Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia.

Heterozygous mutations in GBA1, the gene which encodes the lysosomal enzyme glucocerebrosidase (GCase), are a strong genetic risk factor for the development of Lewy body dementia (LBD). Until this point however, recapitulation of the symptoms and pathology of LBD has been limited to a homozygous GBA1 mouse model which genetically and enzymatically reflects the lysosomal storage disorder Gaucher's disease. This study reports for the first time cognitive impairment by two independent behavioural tests in heterozygous GBA1 mutant mice (D409V/WT) which demonstrate significant cognitive impairment by the age of 12 months. Furthermore, reductions in GBA1 GCase enzyme activity within the brain reflects levels seen in sporadic and GBA1 mutant LBD patients. While there is no overt deposition of Lewy bodies within the hippocampus, alterations to cholinergic machinery and glial proliferation are evident, both pathological features of LBD. Interestingly, we also describe the novel finding of significantly reduced GBA2 GCase enzyme activity specifically within the hippocampus. This suggests that reduced GBA1 GCase enzyme activity dis-equilibrates the finely balanced glycosphingolipid metabolism pathway and that reductions in GBA2 GCase enzyme could contribute to the pathological and behavioural effects seen. Overall, this study presents evidence to suggest that pathological hallmarks associated with LBD specifically affecting brain regions intrinsically linked with cognition are present in the D409V/WT mice. In the absence of Lewy body deposition, the D409V/WT mice could be considered an early pre-clinical model of LBD with potential for drug discovery. Since few robust pre-clinical models of LBD currently exist, with further characterization, the mouse model described here may contribute significantly to developments in the LBD field.

Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.

AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. RESULTS: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P < 0.05) but did not withstand correction for multiple testing. APOE (P = 0.02) and CLU (P = 0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.

Minimally invasive enteroscopically guided small bowel resection.

Localisation of small bowel pathology is often difficult, especially intramural small bowel lesions. Even with the use of laparoscopy, visualisation of small bowel lesion is not always possible. The most accurate method to identify such a lesion is by laparotomy with direct visualisation and palpation of the lesion. However, the recent trend in surgical development aims for minimally invasive procedures while keeping the excision of surgical pathology safe and complete, with less surgical trauma. This report illustrates a case of minimally invasive enteroscopically guided small bowel resection.

Vesicular glutamate transporter and cognition in stroke: a case-control autopsy study.

OBJECTIVES: Vascular dementia (VaD) accounts for approximately 15%-20% of all dementias, but the relationship of progressive cognitive impairment to neurochemical changes is poorly understood. We have therefore investigated glutamatergic synaptic markers in VaD. METHODS: We used homogenates prepared from gray matter from 2 neocortical regions (Brodmann area [BA] 9 and BA 20) and Western blotting to determine the concentrations of key components of the glutamatergic neurotransmitter system, vesicular glutamate transporter 1 (VGLUT1) and excitatory amino acid transporter EAAT2 (GLT-1), and the ubiquitous synaptic protein, synaptophysin, in 73 individuals-48 patients with cerebrovascular disease with and without dementia, 10 patients with AD, and 15 controls-in a case-control design. RESULTS: VGLUT1 concentrations in BA 20 and BA 9 were correlated with CAMCOG total (Rs 0.525, p = 0.018, n = 20; Rs 0.560, p = 0.002, n = 27) and CAMCOG memory scores (Rs 0.616, p = 0.004, n = 20; Rs 0.675, p = 0.000, n = 27). VGLUT1 concentration in BA 9 differed between the different dementia groups and the stroke no dementia group (1-way analysis of variance F = 6.69, p = 0.001 and Bonferroni p < 0.01 in each case), with subjects with stroke who did not develop dementia exhibiting the highest mean value for VGLUT1. CONCLUSIONS: These data suggest that loss of glutamatergic synapses is a feature of VaD and Alzheimer disease but the preservation of synapses, in particular glutamatergic synapses, in the frontal cortex against the temporal cortex plays a role in sustaining cognition and protecting against dementia following a stroke.

Altered glutamate neurotransmission and behaviour in dementia: evidence from studies of memantine.

Behavioural symptoms are a significant problem in Alzheimer's disease (AD). Symptoms including agitation/aggression and psychosis reduce patient quality of life, significantly increase caregiver burden, and often trigger nursing home placement. Underlying changes in the serotonergic, noradrenergic and cholinergic systems have been linked to some behavioural problems, however, the use of antipsychotics in this population has been associated with significant safety concerns. A role for the glutamate system in schizophrenia, as well as in anxiety and depression, has been suggested, and evidence is emerging for a role for dysfunctional glutamate neurotransmission (via N-methyl-D-aspartate (NMDA) receptors) in certain behavioural changes in dementia. For example, the NMDA receptor antagonist, memantine has been shown to improve cognition, function (activities of daily living, ADLs) and, more recently, agitation/aggression, and delusions in AD patients. To date, little information is available regarding the neurochemical basis of agitation/aggression. However, the frontal and cingulate cortices--specifically, the formation of neurofibrillary tangles in glutamatergic pyramidal neurones of these areas--are proposed as regional substrates of these behaviours. Given that memantine displays a favourable tolerability profile, it is relevant to investigate the underlying mechanism linking memantine with the behavioural elements of AD. One hypothesis proposes that memantine corrects dysfunctional glutamatergic neurotransmission in the frontal and cingulate cortices, thereby normalising pathways responsible for causing agitation. An alternative hypothesis is based on the observation that increased tangle formation is associated with agitation, and on recent studies where memantine has been shown to reduce tau phosphorylation via glycogen synthase kinase (GSK)-3 or activation of protein phosphatase (PP)-2A, which might subsequently lead to reduced agitation.

Loss of [3H]4-DAMP binding to muscarinic receptors in the orbitofrontal cortex of Alzheimer's disease patients with psychosis.

RATIONALE: Neuropsychiatric behaviours in Alzheimer's disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic receptors have a role to play in AD behavioural symptoms. OBJECTIVES: To correlate the alterations of neocortical postsynaptic muscarinic receptors with clinical features of AD. MATERIALS AND METHODS: [(3)H]4-DAMP were used in binding assays with lysates of Chinese hamster ovary (CHO) cells stably transfected with M1-M5 receptors. [(3)H]4-DAMP was further used to measure muscarinic receptors in the postmortem orbitofrontal cortex of aged controls and AD patients longitudinally assessed for cognitive decline and behavioural symptoms. RESULTS: [(3)H]4-DAMP binds to human postmortem brain homogenates and M1-, M3-, M4- and M5-transfected CHO lysates with subnanomolar affinity. Compared to the controls, the [(3)H]4-DAMP binding density is reduced only in AD patients with significant psychotic symptoms. The association between reduced [(3)H]4-DAMP binding and psychosis is independent of the effects of dementia severity or neurofibrillary tangle burden. CONCLUSIONS: This study suggests that the loss of non-M2 muscarinic receptors in the orbitofrontal cortex may be a neurochemical substrate of psychosis in AD and provides a rationale for further development of muscarinic receptor ligands in AD pharmacotherapy.

Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.

RATIONALE: Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer's disease (AD). OBJECTIVES: To evaluate in FTD with the major histologies, and compare with AD and controls, neurotransmission indices, as these may help in developing treatment. MATERIALS AND METHODS: Post-mortem grey matter from Brodmann Area 21, 9 and 7 of 51 brains was assayed for ten neurochemical parameters indexing neurotransmission. Repeated measures analyses of variance were carried out for each parameter comparing groups (FTD vs AD vs control) at each anatomical site. RESULTS: In FTD only the indices of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, serotonin (5-HT)(1A) and 5-HT(2A) receptors were significantly reduced from control values. Of the ten parameters only 5-HT(1A) receptors showed significant group x site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M(1), N-methyl-D: -aspartate, NMDA, and kainate), choline acetyltransferase (ChAT) activity, 5-HT and 5-hydroxyindoleacetic acid content and 5-HT reuptake site values were not significantly reduced from control values. Only 5-HT, 5-HT reuptake site and ChAT values were significantly higher in FTD than AD. NMDA receptor and ChAT values were significantly reduced from control only in AD. CONCLUSIONS: Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and 5-HT concentration, which are inhibitory on pyramidal neurones, were relatively preserved. This could lead to an excess of extraneural 5-HT causing underactivity of surviving pyramidal neurones. Pharmacotherapy with a 5-HT(1A) receptor antagonist may be indicated.

Genetic variation in the 5-HT2A receptor and altered neocortical [3H] ketanserin binding in Alzheimer's disease.

A common intronic single nucleotide polymorphism (T102C) in the 5-HT2A receptor gene is associated with the development of different neuropsychiatric symptoms, including hallucinations and depressive symptoms in Alzheimer's disease (AD). Differential 5-HT2A receptor binding has also been associated with the development of these symptoms in AD. However, the relationship between 5-HT2A (T102C) genotype and 5-HT2A receptor binding in AD and control human brains has not been examined. We examined the association between different 5-HT2A (T102C) genotypes and [(3)H] ketanserin binding in the temporal and frontal cortex of 20 AD and 14 control human brains. In homozygotes, but not heterozygotes, there was a significant reduction in B(max) values for [(3)H] ketanserin binding in both areas of cortex in AD compared with control subjects. This study suggests a mechanism for the generation of different neuropsychiatric symptoms in AD from a single nucleotide polymorphism with reduced receptor binding in T102C 5-HT2A receptor gene homozygotes correlating with susceptibility to depressive symptoms, whereas the relative preservation of receptor binding in heterozygotes with AD correlating with susceptibility to hallucinations.

Cyclin-dependent kinase 5, Munc18a and Munc18-interacting protein 1/X11alpha protein up-regulation in Alzheimer's disease.

Besides formation of neurofibrillary tangles and neuron loss, the Alzheimer's disease brain is characterized by neuritic plaques consisting of beta-amyloid peptide deposits and impaired neurotransmission. The proteins Munc18a, Munc18-interacting protein 1 and Munc18-interacting protein 2 mediate exocytosis and decrease beta-amyloid peptide formation. Cyclin-dependent kinase 5 and its activator p35 disrupt Munc18a-syntaxin 1 binding, thereby promoting synaptic vesicle fusion during exocytosis. We investigated protein levels of the signaling pathway: p35, cyclin-dependent kinase 5, Munc18a, syntaxin 1A and 1B, Munc18-interacting protein 1 and Munc18-interacting protein 2 in Alzheimer's disease cortex and found that this pathway was up-regulated in the Alzheimer's disease parietal and occipital cortex. In the cortex of transgenic Tg2576 mice over-expressing human beta-amyloid precursor protein with the Swedish mutation known to lead to familial Alzheimer's disease, which have substantial levels of beta-amyloid peptide but lack neurofibrillary tangles and neuron loss, no alterations of protein levels were detected. These data suggest that the pathway is enhanced in dying or surviving neurons and might serve a protective role by compensating for decreased neurotransmission and decreasing beta-amyloid peptide levels early during the progression of Alzheimer's disease.

Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease.

Neuropsychiatric symptoms seen in Alzheimer's disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in post-mortem frontal and temporal cortex from 22 AD patients who had been prospectively assessed with the Mini-Mental State examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD including aggressive behavior, overactivity, depression and psychosis. Not only cholinergic deficits, but also the cholinacetyltransferase/serotonin ratio significantly correlated with final MMSE score both in frontal and temporal cortex. In addition, decreases in cholinergic function correlated with the aggressive behavior factor, supporting a dual role for the cholinergic system in cognitive and non-cognitive disturbances associated to AD. The serotonergic system showed a significant correlation with overactivity and psychosis. The ratio of serotonin to acetylcholinesterase levels was also correlated with the psychotic factor at least in women. It is concluded that an imbalance between cholinergic-serotonergic systems may be responsible for the cognitive impairment associated to AD. Moreover, the major findings of this study are the relationships between neurochemical markers of both cholinergic and serotonergic systems and non-cognitive behavioral disturbances in patients with dementia.

Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.

RATIONALE: Previous studies have demonstrated reductions of serotonin 5-HT 2A receptors in the neocortex of Alzheimer's disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD. OBJECTIVES: To correlate neocortical 5-HT 2A receptor alterations with cognitive decline in AD. METHODS: Postmortem frontal and temporal cortical 5-HT 2A receptors were measured by [3H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms. RESULTS: 5-HT 2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT 2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms. CONCLUSIONS: Our data suggest that loss of neocortical 5-HT 2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.

Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer's disease.

Growing evidence suggests that a compromised serotonergic system plays an important role in the pathophysiology of Alzheimer's disease (AD). We assessed the expression of 5-HT(1B/1D) and 5-HT(6) receptors and cholinacetyltransferase (ChAT) activity in post-mortem frontal and temporal cortex from AD patients who had been prospectively assessed for cognitive function using the Mini-Mental State Examination (MMSE) and behavioral changes using the Present Behavioral Examination (PBE). 5-HT(1B/1D) and 5-HT(6) receptor densities were significantly reduced in both cortical areas. 5-HT(1B/1D) receptor density was correlated to MMSE decline in the frontal cortex, supporting its implication in memory impairment. The best predictor for lowered 5-HT(6) receptor density in the temporal cortex was the PBE measure of overactivity. The 5-HT(6)/ChAT ratio was related to aggression both in the frontal and temporal cortex. Therefore, antagonists acting at 5-HT(6) receptors could be useful in the treatment of non-cognitive symptoms associated to AD.

[3H]GR113808 binding to serotonin 5-HT(4) receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study.

Abnormalities in neural transmission of serotonin (5-HT) may play a role in both cognitive and neuropsychiatric features of Alzheimer disease (AD). We measured 5-HT(4) receptors in the postmortem frontal and temporal cortex of 34 AD subjects and 15 controls by radioligand binding with [3H]GR113808. Receptor binding data was then correlated with prospectively assessed cognitive (Mini-Mental State Examination, MMSE) and behavioral (Present Behavioural Examination, PBE) data. [3H]GR113808 binding affinity (K(D)) and density (B(max)) in AD were unchanged compared to controls in both cortical regions, and did not correlate with MMSE or PBE data. The binding parameters were also not related to disease duration, senile plaque and neurofibrillary tangle counts, and neuroleptic medication. We conclude that unlike other 5-HT receptors, 5-HT(4) receptor binding affinity and density do not seem to be affected in the frontal and temporal cortex in AD and may not have a direct role in the clinical features of the disease.

Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease.

Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%-28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.

Psychosis of Alzheimer's disease is associated with elevated muscarinic M2 binding in the cortex.

OBJECTIVES: Results from recent drug trials suggest a role for the cholinergic system in the manifestation of neuropsychiatric symptoms in AD. To date, the status of muscarinic acetylcholine receptor subtypes in AD in relation to accompanying behavioral disturbances is unknown. This study aimed to measure alterations of muscarinic M(1) and M(2) receptor binding in the frontal and temporal cortex of AD and to correlate the neurochemical findings with clinical features. METHODS: The cognitive and behavioral features of 26 patients with AD were assessed prospectively using standardized tests. Together with 14 matched controls, the status of muscarinic M(1) and M(2) receptors in the postmortem frontal and temporal cortex of these patients were measured by radioligand binding assays and were correlated with clinical data. RESULTS: Compared with controls, M(2) receptor density was reduced only in the frontal cortex of AD, whereas M(1) was unaffected. Within the AD group, the neurochemical variables were not affected by demographic factors, disease severity, or cognition. Instead, M(2) receptor density was increased in the frontal and temporal cortex of patients with AD with psychotic symptoms compared with those without these symptoms. CONCLUSIONS: This study suggests a role for M(2) receptors in the psychosis of AD and may provide the rationale for treatment of behaviorally perturbed patients with AD with cholinomimetics and M(2) antagonists.

Chronic elevation of amyloid precursor protein in the neocortex or hippocampus of marmosets with selective cholinergic lesions.

In vitro studies have consistently demonstrated a link between cholinergic neurotransmission and amyloid precursor protein metabolism, although few studies have examined such a relationship in vivo and none have been conducted in primate species. The purpose of this study was to test the hypothesis that a reduction in cholinergic activity in neocortical and hippocampal areas consequent upon destruction of ascending cholinergic projections may lead to long-term changes in levels of amyloid precursor protein in these target areas in a primate species. The status of three synaptic proteins associated with neurotransmitter release, synaptophysin, syntaxin and SNAP-25, was also been examined. Selective immunolesions of the basal forebrain cholinergic projections led to increases in amyloid precursor protein-like immunoreactivity in hippocampus and cortex, measured 8 months postlesion. Furthermore, reductions in cortical and hippocampal SNAP-25, but not syntaxin or synaptophysin, immunoreactivity were observed. These results imply that the reduced cholinergic activity characteristic of Alzheimer's disease may contribute to the continuing emergence of neuropathology in addition to the well-known association with cognitive dysfunction.

Expression of amyloid precursor protein, tau and presenilin RNAs in rat hippocampus following deafferentation lesions.

In this study, entorhinal cortex lesions and/or medial septal area cholinergic lesions were used in the rat to mimic some of the principal and earliest affects in Alzheimer's disease, namely hippocampal deafferentation. We wished to test the hypothesis that deafferentation lesions cause changes in the regulation of three proteins that are known to be important in Alzheimer's disease pathology, namely amyloid precursor protein, presenilin and tau. Expression of amyloid precursor protein mRNA was increased in several subfields of hippocampus when examined 1 week after entorhinal cortex lesion, but was reduced, compared to sham operated controls, after medial septal area cholinergic lesions. Cholinergic lesions were combined with entorhinal cortex lesions and produced no change in APP mRNA levels compared to controls. No significant changes were observed in the parietal cortex after entorhinal cortex or cholinergic lesions either alone or in combination. Tau mRNA level in hippocampus was unchanged after lesions. Presenilin-1 mRNA was expressed in the hippocampus at very low levels, and appeared to be increased following entorhinal cortex lesion. Our results support the hypothesis that amyloid precursor protein expression in hippocampal neurons is differentially affected by glutamatergic and cholinergic afferent input, and that presenilin-1, but not tau, may be subject to the same type of control in vivo.

Brain aging research at the close of the 20th century: from bench to bedside.

Remarkable and continued growth in the field of brain aging research has been fueled by a confluence of factors. Developments in molecular biology, imaging, and genetics coupled with the imperative caused by the aging of the population has created fertile ground for improved understanding of the interaction between brain function and behavior. Aging changes in neurochemical systems may account for the spectrum of cognitive and behavioral states of successfully aged pen sons, but may also contribute to enhanced vulnerability to depressive or dementing illness. In particular, the refinement of in vivo imaging approaches to investigating the structure and function of the aging brain has provided the opportunity to strengthen our knowledge of the biological substrate of the aging brain and neuropsychiatrie disorders, and translate these into therapeutics.

Cholinergic deficits contribute to behavioral disturbance in patients with dementia.

BACKGROUND: Noncognitive behavioral changes such as depression, aggressive behavior, psychosis, and overactivity occur frequently in patients with dementia, in addition to cognitive impairment, and often determine the need for institutionalization. The biochemical basis of such changes is poorly understood. Clinical trial data indicate that cholinomimetics improve noncognitive behaviors. This study investigated the relationship between markers of the cholinergic and dopaminergic neurotransmitter systems and noncognitive behavioral symptoms assessed during the course of dementing illness. METHOD: Brains from 46 patients with dementia (36 with AD and 10 with mixed or other dementias using Consortium to Establish a Registry for AD criteria) were examined together with 32 normal controls. The patients with dementia had been evaluated every 4 months, often over several years, for cognitive performance (Mini-Mental State Examination) and behavior (Present Behavioral Examination). Concentrations of dopamine (DA) and major metabolites, choline acetyltransferase activity (ChAT), and density (Bmax) of DA D1 receptors in frontal and temporal cortex were studied by radioligand binding protocols. None of the patients was receiving cholinomimetic drugs. RESULTS: ChAT activity, but no other neurochemical markers, was reduced in AD compared with controls. Loss of ChAT activity correlated with cognitive impairment. Lowered ChAT activity also correlated with increasing overactivity in patients with dementia in both frontal and temporal cortex whereas ChAT:DA and ChAT:D1 ratios in temporal cortex correlated negatively with aggressive behavior. CONCLUSIONS: Disturbance of the cholinergic system may underlie both cognitive and some noncognitive behavioral changes in dementia, providing a basis for rational therapy.-1467