Influences of preclinical dementia and impending death on the magnitude of age-related cognitive deficits

The authors examined the influence of preclinical dementia and impending death on the cross-sectional relationship between age and performance in tasks assessing episodic memory, visuospatial skill, and verbal fluency. Increasing age was associated with a general decrease in cognitive performance. In addition, those who were to be diagnosed with dementia or had died by a 3-year follow-up, were older, and performed at a lower level than the remaining sample across all cognitive tasks at baseline. Nevertheless, removal of the preclinical dementia and impending death groups from the original sample affected the cross-sectional age-cognition relations relatively little. This pattern of findings suggests that the biological aging process exerts negative influences on cognitive functioning beyond those resulting from disease and mortality.     

Clinicopathological findings of suicide in the elderly: three cases

The neuropathological correlates of suicide in older persons have received little research attention. Our recent study of elderly suicide victims from an Australian forensic medicine department (n = 143), unlike a previous case-control study, did not find an increased prevalence of Alzheimer's disease (AD) in older persons who committed suicide despite a history of dementia in 6.3%. Both studies were limited to the examination of AD-related pathology by the availability of tissue. We present clinicopathological data on three cases from our study for whom autopsy findings were available. These cases included: a community-dwelling male in his early eighties with dementia who was found to have multiple cortical and striatal lacunes and glial scars, small vessel cerebrovascular disease (SVD) and AD-related pathology; a community-dwelling male in his mid-seventies with depression and loss of concentration, with brainstem predominant Lewy body disease (LBD) and AD-related pathology; and a female nursing home resident in her nineties with a history of stroke and prior suicide attempts who was found to have infarcts and SVD in frontal regions. Neuropathological findings in elderly suicide victims may include multiple neurodegenerative pathologies. The burden and distribution of neurodegenerative diseases apart from AD, including SVD and LBD, should be assessed as possible pathophysiological factors contributing to late life suicide.     

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.     

Very Early Decline in Recognition Memory for Odors in Alzheimer’s Disease

When in the progression of Alzheimer’s disease (AD) a decline in detection sensitivity and recognition memory for odors begins, and whether a fast progression in dementia is related to a fast loss in odor sensitivity, was determined by studying 78 patients with probable AD, categorized as very mild, mild, or moderate in degree of dementia, and 78 controls. Taste and vision were studied for comparison. Whereas the earliest decline in odor sensitivity and visual memory was found in mild patients, a decline in odor memory was found in the very mild patients. Similar taste thresholds in the four groups suggest that the poor odor detectability in AD was not related to task demands in threshold testing. A fast progression in dementia was also found to be related to a fast loss in odor sensitivity. The findings imply that memory-based olfactory tests may contribute to early diagnosis of AD.     

Nuisance parameters in the assessment of noncognitive manifestations of dementia.

Measures of noncognitive disturbances in dementia typically rely on ratings by informants. In this study, method variance in measures of affect, behavior, and functional competence was evaluated by comparing ratings from 2 types of informants (spouse vs. child) in patients with probable Alzheimer's disease. No differences were observed on 5 variables; for 2 measures of behavior disturbance and 1 measure of functional disability, ratings obtained from child informants were significantly higher than spouse ratings for patients at comparable levels of dementia severity. Although the effect of the rater dimension was relatively small and selective, the findings suggest the need for further research on potential sources of bias in the ratings of noncognitive features of the dementia syndrome.     

Proper names in the early stages of Alzheimer's disease

A short proper name retrieval test was found to discriminate between unselected subjects and age- and education- matched patients affected by Alzheimer's type dementia at a stage where the Mini-Mental State Examination could not detect a difference between these groups. The proper name retrieval task also compared favorably with the 3MS, a more sensitive, modified version of the MMSE. These findings suggest that proper name retrieval could be used to an advantage and become a routine component of short batteries for the early detection of Alzheimer's disease.     

Simulating episodic memory deficits in semantic dementia with the TraceLink model

Although semantic dementia is primarily characterised by deficits in semantic memory, episodic memory is also impaired. Patients show poor recall of old autobiographical and semantic memories, with better retrieval of recent experiences; they can form new memories, and normal performance on pictorial recognition memory has been demonstrated. As these abnormalities in episodic memory are virtually a mirror image of those seen in the amnesic syndromes, semantic dementia poses a challenge to extant models of remote memory and amnesia. Here, we show that one such model, TraceLink, can reproduce some of the principal findings on episodic memory in semantic dementia. A loss of nodes and connections within the trace system, which can be identified with the temporal neocortical memory storage sites implicated in semantic dementia, simulates without further assumptions the findings reported above.     

Simulating episodic memory deficits in semantic dementia with the TraceLink model

Although semantic dementia is primarily characterised by deficits in semantic memory, episodic memory is also impaired. Patients show poor recall of old autobiographical and semantic memories, with better retrieval of recent experiences; they can form new memories, and normal performance on pictorial recognition memory has been demonstrated. As these abnormalities in episodic memory are virtually a mirror image of those seen in the amnesic syndromes, semantic dementia poses a challenge to extant models of remote memory and amnesia. Here, we show that one such model, TraceLink, can reproduce some of the principal findings on episodic memory in semantic dementia. A loss of nodes and connections within the trace system, which can be identified with the temporal neocortical memory storage sites implicated in semantic dementia, simulates without further assumptions the findings reported above.     

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.     

Category and Attribute Knowledge Deterioration in Alzheimer's Disease

A prevalent theory regarding the deterioration of semantic memory in Alzheimer's disease is that it is a bottom-up process. If this is true, performance on tests of attribute knowledge should decline more rapidly than performance on tests of categorical knowledge as dementia severity increases. In the present study, a convincing pattern of findings to either support or reject the theory failed to emerge. This raised questions regarding the ability to separate attribute and categorical knowledge, and whether one can be tested without influence of the other. Questions also were raised regarding the additional cognitive processes needed to complete tasks of semantic memory.     

The organization of narrative discourse in Lewy body spectrum disorder

Narrative discourse is an essential component of day-to-day communication, but little is known about narrative in Lewy body spectrum disorder (LBSD), including Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB). We performed a detailed analysis of a semi-structured speech sample in 32 non-aphasic patients with LBSD, and we related their narrative impairments to gray matter (GM) atrophy using voxel-based morphometry. We found that patients with PDD and DLB have significant difficulty organizing their narrative speech. This was correlated with deficits on measures of executive functioning and speech fluency. Regression analyses associated this deficit with reduced cortical volume in inferior frontal and anterior cingulate regions. These findings are consistent with a model of narrative discourse that includes executive as well as language components and with an impairment of the organizational component of narrative discourse in patients with PDD and DLB.     

Object alternation and orbitofrontal system dysfunction in Alzheimer's and Parkinson's disease

Previous performance on measures of frontal system function have suggested prominent orbitofrontal system damage in Alzheimer's disease, but not in Parkinson's dementia. Object alternation (OA), a task sensitive to orbitofrontal system dysfunction in non-human animals, was therefore administered to determine whether this measure would distinguish Alzheimer's from Parkinson's dementia. OA was significantly impaired in Alzheimer's disease compared to Parkinson's dementia, even though both groups were equated for severity of dementia. Although the patients with Parkinson's dementia also showed impairment on OA compared to normals, an error analysis revealed that the performance of the Alzheimer's patients, but not the Parkinson's patients, was characterized by abnormal response perseveration. The marked perseverative deficit in Alzheimer's disease may reflect orbitofrontal system dysfunction whereas the milder, and qualitatively different, deficits in Parkinson's disease may reflect dorsolateral frontal system involvement.     

Impairments of speech fluency in Lewy body spectrum disorder

Few studies have examined connected speech in demented and non-demented patients with Parkinson’s disease (PD). We assessed the speech production of 35 patients with Lewy body spectrum disorder (LBSD), including non-demented PD patients, patients with PD dementia (PDD), and patients with dementia with Lewy bodies (DLB), in a semi-structured narrative speech sample in order to characterize impairments of speech fluency and to determine the factors contributing to reduced speech fluency in these patients. Both demented and non-demented PD patients exhibited reduced speech fluency, characterized by reduced overall speech rate and long pauses between sentences. Reduced speech rate in LBSD correlated with measures of between-utterance pauses, executive functioning, and grammatical comprehension. Regression analyses related non-fluent speech, grammatical difficulty, and executive difficulty to atrophy in frontal brain regions. These findings indicate that multiple factors contribute to slowed speech in LBSD, and this is mediated in part by disease in frontal brain regions.     

Difficulty processing temporary syntactic ambiguities in Lewy body spectrum disorder

While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson’s disease (PD), Parkinson’s dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb’s statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.     

Awareness of memory task impairment versus everyday memory difficulties in dementia

The study investigated different types of awareness of memory dysfunction in dementia, specifically judgements concerning memory task performance or appraisal of everyday memory functioning and also exploring the neuropsychological correlates of such awareness. This was investigated in 76 people with dementia, comprising 46 patients with Alzheimer's disease (AD) and 30 patients with vascular dementia (VaD). The Memory Awareness Rating Scale (Clare et al., 2002, Neuropsychol Rehabil, 12, 341–362) was used, which includes an Objective‐Judgement Discrepancy (OJD) technique involving comparison of subjective evaluation of performance on specific memory tasks with actual performance, and a Subjective Rating Discrepancy (SRD) technique, which compares self versus informant judgement of everyday memory function. The AD and VaD groups showed lower awareness than a normal control group for both types of measures, the AD group showing less awareness than the VaD group on the OJD measure. Regression analyses supported associations for both groups between memory impairment and the OJD measure and between naming impairment and the SRD measure. The findings are discussed in terms of neurocognitive theories accounting for loss of awareness in dementia.     

The role of cardiovascular risk factors in Alzheimer's disease

The distinction between Alzheimer's disease and vascular dementia, the two most common types of dementia, has been undermined by recent advances in epidemiologic, clinical, imaging, and neuropathological studies. Cardiovascular risk factors, traditionally regarded as distinguishing criteria between the two entities, have been shown to be associated with both AD and vascular dementia. In this article, we propose mechanisms of action of cardiovascular risk factors in AD, suggest possible explanations for the overlap with vascular dementia and discuss the implications this might have on future differential diagnosis, research, and treatment strategies.     

Current and emerging pharmacological treatment options for dementia

Treatments for the symptomatic relief of Alzheimer's disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer's disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued.     

Cognitive Functioning in Aging and Dementia: The Kungsholmen Project

The Kungsholmen Project (KP) is a community-based longitudinal study of aging and dementia targeting the 75+ population. In this article, we review empirical studies with a cognitive focus from the KP. The main findings indicate that (a) there is an age-related decline for some cognitive domains (e.g., episodic memory, verbal fluency, visuoconstructive skill, psychomotor speed), but not for others (e.g., primary memory, visuoperceptive skill, motor-hand coordination), (b) multiple individual-difference variables within demographic (e.g., sex, education) life-style (e.g., activity levels), genetic (e.g., apolipoprotein E genotype), and health-related (e.g., vitamin B deficiency, depression, diabetes) domains are related to late-life cognitive functioning, (c) a potential for improving cognitive performance – a reserve capacity – is present also among very old adults, (d) the 2 most common dementia diseases, Alzheimer’s disease (AD) and vascular dementia (VaD), affect cognition in a strikingly similar manner, (e) the role of individual-difference variables in cognitive functioning is markedly reduced in dementia – the pathogenesis itself may overshadow the influence of other variables, and (f) there is a long preclinical period in dementia during which cognitive deficits are detectable. As is true with the other projects represented in this issue, the KP portrays a rather diversified picture of cognitive aging, although systematic patterns are evident with regard to the variability of late-life cognitive functioning.     

Assessing inhibitory control in early-stage Alzheimer's and Parkinson's disease using the Hayling Sentence Completion Test

The ability to inhibit irrelevant information is essential for coping with the demands of everyday life. Inhibitory deficits are present in all stages of dementia and commonly observed in people with Parkinson's disease (PwPD). Inhibition is frequently tested with the Stroop test, but this may lack ecological validity. This study investigates inhibitory control in people with Alzheimer's disease dementia (PwD) and PwPD using the Hayling Sentence Completion Test (HSCT), which aspires to be a more ecologically valid task. A total of 117 people completed the HSCT, a test where participants have to complete a sentence with an unrelated word. The sample comprised 30 PwD, 33 PwPD, and 54 healthy older controls. We compared response times and the number and type of errors across the three groups. Completion time in Part B (Inhibition) did not distinguish between PwD, PwPD, and controls when controlling for the initiation speed, but a higher proportion of Category A errors (producing a word that fits the sentence when instructed otherwise) was a unique characteristic of inferior performance in PwD and PwPD. While not part of the standard test scoring protocol, controlling for the initiation speed and distinguishing between speed and accuracy in test performance appear to be essential for accurate evaluation of the inhibitory control in HSCT in older people. The findings suggest that the HSCT may be sensitive to verbal suppression deficits and may provide insight into inhibitory control in PwD and PwPD.     

The Burden of Dementia: A Medical and Research Perspective

Alzheimer's disease remains the most common form of dementia. Dementia symptoms vary depending on individual personality, life experience, and social and cultural influences. As dementia progresses, involvement of multi-disciplinary health care professionals is needed to manage the disease. Alzheimer research is progressing rapidly. While 5% of all Alzheimer's disease may be genetically determined, the majority is not. Susceptibility genes can reveal the risk of contracting Alzheimer's disease. Early life risk factors such as education, nutrition, and vascular disease may increase the likelihood of dementia in later life. In the United States, two acetylcholinesterase inhibitors have been approved as cognitive enhancers. Possible prevention and symptomatic treatment interventions have focused on estrogen replacement therapy, antioxidants, and anti-inflammatory medications. Research advances have improved the clinical management of dementia. Ethical implications to the patient, family, and society are multiple and remain challenging.