles of SDAT is present in various quantities in microtubule fractions of normal brain.

Alzheimer's disease may arise from an interaction between a conventional infective agent and a particular disease susceptibility (related to the HLA-A or B locus). HLA antigens and antibodies to conventional infective agents were examined in 14 patients with pre-senile dementia. Most of the sample probably suffered Alzheimer's disease, though one subject may have had Pick's disease. No particular HLA type or antibody was associated with the sample.

Antibodies to negatively charged phospholipids including cardiolipin have been recognized in the sera of patients with systemic lupus erythematosus and other disorders. We report 4 patients who experienced cerebral infarctions and dementia in association with anticardiolipin antibodies. These patients did not have the characteristic lupus anticoagulant or systemic lupus erythematosus. The occurrence of anticardiolipin antibodies in patients with multiple cerebral infarctions who do not have evidence of a systemic vasculitis or inflammatory condition suggests that this association may be more common than previously recognized. It may be useful to test for the presence of anticardiolipin antibodies in patients who have unexplained cerebral infarctions.

A preliminary study of Alzheimer's disease showed an apparent excess of the antigen A2 in patients who presented the disease before the age of 60, whereas those with onset after 64 showed different frequencies of the antigens A1 and A3 when compared with the local population. There was no abnormality in the distribution of B locus antigens. The findings are briefly discussed.

The present report describes the distribution of histocompatibility antigens in 52 patients with Alzheimer's disease. No significant associations were observed between this illness and particular HLA types before or after statistical correction for multiple comparisons. These findings are discussed in terms of the difficulties inherent in the clinical diagnosis of Alzheimer's disease and with regard to the choice of suitable control populations.

The results obtained with direct immunofluorescence techniques on normal, senile and Alzheimer's disease brains are reported. The antisera used were directed against C3c, IgG (gamma chain), IgG Fc., kappa and lambda light chains and anti-Ig (total). The brain samples were prepared in different ways: formalin-fixed and paraffin embedded; fresh frozen samples and alcohol fixed, paraffin-embedded samples. The images obtained with the different processing methods did not coincide. In order to obtain a more complete picture, we suggest the use of different methods on the same samples. In Alzheimer's disease brains, abundant but probably not monoclonal Ig antigenic determinants were found. Ig were found diffusely in the tissue, connected to amyloid (both in senile plaques and blood vessel walls), in glial cells and neurons. The significance of such data in relation to the genesis of brain amyloid are discussed.

Among Guamanian natives, serum IgA and IgG levels were found to be higher than normal in amyotrophic lateral sclerosis (ALS); serum IgA was higher and IgM lower than normal in parkinsonism-dementia (PD). IgA levels increased with age in ALS, PD, and normal subjects; IgG increased with age in ALS and IgM decreased with age in PD. Serum immunoglobulin (Ig) levels did not correlate with the duration of either disease. Immunodeficient ALS and PD patients had higher IgM and lower IgA levels than the other ALS and PD patients. Neither differences in viral antibody titers nor the presence of autoantibodies or circulating immune complexes could account for the variations in serum Ig levels between patients and controls. We conclude that differences in serum Ig levels in ALS and PD patients are probably due to repeated infections and abnormal immunoregulation accompanying immunodeficiency during the course of ALS and PD, rather than to a specific antiviral or autoimmune response.

The brains of 43 patients, some with various neurological disorders, other controls, were examined for herpes simplex virus (HSV) antigen using immunoperoxidase technique. The three patients with herpes simplex encephalitis shared a pattern of staining, consistent with that reported previously. However, of the other 40 patients, only two (one a patient with Alzheimer's disease, the other a control patient) showed areas of brain positive for HSV antigen (VA). In the patient with Alzheimer's disease VA was present within nerve and glial cells of the amygdala, within oligodendrocytes of the optic and olfactory tracts and in macrophages within the temporal cortex hippocampus and cerebellum. In the control patient VA was seen only in oligodendrocytes of optic chiasma and olfactory tract. The scarcity of these findings suggests "coincidental disease" processes within these two patients and means that any hypothesis implicating HSV as an aetiological agent in degenerative disease must still remain extremely speculative.

Intradermal tests with a mixture of Herpesvirus hominis 1 (HVH 1) antigens containing quantitated neutralization antigen were done in 39 schizophrenics (SCH), 42 senile demented (DS) persons, 28 alcoholics, neurotics and psychopaths (ANP) and 33 control persons. Local induration, erythema and fading was evaluated according to diameter and intensity after 15 to 30 min for anaphylactic type I reaction, after 5 hr for Arthus type III reaction and after 24 and 48 hr for delayed hypersensitivity (type IV). The diagnosed clinical forms influenced the incidence of positive reactions I, III or IV at the level alpha = 0.01. The incidence of positivity in all reactions (I, III plus IV) was significantly higher in the patients than in the control group. Type I and III reactions were most intensive in ANP and SCH, respectively. Type IV reaction was most pronounced in SCH, including the highest incidence of purple lesions, eventually with a lightly cyanotic target. In the DS group, type IV reaction surpassed the control the least of all patients' groups. Unfavourable side effects of the skin tests were not observed. The importance of repeated contact with HVH 1 for a marked type IV reaction ws confirmed in experimentally infected guinea pigs, which also served for safety tests and selection of antigen preparations.

We compared patients with senile dementia of the Alzheimer's type (SDAT) and age-matched controls with respect to T8+-cell-mediated suppressor function using a pokeweed mitogen (pwm)-induced IgG secretion assay. The responding B cells were allogeneic to the T-regulator cells. T8+-cell-mediated suppression was lower in SDAT patients than the controls when we used either 2 X 10(4) or 5 X 10(4) T8+ cells. Suppressor function was lower in both SDAT and elderly controls than in young adults. SDAT patients and controls did not differ with regard to T4+-cell-mediated helper activity. In SDAT patients, there seems to be an exaggeration of the age-related decline in suppressor-cell function. Whether such changes reflect accelerated changes of intrinsic lymphocyte properties or aberrant neural influences on lymphocytes remains to be resolved.

Thrity-four unrelated patients with Alzheimer's disease were typed for HLA-A, -B and -C serological determinants. HLA-Cw3 was increased over control antigen frequencies. This difference lost significance when corrected for the number of antigens tested.

Etiology and source of amyloid deposition in senile plaques of Alzheimer's disease (AD) are still unknown. In order to know whether or not fibronectin (Fn), an adhesive glycoprotein, is related to the amyloid deposition in the senile plaque, we conducted immunohistochemical studies using polyclonal anti-Fn and affinity-purified anti-amyloid component (Affi 28). Affi 28 was made by immunizing a rabbit against the synthetic peptide corresponding to residues 1-28 of the amyloid core protein reported by Masters et al. (1985). According to this study, four points became clear. First, Affi 28 is able to stain the subpial regions of AD as well as cerebrovascular amyloid and amyloid plaque cores. Second, it is suggested either that the etiology and source of neurofibrillary tangles and Pick body is distinct from that of the senile plaque or that any Affi 28 determinants of neurofibrillary tangles and Pick body are obscured sterically. Third, Affi 28 is useful to distinguish the senile plaque from the amyloid plaque of Creutzfeldt-Jakob disease. Last, there is no association between the amyloid in the senile plaque and Fn, at least immunohistochemically. The absence of Fn in the senile plaque suggests that Fn may not be requested for the deposition of amyloid fibrils.

The frequency of antinuclear antibodies was evaluated in older men and women aged 60 to 100 years with presumptive diagnoses of chronic brain syndrome or dementing illness. Thirteen per cent of the women and none of the men with organic brain syndrome had positive titers, compared to 3% for older men and women aged 60 to 89 years evaluated in a medical clinic population. It would appear to be valuable to evaluate the significance of antinuclear antibodies and other autoantibodies in the pathogenesis of dementing illness in the elderly.

Using a fluorescent antibody technique, sections of the brains of patients with senile dementia or Alzheimer's disease containing senile plaques were treated with rabbit antihuman immunoglobulins labelled with FITC (fluorescein isothiocyanate, BBL). The senile plaques and the cerebral amyloid angiopathy (drusige Entartung, Scholz, 1938) in the brains of patients with senile dementia or Alzheimer's disease showed specific fluorescence. Control sections from the brains of a girl who died from carcinoma of the stomach and of a female schizophrenic who died from lung abscess, showed only slight fluorescence in a few vessel walls. The presence of components or fragments of immunoglobulins in a senile plaques may mean that immunological factors are involved in their pathogenesis and probably also in that of senile dementia and Alzheimer's disease.

In ten patients with presenile dementia of the Alzheimer type and in a control group the levels of the different immunoglobulins were determined in both serum and cerebrospinal fluid (CSF), and gel electrophoretic techniques used to determine possible oligoclonal bands in the gamma-globulin region. There is no indication that patients with Alzheimer disease produce immunoglobulins within the central nervous system.

A monoclonal antibody produced by a hybridoma between a plasmacytoma cell and a spleen cell from a mouse immunized with human brain microtubule fraction was demonstrated to stain neurofibrillary tangles of senile dementia of the Alzheimer type (SDAT). The antibody recognized at least 50% of the tangles in neuronal perikarya isolated from SDAT brains and stained a filamentous network in HeLa cells, fibroblasts, and astrocytes. It did not stain skin epithelial cells or neurons isolated from normal brains but reacted with Z bands in skeletal muscle. The monoclonal antibody stained coils in colchicine or colcemid-treated cultured cells in a pattern characteristic of 10-nm intermediate-sized filaments. Immunoblotting of Triton-insoluble cytoskeletal proteins of cultured cells electrophoresed in SDS polyacrylamide gels showed that the antigenic determinant is present in proteins of molecular weight 58,000 which comigrates with vimentin. Thus, it appears that the neurofibrillary tangles in SDAT share an antigenic determinant with vimentin.

CSF and serum samples from 16 AIDS patients were tested for the presence of anti-HIV antibodies either by classical serological methods or by an immunoblot technique based on agarose gel isoelectric focusing and transfer of the specific IgG antibodies onto HIV antigens-loaded nitrocellulose sheets. This method enabled the demonstration of an intrathecal synthesis of anti-HIV oligoclonal IgG antibodies, often superimposed on diffuse polyclonal production, in 14 patients. The two negative cases were devoid of neurological signs or symptoms. However, two patients classified in stage II of the disease (asymptomatic infection) displayed an intrathecal synthesis of anti-HIV antibodies.

Previous studies have indicated an increase in brain-reactive antibodies (BRA) in sera of aging mammals and an autoimmune disorder underlying senescence has been suggested. Since New Zealand Black (NZB) mice have a shorter lifespan and greater propensity for autoimmune diseases than C57BL/6 mice, various age groups from both strains of mice were investigated for simultaneous occurrence of BRA serum titer and deficits in learning. NZB mice exhibited a marked learning deficit as well as higher BRA levels at all ages. C57BL/6 mice showed increased BRA and a learning deficit only at advanced ages. The findings of "precocious" BRA titers along with marked learning deficits, both occurring at young ages in NZB mice and both similar to defects seen in the normal mice at senescence and in patients with senile-dementia, suggest that NZB mice may serve as a useful animal model of pre-senile dementia.

A 50,000-dalton polypeptide has been purified from fractions enriched with neurofibrillary tangles of paired helical filaments from human autopsy specimens of Alzheimer disease and senile dementia of the Alzheimer type. An antiserum to this polypeptide was raised in a rabbit. This antiserum formed an immunoprecipitation line with the purified antigen and with human neurotubules in ouchterlony double-diffusion plates. The reactivity of the anti-paired helical filament protein serum with neurofibrillary tangles was studied by immunofluorescence on cryostat sections of hippocampus from Alzheimer autopsy tissue and by the peroxidase-antiperoxidase technique on paraffin sections of an Alzheimer brain biopsy. The tangles were stained with the antiserum in both systems. Preimmune rabbit serum and unrelated hyperimmune sera, used as controls, did not stain the tangles. These results show that the 50,000-dalton polypeptide purified from the neurofibrillary tangle-enriched fractions is a constituent of Alzheimer neurofibrillary tangles and, perhaps, of the paired helical filaments of which the tangles are composed.

Albumin and IgG have been determined in the serum and cerebrospinal fluid (CSF) of 64 patients affected by Alzheimer's disease and senile dementia of Alzheimer type (SDAT/AD), 17 multi-infarct dementia (MID) patients and 52 controls. The concentrations of albumin and IgG in the serum and CSF have been taken into account to evaluate the integrity of the blood-brain barrier (BBB) and the occurrence of intrathecal immunological activation in demented patients. Clear-cut signs of BBB damage have been shown only in the group of patients affected by MID, whilst none of the two groups of patients displayed signs of immunological activation, expressed by an increase in IgG index, nor abnormally low CSF/serum ratios for IgG, previously suggested as expressive of a "consumption" of IgG by the brain parenchyma.

Peripheral blood from patients with Alzheimer's disease, elderly normal subjects and young (normal subjects) was examined with respect to leucocyte phenotypes and proliferative responses to lectins. Whole blood cell analysis showed that the neutrophil count was similar in all three groups. However, the lymphocyte count was depressed in the Alzheimer group. The monocyte count was reduced in the healthy aged and further reduced in the Alzheimer group. Analysis of peripheral blood mononuclear cells showed no change in the proportion of E+ cells, total T determined with the monoclonal antibody UCHT1 (similar to OKT3) and the T cell subsets: active E and T dot (discrete esterase staining). However, the proportion of T cells bearing the antigen detected by UCHT3 monoclonal antibody (similar to Leu 1 and OKT1) was reduced in the healthy aged and further reduced in the Alzheimer group. Proliferative responses to PHA, Con A, PA, and PWM were similarly depressed in both the aged and Alzheimer groups.

A technique whereby immune complexes (ICs) are detected in the CSF and serum from their inhibitory effect on the agglutination of IgG-coated latex particles by rheumatoid factor (RF) has been applied to patients with the following neurological diseases: multiple sclerosis (MS), inflammatory diseases, extradural peripheral neuropathies (EPN), CNS tumors, dementia, and a control group of other neurological diseases (OND). The groups did not differ significantly in respect of IC positivity either in CSF or serum. The MS group was tested for correlations between percentage of IC positives and CSF IgG/Albumin ratio on the one hand and presence of oligoclonal bands on isoelectric focusing on the other. The specificity of ICs to the dysimmune condition is discussed.

Neurologic complications and cerebrospinal fluid (CSF) abnormalities are common in AIDS. We found that a substantial number of AIDS patients with neurologic involvement had oligoclonal IgG bands in CSF and sera by IEF. Using an IEF-Ag overlay technique, anti-gp120 antibody activity was demonstrated more frequently than anti-p24 antibody activity. These antibody activities exhibited restricted heterogeneity of their IEF pattern; this restriction may contribute to the relatively low titers of neutralizing antibody found in AIDS sera. None of the CSF and serum oligoclonal bands showed anti-HIV antibody activity, suggesting that they are directed against opportunistic agents or result from immunodysregulation.

The study population consisted of 1010 in patients and 81 control subjects. Patients suffering from schizophrenia, cerebral atrophy of unknown origin, dementia, depression, mental retardation, and ethanol-induced brain deterioration (alcoholics) were skin tested with 25 micrograms of S-100 protein and neuron-specific enolase isolated from fresh human brain. Evaluation of delayed skin hypersensitivity reactions at 24 hr revealed a high incidence of positive responses to S-100 protein: heavy alcoholism, 96.8%; depression, 94.1%; cerebral atrophy, 92.6%; dementia, 91.2%; schizophrenia, 87.7%; and mental retardation, 69.4%. The incidence of positive reactions to neuron-specific enolase in schizophrenics was 91.6%. Of 58 control subjects tested with S-100 protein, 6.8% were positive, whereas of 23 normal individuals tested with neuron-specific enolase, 6.4% developed mild skin reactions. These data suggest a close relationship between delayed hypersensitivity to neural tissue antigens and immunopsychiatric diseases, and they imply that cell-mediated immune mechanisms are involved in the pathogenesis of certain mental disorders.

To confirm and extend previous observations concerning the correlation between cell-mediated immunity and psychiatric diseases, 511 patients with schizophrenia, cerebral atrophy, dementia, and mental retardation, and 32 control subjects and 27 control patients were skin-tested with human brain S-100 protein and human liver protein: 70.2-93.1% of tested psychiatric patients developed positive skin hypersensitivity reactions to S-100 protein, while 2.8-20.7% of patients reacted to liver protein. Of control subjects, 6.2-7.4% responded to S-100 protein, and 7.4-9.4% to liver protein. The findings indicate that cell-mediated immune processes may be involved in brain mechanisms underlying cerebral atrophy, depression, dementia, schizophrenia, and mental retardation.

Scrapie-associated fibrils (SAF) are disease-specific markers for the unconventional agent-induced, transmissible spongiform encephalopathies. Polyclonal rabbit antiserum to SAF protein was reacted with brain sections from scrapie-infected mice, two familial cases of transmissible dementia, and three cases of Alzheimer's disease (AD). Specific immunostaining of cerebral amyloid plaques occurred in the scrapie-infected mice and in the two familial cases of transmissible dementia. No immunoreactivity was detected in senile plaques or neurofibrillary tangles in the three cases of AD. Our results suggest that SAF, the causative pathogenic agent, and extracellular deposits of amyloid in the brain are closely related. Immunohistochemical detection of SAF protein could serve as a useful diagnostic adjunct in the postmortem evaluation of difficult cases of dementia. The identification of SAF protein in the brains of two affected members of a family combining the clinical and pathological features of Creutzfeldt-Jakob disease (CJD) and the Gerstmann-Straüssler syndrome (GSS) substantiates earlier conclusions of a nosological relationship between the two. Our study provides further evidence of the similarity of SAF protein to prion protein (PrP 27-30).

Patients with human immunodeficiency virus (HIV) have often progressive dementia. Human T cell lymphotropic virus Type I (HTLV-I) infection has not been reported to cause dementia. We tested antibodies to HTLV-I and HIV in serum and cerebrospinal fluid in 69 Finnish patients referred because of dementia to an outpatient department of neurology. No antibodies to HTLV-I and HIV were detected in patients with the clinical diagnosis of Alzheimer's disease, vascular dementia, secondary dementia due to a specific cause, or in cases of atypical dementia.