Differential Diagnosis of the Major Progressive Dementias and Depression in Middle and Late Adulthood: A Summary of the Literature of the Early 1990s

There is a preponderance of research on the neuropsychology of the various dementias. There are also direct comparisons between two or more dementias available in the literature. This paper sought to summarize the most recent literature, primarily from 1990 through mid-1996, including recent reviews of the literature from previous decades. The purpose was to provide, in one location, a summary of neuropsychological (i.e., cognitive, motor, and psychiatric) characteristics of major noninfectious, progressive dementias and depression of middle and late adulthood. It is hoped that this review, particularly a summary table provided, will serve as a guide in the differential diagnosis of the dementias by clinicians. In addition to Alzheimer's disease, vascular dementias, Parkinson's disease, Lewy body dementia, Huntington's disease, and frontal lobe dementia, the impact of depression on cognitive functioning is covered given the frequency with which neuropsychologists are asked to differentiate depression from primary dementia.     

Sekundäre Demenzen

The majority of dementias are caused by degenerative disorders, followed by dementias with a vascular etiology. A mixed etiology is especially common in the elderly. Dementias associated with other disorders are relatively rare accounting for about 10?% of all cases and result from structural, inflammatory or metabolic disorders of the brain. The spectrum of etiologies covers such different disorders as limbic encephalitis, intracranial malignancies, AIDS, vitamin deficiencies, alcoholism and even normal pressure hydrocephalus. The symptomatic nature of these disorders enables the possibility of a causal treatment in some cases.     

Cholinesterase-inhibitor therapy for dementia: novel clinical substrates and mechanisms for treatment response

Historically, drugs that increase central cholinergic transmission have primarily been investigated for relieving cognitive symptoms in mild-to-moderate Alzheimer's disease. These efforts have led to the somewhat unexpected findings that cholinergic therapy has a beneficial effect on selected neuropsychiatric symptoms in AD across disease stages. In Parkinson's disease with dementia and dementia with Lewy bodies, cholinergic deficits are more severe than in AD, and there is emerging evidence that cholinesterase inhibitors are efficacious in treating core symptoms of attentional disturbance and psychosis. Recent data also suggest a rational basis for cholinergic therapy in vascular dementia. The cognitive and neuropsychiatric effects of cholinergic therapy observed in AD and other dementias form the crux of an integrative model of cholinergic therapeutic efficacy that encompasses the diverse central nervous system actions of acetylcholine and its complementary interactions with central monoamine transmitters. This heuristic framework highlights the broader therapeutic potential of cholinergic therapy for symptom-based indications in other neuropsychiatric disorders.     

Considering olfactory stimulation for adults with age-related dementia.

Behavioral interventions and activities for adults with age-related dementias sometimes use olfactory stimulation; however, limitations to the usefulness of such stimulation are suggested by both neurological studies which show a large amount of degeneration in the cells of the olfactory bulb and studies of perception which indicate that adults with Alzheimer's disease and related dementias perform poorly on tests of smell identification and detection. Current approaches to using olfactory stimulation as a component of interventions for adults with age-related dementia may need to be either abandoned or reassessed.     

Executive Control Functions in Degenerative Dementias: A Comparative Review

This paper reviews the literature concerning executive control impairments in degenerative dementias. The construct of executive control functioning is examined, as is the neuroanatomy of frontal–subcortical networks, believed to underlie executive function (EF) impairments. The pattern of EF impairments in Alzheimer's disease (AD) which affects temporal and parietal brain regions most severely is contrasted with observed executive dysfunctions in patients with dementias involving degeneration of primarily frontal and frontal–subcortical brain areas. EF impairments are present in each of these types of dementing illnesses. Although EF impairments are present in AD, they are less prominent than the memory disorder in the neuropsychological profile of the disease and tend to become more pronounced later in the course of the illness. In contrast, patients with frontal or frontal–subcortical dementia may demonstrate executive dysfunction, which occurs earlier in the disease progression and may be initially more severe.     

Mood, memory, and motor performance and the severity of tardive dyskinesia

This study tested the hypothesis that the features of tardive dyskinesia were associated with motor slowing, memory impairment, and depressive apathy all of which are considered to characterize the so-called subcortical dementias. In a sample of 48 psychiatric patients all fulfilling research criteria for tardive dyskinesia and without other signs of organic illness age-independent correlations were observed between severity of orofacial dyskinesia and measures of memory, motor performance and mood providing some empirical support for the hypothesis.     

Category and letter fluency in semantic dementia, primary progressive aphasia, and Alzheimer's disease

This study examined the impact of various degenerative dementias on access to semantic knowledge and the status of semantic representations. Patients with semantic dementia, primary progressive aphasia, and Alzheimer's disease were compared with elderly controls on tasks of category and letter fluency, with number of words generated, mean lexical frequency and errors recorded. The findings are consistent with the view that category and letter fluency rely on both common and unique cognitive processes. Fluency tasks, with the richness of data obtained, are valuable in distinguishing different dementia syndromes from one another.     

Unawareness of Deficits in Alzheimer's Disease and Other Dementias: Operational Definitions and Empirical Findings

Individuals with dementia frequently demonstrate decreased awareness of their cognitive difficulties. Empirical research examining this phenomenon has addressed a number of aspects of unawareness in Alzheimer's disease and other dementias, including occurrence in various disorders; possible neuroanatomical substrates; relationship to general cognitive functioning, executive functioning, and psychiatric symptomatology; and progression over time and across cognitive domains. Limitations of the current research literature are discussed, particularly issues surrounding operational definitions of unawareness and the current limited understanding of the role of the frontal lobes. A number of conclusions regarding unawareness that appear to be supported by the current body of empirical research and possible future directions are discussed.     

Alzheimer disease and the "then" self

The authority of the intact self over the future severely demented self is based on notions of integrity and precedent autonomy. Despite criticism of this authority, the principle of precedent autonomy in the care of people with Alzheimer disease or other progressive and irreversible dementias retains its moral significance.     

Comparative study of neurolinguistic variables in Alzheimer patients, traumatic aphasias and Korsakoff psychoses and normal control probands

There are few studies of the breakdown of language in specific dementias and there is some dispute that language pathology in brain failure is comparable to that of focal lesions. It is recognized that while aphasic language is a disturbance of receptive and propositional speech, disturbances of "InnerLanguage" disrupt the planning and regulatory basis of behavior. This paper presents a comparison of three pathological groups to match normal controls and suggest that in its initial stages reduced cognitive performances in Alzheimers type Dementia and Korsakow Psychosis on non verbal measures maybe a further of the regulatory role of inner speech comparison with traumatic Aphasia which more clearly exists on a deficit of verbal comprehension and expression.     

Diffuse Lewy Body Disease: Clinical,Pathological, and Neuropsychological Review

The pathophysiological etiologies and clinical presentations of neurodegenerative dementias have been found to be complex and heterogeneous. Recently, Lewy body inclusions have been identified as an etiological factor in 20–34% of autopsied dementia cases. The term diffuse Lewy body disease (DLBD) is generally accepted as the diagnostic term representative of this currently under-reported and under-recognized disease. This article reviews the literature on the clinical, pathological, and neuropsychological features of this disorder. Differential diagnostic issues are discussed as well as current pharmacological treatment. Nine confirmed cases of DLBD are presented to demonstrate the various features of this disorder. The diagnostic implications of neuropsychological examination results are discussed in relation to other common dementing neurologic diseases.     

Aging, dementia and Gibson Spiral Maze performance: a brief note

A comparison between normal and dementing subjects' performance on the Gibson Spiral Maze was carried out between two age groups (60-70 and 70-89 yr.). Analysis indicated that a differential pattern of impairment existed between early and late onset dementias (ns = 54 and 75), the latter characterized by poor accuracy, the former by abnormal slowing, when compared with their normal peers.     

The neuropsychological assessment of dementia

It has become standard practice to base the diagnosis of dementia on the combination of neuropsychological and non-behavioral findings. The present article provides a short, clinically oriented synopsis of the targets, investigational procedures, and difficulties of the modern neuropsychological approach to the diagnosis of dementia. Over the years, neuropsychology has developed assessment tools to evaluate the cognitive and behavioral abnormalities of many dementias. Validated tests of memory, language, executive, and other cognitive functions are used to screen for dementia and identifying certain dementia profiles. Behavioral assessment procedures are available for non-cognitive neurodegenerative alterations. At present, problems arise mainly with the behavioral heterogeneity of certain dementia syndromes. Especially problematic are discrimination of age-associated or mild cognitive impairments from incipient dementia and the impact of psychiatric symptoms on cognitive functions. It is concluded that neuropsychology offers a valuable contribution to the diagnosis and differential diagnosis of dementia.     

Mitochondrial defects in neurodegenerative disease

Over the past 12 years, a wide variety of neurodegenerative diseases has been linked to mutations in mitochondrial genes located in either the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). These disorders encompass an array of unorthodox inheritance patterns and a plethora of symptoms ranging from lethal neonatal multi-symptom disorders to later onset myopathies, cardiomyopathies, movement disorders, and dementias. The bases for the genetic and phenotypic variability of mitochondrial diseases lie in the multiplicity of the mitochondria genes dispersed across the human genome and the variety of cellular pathways and functions in which the mitochondria play a central role.     

Priming semantic relations in patients with Huntington's disease

To investigate the hypothesis that Huntington's Disease involves a breakdown in the organization of the lexico-semantic representational system, mildly and moderately demented patients with Huntington's Disease and age-matched normal control subjects were given a brief battery of language tests and a semantic priming free association task. Results of the language tests provided suggestive, but confounded, evidence for a semantic deficit in Huntington's Disease. Less equivocal evidence was yielded by results of the priming task, which showed a decline in the effect of association strength of primed stimulus-target word pairs on target hit rates. This finding was interpreted as a disruption in the system of spreading activation in a lexico-semantic network. This breakdown was contrasted with the more severe language deficits found in dementias which are primarily cortical in origin.     

Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia

To test the idea that scopolamine provides a suitable pharmacological model of the memory defects associated with cortical or subcortical dementias, we assessed memory on a battery of tasks in healthy young normal subjects who received 0.5 mg scopolamine, 0.1-0.2 mg glycopyrrolate or physiological saline, once each on three separate occasions, and compared the pattern of memory failure induced by scopolamine to that observed on the same tasks in patients with Alzheimer's disease (AD) or Huntington's disease (HD). In agreement with previous reports, scopolamine impaired acquisition and delayed recall of a 14-word list and disrupted retention on the Brown-Peterson distractor task, whereas the peripherally active anticholinergic glycopyrrolate was without effect. However, under scopolamine the pattern of errors made on these memory tasks was quite different from that seen in patients with AD. Scopolamine did not increase the number of false positive errors on delayed recognition of the word list and also failed to increase the number of prior-item intrusions on the Brown-Peterson task. Also, scopolamine did not impair learning of a symbol-digit paired-associate task, and did not reduce the number of words retrieved or increase the number of words repeated on a standardized verbal fluency test. When the effects of scopolamine on memory were compared to the pattern of impairments observed in demented patients with HD, several differences were found. Although scopolamine clearly produces deficits on some measures of anterograde memory, the present findings question whether anticholinergic drugs adequately mimic the full range of memory impairments observed in cortical or subcortical dementias.     

Learning and memory deficits upon TAU accumulation in Drosophila mushroom body neurons

Mutations in the neuronal-specific microtubule-binding protein TAU are associated with several dementias and neurodegenerative diseases. However, the effects of elevated TAU accumulation on behavioral plasticity are unknown. We report that directed expression of wild-type vertebrate and Drosophila TAU in adult mushroom body neurons, centers for olfactory learning and memory in Drosophila, strongly compromised associative olfactory learning and memory, but olfactory conditioning-relevant osmotactic and mechanosensory responses remained intact. In addition, TAU accumulation in mushroom body neurons did not result in detectable neurodegeneration or premature death. Therefore, TAU-mediated structural or functional perturbation of the microtubular cytoskeleton in mushroom body neurons is likely causal of the behavioral deficit. These results indicate that behavioral plasticity decrements may be the earliest detectable manifestations of tauopathies.     

Galantamine facilitates acquisition of hippocampus-dependent trace eyeblink conditioning in aged rabbits

Cholinergic systems are critical to the neural mechanisms mediating learning. Reduced nicotinic cholinergic receptor (nAChR) binding is a hallmark of normal aging. These reductions are markedly more severe in some dementias, such as Alzheimer's disease. Pharmacological central nervous system therapies are a means to ameliorate the cognitive deficits associated with normal aging and aging-related dementias. Trace eyeblink conditioning (EBC), a hippocampus- and forebrain-dependent learning paradigm, is impaired in both aged rabbits and aged humans, attributable in part to cholinergic dysfunction. In the present study, we examined the effects of galantamine (3 mg/kg), a cholinesterase inhibitor and nAChR allosteric potentiating ligand, on the acquisition of trace EBC in aged (30–33 months) and young (2–3 months) female rabbits. Trace EBC involves the association of a conditioned stimulus (CS) with an unconditioned stimulus (US), separated by a stimulus-free trace interval. Repeated CS–US pairings results in the development of the conditioned eyeblink response (CR) prior to US onset. Aged rabbits receiving daily injections of galantamine (Aged/Gal) exhibited significant improvements compared with age-matched controls in trials to eight CRs in 10 trial block criterion (P = 0.0402) as well as performance across 20 d of training [F(1,21) = 5.114, P = 0.0345]. Mean onset and peak latency of CRs exhibited by Aged/Gal rabbits also differed significantly [F(1,21) = 6.120/6.582, P = 0.0220/0.0180, respectively] compared with age-matched controls, resembling more closely CR timing of young drug and control rabbits. Galantamine did not improve acquisition rates in young rabbits compared with age-matched controls. These data indicate that by enhancing nicotinic and muscarinic transmission, galantamine is effective in offsetting the learning deficits associated with decreased cholinergic transmission in the aging brain.     

HOLDING ONE ANOTHER (WELL, WRONGLY, CLUMSILY) IN A TIME OF DEMENTIA

Abstract: This essay takes a close look at a species of care that is particularly needed by people with progressive dementias but that has not been much discussed in the bioethics literature: the activity of holding the person in her or his identity. It presses the claim that close family members have a special responsibility to hold on to the demented person's identity for her or him, and offers some criteria for doing this morally well or badly. Finally, it considers how even those with dementia can hold others in their identities, and suggests that this kind of holding too can have great moral worth.