Modelling dementia: effects of scopolamine on memory and attention

Scopolamine, a muscarinic cholinergic antagonist, is capable of inducing transient memory impairment in normal subjects. Against the background of the cholinergic hypothesis of Alzheimer's disease (AD) the present study was designed to investigate the effects of low oral doses of scopolamine on a range of cognitive functions known or hypothesized to be affected in AD. Twenty healthy volunteers (18-48 yr) performed a battery of automated cognitive tasks under each of five treatments: oral scopolamine 0.3 mg, 0.6 mg, 1.2 mg; oral methylscopolamine 0.6 mg; placebo. Alongside analogous tests of verbal and non-verbal memory, the battery enabled assessments of a range of attentional functions: alerting, sustained attention, selective attention, and covert orientation. A profile of effects was observed within and beyond the realm of memory. While some functions were unaffected by the drug (e.g. alerting) and others were impaired at the highest dose (e.g. verbal learning) still others were affected in a linear dose-dependent manner (sustained attention; visual contrast sensitivity). These observations are discussed in the context of the "scopolamine model" of AD.     

Review: Modelling the pathology and behaviour of frontotemporal dementia

Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.     

The dementia of dementia praecox

A group of 18 long-stay patients with a diagnosis of schizophrenia were compared with a group of 10 age-matched subjects who had been institutionalized by reason of physical disease, on performance on tests of intellectual function; and with a group of agematched healthy subjects, both on tests of intellectual function, and radiographically, using the technique of computerized axial tomography (EMI scan) of the brain. By comparison with the normal controls the patients with schizophrenia had increased cerebral ventricular size (assessed as cross-sectional area) and, by comparison with both control groups, showed substantial impairments on intellectual testing. The differences in ventricular area between patients and controls remained significant (P < 0.01) after four patients who had been leucotomized had been excluded. Within the non-leucotomized patient group ventricular area was unrelated to previous neuroleptic medication, ECT or insulin coma therapy, but there was a significant relationship between ventricular area and intellectual impairment (P < 0.01). Intellectual impairment, as assessed by the Withers & Hinton test battery, the Inglis paired associate learning test, and the digits-backward test, was greater (P < 0.05) in patients with negative features (affective flattening, retardation, poverty of speech) than in those without such features. Premorbid occupational histories suggested that nearly all of these patients had at one time functioned at an adequate intellectual level. The findings suggest that within the group of patients with schizophrenia there is a subgroup whose illnesses have hitherto been considered typically schizophrenic, who have severe intellectual impairment associated with evidence of structural brain disease. The size of this subgroup and the significance of the cerebral changes remain to be determined.     

Primary alcoholic dementia and alcohol-related dementia

Clinicopathological issues regarding so‐called ‘alcoholic dementia’ remain under debate. Although clinical observation favors the diagnosis of primary alcohol dementia, caused by direct alcohol neurotoxicity, further confirmation from neuropathological and biochemical perspectives is warranted. Repeat episodes of subclinical Wernicke–Korsakoff’s syndrome may partially account for the chronic state of primary alcoholic dementia, thus supporting the notion that primary alcoholic dementia exists in continuum with chronic and subclinical types of Wernicke–Korsakoff’s syndrome. Diagnostic criteria for alcohol related dementia, as detailed by Oslin et al., represent a purer form of alcoholic dementia and are useful for the scientific discussion of this condition.     

Family history of dementia: dementia with lewy bodies and dementia in Parkinson's disease

Parkinson's disease with dementia (PD-D) and dementia with Lewy bodies (DLB) may result from the same neurodegenerative process with different temporal and spatial courses. The authors report an association between DLB and family history of dementia in a comparison study between patients with a clinicopathological diagnosis of PD-D and DLB. Findings suggest that positive family history for dementia is associated with DLB with a yet unknown mechanism.     

Multi-infarct dementia

Fifty-two patients presenting with dementia were divided into a group in whom clinical features suggested an ischaemic basis (multi-infarct dementia) and a group in whom a primary degenerative process seemed more likely. Focal EEG changes and angiographic evidence of ischeamic areas and atheromatous disease of intracranial vessels were more common in the “ischaemic” than in the primary degenerative group. CBF was significantly reduced in the former but the regional pattern was equally distorted in the two groups. These findings strengthen the belief that the ischaemic score can identify those patients whose dementia is associated with vascular disease.     

Thalamic dementia

Report with complementary clinical examinations and detailed neuropathological findings of a case of subacute progressing "thalamic dementia", interpreted as combined systemic degeneration of the dorsal and medial thalamic nuclei. For the development of the EEG changes, which were followed from beginning of the disease, a slowly advancing reduction of the function of the meso-diencephalic activating system proved responsible. The inferior olives were symmetrically atrophied and the fasciculus tegmenti centralis was on both sides completely degenerated. It is to be considered that the inferior olives are directly subordinated to the medial thalamic nuclei by the way of the fasciculus tegmenti centralis. In the cerebellum nerve cell groups and fiber bundles, which are closely connected with the reticular system, are degenerated. The systemic medial degenerations of the thalamus belong to the abiotrophies in the sense of Gowers original conception.     

Poststroke dementia

Dementia is one of the major causes of dependency after stroke. The prevalence of poststroke dementia (PSD)-defined as any dementia occurring after stroke-is likely to increase in the future. In community-based studies, the prevalence of PSD in stroke survivors is about 30% and the incidence of new onset dementia after stroke increases from 7% after 1 year 48% after 25 years. Having a stroke doubles the risk of dementia. Patient-related variables associated with an increased risk of PSD are increasing age, low education level, dependency before stroke, prestroke cognitive decline without dementia, diabetes mellitus, atrial fibrillation, myocardial infarction, epileptic seizures, sepsis, cardiac arrhythmias, congestive heart failure, silent cerebral infarcts, global and medial-temporal-lobe atrophy, and white-matter changes. Stroke-related variables associated with an increased risk of PSD are stroke severity, cause, location, and recurrence. PSD might be the result of vascular lesions, Alzheimer pathology, white-matter changes, or combinations of these. The cause of PSD differs among studies in relation to the mean age of patients, ethnicity, criteria used, and time after stroke. In developed countries, the proportion of patients with presumed Alzheimer's disease among those with PSD is between 19% and 61%. Patients with PSD have high mortality rates and are likely to be functionally impaired. These patients should be treated according to the current guidelines for stroke prevention.     

Frontotemporal dementia

Frontotemporal dementia (FTD) is a unique neurodegenerative disease that can be differentiated from Alzheimer's disease and other diseases that result in cognitive complaints. The primary anatomic focus of degeneration determines the clinical presentation, which can vary from aphasia to behavioral symptoms. Expanding knowledge about the genetics and biochemistry of FTD may lead to specific treatments.     

Vascular dementia

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's dementia (AD). It is characterized by loss of executive function with milder memory loss as compared with AD and is associated with cerebral brain infarction or hemorrhage. Treatment is predominantly focused on cardiovascular risk factor reduction, but anticholinesterase inhibitors and memantine may play a role. The data is most robust for donepezil.     

Poststroke dementia

The association between stroke and dementia is frequent. The prevalence of poststroke dementia (PSD) ranges from 6 to 32%, depending on the population studied, the criteria used for the diagnosis of dementia, and the time interval between the stroke and the neuropsychological assessment. The risk of PSD is high immediately after stroke and remains higher than in controls in stroke patients nondemented 3 months after stroke. Not all cases of PSD are vascular in origin, with about one third of demented patients diagnosed as having Alzheimer's disease plus stroke. The pathophysiology of PSD is probably multifactorial, with an influence of vascular lesions, associated Alzheimer's lesions and white matter changes. The risk of dementia is higher in older patients and in patients with preexisting cognitive decline - no dementia, severe stroke, a history of stroke, white matter changes and cerebral atrophy. The influence of stroke location, vascular risk factors and silent infarcts remains to be determined. PSD adversely influences the outcome in stroke patients.     

Frontotemporal dementia

PURPOSE OF REVIEW: The syndromes of frontotemporal lobar degeneration are increasingly recognized as an important cause of early-onset dementia. Diagnostic consensus criteria have now been established for almost a decade, and form the framework for its clinical classification. While these criteria remain useful, a growing body of evidence suggests that revisions may be necessary to improve their validity and applicability. RECENT FINDINGS: In each individual syndrome, the core features are not uniformly present, and criteria that are currently used to exclude a condition, such as impaired episodic memory, are often present. Imaging, however, may warrant increased diagnostic prominence, particularly for diagnosis in semantic dementia and prognosis in behavioural syndromes. There is clinical and pathological overlap between the syndromes, but the clinical distinction between progressive nonfluent aphasia and semantic dementia is strengthening. Several series have refined our understanding of the correspondence between clinical syndromes and histopathological subtype: strong for tau-negative, ubiquitin-positive forms and more variable for tau-positive forms, yet prospective studies are still rare. The influence of genetic factors varies substantially across the syndromes. SUMMARY: Further research should aim to integrate detailed clinical, radiological, pathological and genetic information.     

Vascular dementia

Advances in medical practice have significantly increased the longevity of our population during the last 100 years. As the number of persons with dementia has grown, the significance of the contribution of cerebrovascular disease has become apparent, and it is now recognized to be the second most frequent cause of dementia in Western countries and perhaps the most frequent cause of dementia in Asian countries. Factors that increase the risk of vascular dementia include stroke, particularly more severe strokes involving the left hemisphere; vascular risk factors, such as diabetes mellitus; and host characteristics, such as older age and fewer years of education. Genetic factors are causative in familial disorders such as CADASIL, and the apolipoprotein E 4 allele may also make a contribution. Certain patients with vascular dementia may exhibit the stereotypic clinical features of executive dysfunction and a stepwise course of cognitive decline, particularly when subcortical disease is predominant, but the clinical distinctions between cerebrovascular disease and Alzheimer's disease may be subtle, in part because those two diseases frequently coexist. Two approaches to the treatment of patients with vascular dementia should be considered. First, treatment for stroke prophylaxis, including the careful management of vascular risk factors, could be worthwhile. Second, a variety of agents that have been investigated for the treatment of Alzheimer's disease might also prove to be beneficial for patients with vascular dementia, including cholinesterase inhibitors, neuroprotective agents, statins, calcium-channel blockers, anti-inflammatory medications, and antioxidants.