Alzheimer's disease paired helical filaments contain abnormally phosphorylated tau (PHF-tau) which has reduced electrophoretic mobility on sodium dodecyl sulphate polyacrylamide electrophoresis. We have investigated the...Alzheimer's disease paired helical filaments contain abnormally phosphorylated tau (PHF-tau) which has reduced electrophoretic mobility on sodium dodecyl sulphate polyacrylamide electrophoresis. We have investigated the effects of cyclic-AMP-dependent protein kinase (PKA) on recombinant human tau isoforms and two recombinant tau fragments. PKA phosphorylated tau and reduced its electrophoretic mobility, phosphorylation towards the C-terminus of tau having a major influence on this property. Substitution of serine396 (phosphorylated in PHF-tau) or serine416 (phosphorylated by calcium/calmodulin kinase II) by alanine demonstrated that these are not major sites for PKA phosphorylation. Although the phosphorylated forms of tau generated by PKA are not identical to those of PHF-tau, PKA may be involved in the generation of PHF-tau in Alzheimer's disease via phosphorylation of additional, as yet unidentified, sites on tau.
The density of diffuse, primitive, classic and compact beta/A4 deposits was estimated in the cortex and hippocampus in Alzheimer's disease (AD) cases with and without pronounced congophilic angiopathy (CA). The total den...The density of diffuse, primitive, classic and compact beta/A4 deposits was estimated in the cortex and hippocampus in Alzheimer's disease (AD) cases with and without pronounced congophilic angiopathy (CA). The total density of beta/A4 deposits in a given brain region was similar in cases with and without CA. Significantly fewer diffuse deposits and more primitive/classic deposits were found in the cases with CA. The densities of the primitive, classic and compact deposits were positively correlated in the cases without CA. However, no correlations were observed between the density of the mature subtypes and the diffuse deposits in these cases. In the cases with CA, the density of the primitive deposits was positively correlated with the diffuse but not with the classic deposits. The data suggest that the mature beta/A4 deposits are derived from the diffuse deposits and that the presence of pronounced CA enhances their formation.
The current study examined changes in the dendritic arbor of basolateral amygdaloid neurons in Alzheimer's disease (AD). Quantitative analysis of Golgi Kopsch-impregnated tissue samples revealed a significant reduction i...The current study examined changes in the dendritic arbor of basolateral amygdaloid neurons in Alzheimer's disease (AD). Quantitative analysis of Golgi Kopsch-impregnated tissue samples revealed a significant reduction in the total dendritic length per neuron in AD. Terminal and nonterminal dendritic segments were affected similarly. Somatofugal ordering of the same segments, however, indicated that the reductions were restricted to the inner portion of the dendritic tree, coupled with significant AD-related increases in the length and number of the highest order segments. These data suggest that despite an overall AD-related loss of dendritic length in this amygdaloid subregion, new dendritic segments continue to form. The loss of proximal segments, combined with the gain of distal segments, may be interpreted as dendritic remodeling in the course of the disorder.
The galanin (GAL) containing peptide fiber system circuit which innervates acetylcholine containing basal forebrain neurons has been shown to hypertrophy and hyperinnervate remaining cholinergic Ch4 perikarya in Alzheime...The galanin (GAL) containing peptide fiber system circuit which innervates acetylcholine containing basal forebrain neurons has been shown to hypertrophy and hyperinnervate remaining cholinergic Ch4 perikarya in Alzheimer's disease (AD). The present study examined whether a similar hyperinnervation occurs within the cholinergic vertical limb of the diagonal band nucleus (Ch2), a portion of the basal forebrain which, unlike Ch4, exhibits only modest degeneration in AD. Furthermore, we evaluated whether GAL hyperinnervation occurs within the basal forebrain in Down's syndrome, a genetic disorder with extensive AD-like pathology including cholinergic basal forebrain neuron degeneration. The present study revealed that virtually all Ch2 neurons were GAL immunonegative. However, this region was innervated by GAL immunoreactive (ir) interneurons and fibers associated with a major galaninergic pathway which travels through the substantia innominata enroute to the hypothalamus, bed nucleus of the stria terminalis as well as vertical limb of diagonal band nucleus. GAL-ir fibers coursing within this fiber bundle hypertrophied in AD relative to age matched controls and the Down's cases. Within the putative Ch2 terminal zones in AD, many of the remaining cholinergic neurons were hyperinnervated by GAL despite the modest reduction in Ch2 neurons. In contrast, GAL-ir fibers were not hypertrophied in Down's syndrome despite extensive cholinergic cell loss within Ch4. Taken together these findings suggest that extensive cholinergic basal forebrain cell loss alone is not sufficient to trigger the basal forebrain GAL plasticity response found in AD.
The empirical literature has been contradictory regarding whether frontal functions decline with age, perhaps due to important differences across studies in medical and psychiatric exclusion criteria. We review literatur...The empirical literature has been contradictory regarding whether frontal functions decline with age, perhaps due to important differences across studies in medical and psychiatric exclusion criteria. We review literature and present preliminary data suggesting that frontal lobe functions are particularly affected by several medical and psychiatric disorders common in old age. Investigations of frontal lobe functions in aging require careful screening of subject samples; otherwise, any impact of age on cognition is contaminated by the effects of coexistent physical and/or psychiatric illness.
The patterns of language disorder associated with 'progressive aphasia' due to lobar atrophy were compared with the language dysfunction of patients with dementia of frontal lobe type (DFT). The progressive aphasias were...The patterns of language disorder associated with 'progressive aphasia' due to lobar atrophy were compared with the language dysfunction of patients with dementia of frontal lobe type (DFT). The progressive aphasias were characterised primarily by impairment at the structural levels of language: phonology, grammar and semantics, whereas DFT was associated primarily with spontaneity and loss of generative capability. However, there was overlap in language symptomatology, particularly with progression of disease. The findings lend support to the argument that progressive aphasia and DFT represent different clinical manifestations of a common pathology, and form part of the spectrum of lobar atrophies.
The quality of the neuropsychological investigation of behavioural changes in frontal dementias is dependent on the specificity of the behavioural analyses. A review of methodological issues and published findings identi...The quality of the neuropsychological investigation of behavioural changes in frontal dementias is dependent on the specificity of the behavioural analyses. A review of methodological issues and published findings identifies possible potential reasons for misinterpretation of research neuropsychological data in these studies. The areas reviewed include the operational definitions of terms such as 'frontal lobes' and 'frontal functions'; identification of experimental limitations in frontal lobe research; and highlights of neuropsychological investigations of frontal lobe functions. These deliberations suggest a practical approach to the behavioural assessment of frontal dementias.
Neuropsychological investigations were performed on 18 patients with a clinical diagnosis of frontal lobe dementia supported by regional cerebral blood flow measurements. Nature and degree of cognitive impairment were ex...Neuropsychological investigations were performed on 18 patients with a clinical diagnosis of frontal lobe dementia supported by regional cerebral blood flow measurements. Nature and degree of cognitive impairment were examined with a comprehensive test battery. The results of the neuropsychological assessment could be described as three levels of cognitive impairment. The increasing levels of cognitive impairment were accompanied by corresponding levels of reduced cerebral blood flow in frontotemporal areas. No apparent relationship emerged between impairment level and illness duration, indicating a considerable individual variation in the clinical course of frontal lobe dementia.
The behavioral, neuropsychological and single photon emission computerized tomography characteristics of 5 patients with progressive degeneration of the right hemisphere are described. In all, the brain regions with grea...The behavioral, neuropsychological and single photon emission computerized tomography characteristics of 5 patients with progressive degeneration of the right hemisphere are described. In all, the brain regions with greatest involvement were right-frontal and temporal. Psychosis, compulsions and behavioral disinhibition were the dominant, and often first, symptoms. Affect was flattened and the patients seemed distant and remote. Neuropsychological testing did not reveal a consistent pattern that helped localize the abnormality to the right frontotemporal region. These patients contrast dramatically to those with left frontotemporal degeneration in whom behavior and psychiatric status is often normal. This study suggests that the right hemisphere may be primary for the control of social conduct.
A 58-year-old man developed progressive difficulty with comprehension and verbal output with dementia. Positron emission tomography with 18F 2-fluoro-2-deoxy-D-glucose demonstrated asymmetrical frontal and anterior tempo...A 58-year-old man developed progressive difficulty with comprehension and verbal output with dementia. Positron emission tomography with 18F 2-fluoro-2-deoxy-D-glucose demonstrated asymmetrical frontal and anterior temporal lobe loss of glucose use. Scopolamine infusion (0.3 mg) did not influence memory. Postmortem studies revealed evidence of Pick's disease, with Pick bodies, loss of somatostatin, preservation of choline acetyltransferase and immunostaining with neurofilament antibodies. Pharmacological challenge and positron imaging offer valuable means for the noninvasive assessment of dementing illness. The contributions of functional imaging to our knowledge of frontal involvement in dementing illness are reviewed.
The present study examined the utility of the Word Fluency Test (WFT) as a frontal-lobe-activating test in brain imaging. Regional cerebral blood flow (rCBF) was measured during rest and during the WFT in 49 healthy volu...The present study examined the utility of the Word Fluency Test (WFT) as a frontal-lobe-activating test in brain imaging. Regional cerebral blood flow (rCBF) was measured during rest and during the WFT in 49 healthy volunteers and in 15 patients with frontal lobe dementia (FLD). The results showed a highly significant frontal lobe activation in 85% of the normal subjects. This finding was not related to age or to the level of performance on the WFT. A significant frontal activation was seen in 13 of the 15 FLD patients. The frontal flow increase did not reach normal levels, and was not related to age, illness duration or severity of clinical symptoms. The results suggest that the WFT is an ideal test to use in conjunction with functional imaging in normals as well as in patients with organic dementia.
Twenty-five out of 26 cases of autopsy-verified frontal lobe degeneration of non-Alzheimer type (FLD) were found to have focal frontal or frontotemporal blood flow reductions involving both hemispheres. The deviant case...Twenty-five out of 26 cases of autopsy-verified frontal lobe degeneration of non-Alzheimer type (FLD) were found to have focal frontal or frontotemporal blood flow reductions involving both hemispheres. The deviant case had an asymmetric frontal pathology only apparent on the right side. Focal reduction of blood flow in the frontal lobes is, however, a common and unspecific flow abnormality found in e.g. Pick's disease. Creutzfeldt-Jakob's disease, and in some cases of Alzheimer's disease. Low frontal flow has also been reported in schizophrenia and in toxic encephalopathy. Since a characteristic feature of FLD is a steady progress of the pathology, serial flow measurements extending over several years are especially informative.
Molecular genetics has led to considerable advances in our understanding of the transmissible spongiform encephalopathies. The identification of pathogenic mutations in the prion protein gene has enabled a molecular recl...Molecular genetics has led to considerable advances in our understanding of the transmissible spongiform encephalopathies. The identification of pathogenic mutations in the prion protein gene has enabled a molecular reclassification of the familial forms of these diseases, which may now be referred to as inherited prion diseases. Prion diseases of both humans and animals are associated with deposition of an abnormal isoform of a host-encoded protein, the prion protein (PrP). Human prion diseases have inherited, sporadic and acquired forms. A considerable body of evidence now supports the idea that the transmissible agent in these diseases may be an abnormal isoform of the prion protein. The identification of pathogenic mutations in the PrP gene has enabled the identification of cases of inherited prion disease that would not have been recognised using existing clinical and pathological diagnostic criteria. Since marked clinical and neuropathological overlap between the different neurodegenerative disorders is well recognised, PrP gene analysis is of increasing importance in differential diagnosis. Frontal lobe dementia of non-Alzheimer type and Pick's disease share a number of important clinical and pathological features with prion diseases, and could be considered as candidate prion diseases. However, we have not been able to demonstrate either PrP mutations or the presence of the disease-associated isoform of prion protein in several well-characterised families with these disorders.
Non-Alzheimer's dementia due to lobar atrophy had choline acetyltransferase activities comparable with control rather than Alzheimer's disease values, based on 3 autopsy proven cases on Pick's disease and biopsies from 3...Non-Alzheimer's dementia due to lobar atrophy had choline acetyltransferase activities comparable with control rather than Alzheimer's disease values, based on 3 autopsy proven cases on Pick's disease and biopsies from 3 examples of dementia of frontal lobe type. Muscarinic cholinergic receptors were relatively spared only in Alzheimer's disease. Serotonin receptors were markedly reduced (based on Pick cases) whereas measures that reflected presynaptic serotonergic activity were either not affected or increased. Cerebrospinal fluid and brain tissue measurements suggested that inhibitory interneurones and dopamine release were relatively spared. There was no in vitro evidence of hypometabolism.
The two major primary degenerative dementias, dementia of Alzheimer type (DAT) and frontal lobe degeneration of non-Alzheimer type (FLD) have several clinical features in common but also many symptoms that differ. In a c...The two major primary degenerative dementias, dementia of Alzheimer type (DAT) and frontal lobe degeneration of non-Alzheimer type (FLD) have several clinical features in common but also many symptoms that differ. In a clinical material of 80 patients with either of the two forms of dementia (DAT = 39, FLD = 41) we have studied the levels of neuropeptides in the cerebrospinal fluid (CSF) in order to find biochemical markers for CNS affection. The dementia forms were evaluated by careful clinical analysis, psychometric testing and measurement of regional cerebral blood flow. Approximately one third of the subjects died during the completion of the study and neuropathology was performed, confirming the diagnoses. We observed reductions in the CSF levels of antidiuretic hormone and somatostatin in both DAT and FLD. A strong tendency to reduction was noted for neuropeptide Y (NPY). There was a correlation with the duration of disease demonstrating a significant reduction in NPY levels in subjects with DAT. Most notably there was a strong reduction in the levels of delta sleep inducing peptide (DSIP) in DAT cases only. The levels of DSIP in FLD were the same as in controls. The reverse was found for corticotropin releasing factor (CRF) which had a significant reduction in FLD patients but not in those with DAT. The present study indicates a difference in the CSF levels of neuropeptides, observations that these may serve as biochemical markers which differentiate DAT and FLD.
We present genetic linkage data in a large family in which non-specific dementia is inherited as an autosomal dominant trait. We have analyzed 45 highly polymorphic microsatellite sequences and excluded a quarter of the...We present genetic linkage data in a large family in which non-specific dementia is inherited as an autosomal dominant trait. We have analyzed 45 highly polymorphic microsatellite sequences and excluded a quarter of the genome as the site of the pathogenic mutation in this family.
The etiology of frontal lobe dementia of non-Alzheimer type (FLD) is still unknown. There is strong evidence of genetic factors with positive heredity. In this paper, a Swedish family, with several generations affected b...The etiology of frontal lobe dementia of non-Alzheimer type (FLD) is still unknown. There is strong evidence of genetic factors with positive heredity. In this paper, a Swedish family, with several generations affected by FLD is described. In 3 patients typical FLD was confirmed postmortem. The clinical and neuropathological similarities between the patients are impressive.
Three clinical syndromes associated with fronto-temporal cerebral atrophy, studied in one centre are discussed: dementia of frontal type (DFT), DFT and motor neurone disease (MND) and progressive aphasia (PA). The pathol...Three clinical syndromes associated with fronto-temporal cerebral atrophy, studied in one centre are discussed: dementia of frontal type (DFT), DFT and motor neurone disease (MND) and progressive aphasia (PA). The pathological findings in DFT (13 brains), DFT and MND (5 brains) and PA (5 brains) permit a number of clinical pathological groupings. The nosological status of fronto-temporal atrophy is discussed with reference to the literature and it is suggested that a common underlying pathology, including Picks disease as strictly defined by the presence of inclusion bodies, underlies the clinical syndromes, each being determined by the anatomical distribution of the pathology.
A number of causes of progressive mental impairment show a preponderance of frontal lobe symptoms. It is proposed that these disorders can be subdivided into primary and secondary frontal dementias, based on the symptoma...A number of causes of progressive mental impairment show a preponderance of frontal lobe symptoms. It is proposed that these disorders can be subdivided into primary and secondary frontal dementias, based on the symptomatology and the site of major pathological disruption. An anatomical explanation, based on variations in cortical and subcortical influences, aids in understanding the clinical differences.
Frontal lobe degeneration of non-Alzheimer type (FLD) is the second most common primary degenerative dementia in southern Sweden. Clinical findings in 30 FLD cases with postmortem-verified diagnoses are described. FLD st...Frontal lobe degeneration of non-Alzheimer type (FLD) is the second most common primary degenerative dementia in southern Sweden. Clinical findings in 30 FLD cases with postmortem-verified diagnoses are described. FLD starts in the presenium with a mean disease duration of 7.5 years (range 3-17 years). Clinical onset is insidious and slow and the early stage is dominated by personality changes with lack of insight and judgement and signs of disinhibition. A typical feature is progressive loss of expressive speech with stereotyped phrases, late mutism and amimia. Restlessness, changes of oral/dietary behavior and utilization behavior are prevalent as also psychotic features. Temporal and spatial orientation are usually preserved for a long time in contrast to Alzheimer's disease. Dementia in FLD is similar to that of Pick's disease and ALS with dementia. Early recognition of FLD seems possible based on standardized clinical evaluation supported by neuropsychological tests, measurement of regional cerebral blood flow and other types of brain imaging. The etiology of FLD is unknown but a positive heredity was reported in 60%.