Dementia and Geriatric Cognitive Disorders

<i>Aims:</i> To investigate midlife cholesterol in relation to Alzheimer’s disease (AD) and vascular dementia (VaD) in a large multiethnic cohort of women and men. <i>Methods:</i> The Kaiser Permanente Northern California Medical Group (healthcare delivery organization) formed the database for this study. The 9,844 participants underwent detailed health evaluations during 1964–1973 at ages 40–45 years; they were still members of the health plan in 1994. AD and VaD were ascertained by medical records between 1 January 1994 and 1 June 2007. Cox proportional hazards models – adjusted for age, education, race/ethnic group, sex, midlife diabetes, hypertension, BMI and late-life stroke – were conducted. <i>Results:</i> In total, 469 participants had AD and 127 had VaD. With desirable cholesterol levels (<200 mg/dl) as a reference, hazard ratios (HR) and 95% CI for AD were 1.23 (0.97–1.55) and 1.57 (1.23–2.01) for borderline (200–239 mg/dl) and high cholesterol (≥240 mg/dl), respectively. HR and 95% CI for VaD were 1.50 (1.01–2.23) for borderline and 1.26 (0.82–1.96) for high cholesterol. Further analyses for AD (cholesterol quartiles, 1st quartile reference) indicated that cholesterol levels >220 mg/dl were a significant risk factor: HR were 1.31 (1.01–1.71; 3rd quartile, 221–248 mg/dl) and 1.58 (1.22–2.06; 4th quartile, 249–500 mg/dl). <i>Conclusion:</i> Midlife serum total cholesterol was associated with an increased risk of AD and VaD. Even moderately elevated cholesterol increased dementia risk. Dementia risk factors need to be addressed as early as midlife, before underlying disease(s) or symptoms appear.

The Bayer Activities of Daily Living Scale (B-ADL) has been developed on an international basis to assess deficits in the performance of everyday activities. The scale’s main target group is community dwelling patients who suffer mild cognitive impairment or mild-to-moderate dementia. It comprises 25 items and takes the form of a questionnaire to be completed by a caregiver or other informant sufficiently familiar with the patient. Statistical, clinical and domain-related criteria were used to select items from among a large number of activities of daily living (ADL) questions field tested in pilot studies in the USA, Germany, UK, Russia and Greece. The items included in the B-ADL have been chosen for their sensitivity to cognitive impairment, simplicity of concept, international applicability and their relevance to patients coping with the demands of everyday life. The scale uses items which reflect a wide range of domains. On account of its brevity, it is thought especially suitable for application within a GP and primary care context for both screening a patient’s ADL capacities as well as for documentation of treatment effects and the progress of dementia. This paper focuses on a description of the scale and its application.

The efficacy of cognitive training was assessed in persons with mild cognitive impairment (MCI) and persons with normal cognitive aging. Forty-seven participants were included in this study: 28 with MCI and 17 controls. Twenty-one participants received intervention (20 MCI and 9 controls) and 16 participants (8 MCI and 8 controls) received no intervention (waiting-list group). The intervention focused on teaching episodic memory strategies. Three tasks of episodic memory (list recall, face-name association, text memory) were used as primary outcome measures. Results were analyzed using analyses of variance. The intervention effect (pre- and post-intervention difference) was significant on two of the primary outcome measures (delayed list recall and face-name association). A significant pre-post-effect was also found on measures of subjective memory and well-being. There was no improvement in the performance of groups of individuals with MCI and normal elderly persons who did not receive the intervention. These results suggest that persons with MCI can improve their performance on episodic memory when provided with cognitive training.

As heavy metal ions may be implicated in the formation of senile plaques in Alzheimer-afflicted brains, treatment with clioquinol was tested in 20 patients with Alzheimer’s disease. Clioquinol is a chelator that crosses the blood-brain barrier and has greater affinity for zinc and copper ions than for calcium and magnesium ions. Treatment was given for 21 days at doses of 20 mg/day to 10 patients and 80 mg/day to another 10 patients. The study was blind to the dosages but included no controls. Cerebrospinal fluid (CSF) investigations revealed a significant increase at day 7 and a decrease at day 21 in Tau protein and growth-associated protein (GAP43). These proteins are increased in Alzheimer’s disease and considered as rather stable markers. The initial increase may indicate a temporary cytotoxicity to the brain and/or an increased release into the CSF from stores in the tissue, possibly from senile plaques where the proteins are accumulated. The levels of CSF-Tau protein correlated positively and significantly with the serum levels of copper and also with the serum copper/zinc ratio. Clinical ratings showed slight improvement after 3 weeks treatment with clioquinol in this open study.

Delirium has been considered a syndrome of generalized dysfunction of higher cortical functions due to its breadth of symptoms and associated diffuse slowing on electroencephalogram. Advances in neuropsychiatry have revealed differences between brain regions, including the hemispheres, which may underlie the constellation of symptoms among different psychiatric disorders. For example, different neural pathways are involved in major depression and obsessive-compulsive disorder, including lateralization to one or the other hemisphere. In this article the author proposes that delirium, too, involves particular neural pathways and that lateralization to the right may be relevant. Structural and functional neuroimaging reports and recent neuropsychological studies support this lateralization. Prefrontal cortices, anterior and right thalamus, and right basilar mesial temporoparietal cortex may play a significant role in subserving delirium symptoms and may be the ‘final common pathway’ for delirium from a variety of etiologies. The final common pathway may be responsible for certain ‘core symptoms’ (disorientation, cognitive deficits, sleep-wake cycle disturbance, disorganized thinking, and language abnormalities), while other symptoms (delusions, hallucinations, illusions, and affective lability) may occur depending on the etiology causing delirium. An imbalance in the cholinergic and dopaminergic neurotransmitter systems is most commonly implicated in causing delirium, and could both account for delirium symptoms and be consistent with the neuroanatomical pathways being implicated.

<i>Background:</i> Research on the epidemiology of dementia has focused on the elderly. Few investigations have studied differences in etiologic frequencies between early-onset dementia (EOD), with onset at an age of less than 65 years old, and the more common late-onset disorder. <i>Objectives:</i> To determine relative frequencies and characteristics of EOD versus late-onset dementia (LOD; age of onset ≧65 years) diagnosed in a large memory disorders program over a 4-year period. <i>Methods:</i> We reviewed medical records, including an extensive neurobehavioral and neurological evaluation, of all patients seen at a large Veteran’s Affairs Medical Center Memory Disorders clinic between 2001 and 2004 and assessed demographic variables, final diagnoses, presence of dementia, and differential diagnosis of dementing illnesses. <i>Results:</i> Among 1,683 patients presenting for evaluation of an acquired decline in memory or cognition, 948 (56%) met established clinical criteria for a dementing illness. About 30% (n = 278) of these had an age of onset of <65 years, compared to 670 with LOD. Patients were predominantly male (98%). Compared to the late-onset group, the EOD patients were less severely impaired on presentation, but they did not differ in gender distribution or educational background. The EOD group had significantly more dementia attributed to traumatic brain injury, alcohol, human immunodeficiency virus (HIV), and frontotemporal lobar degeneration compared to the LOD patients. In contrast, the LOD group had significantly more Alzheimer’s disease compared to the EOD group. <i>Conclusions:</i> This study, conducted at a Veterans Affairs Hospital, is the largest series to date on EOD, and found a previously unexpectedly large number of patients below the age of 65 with cognitive deficits and impaired functioning consequent to head trauma, alcohol abuse, and HIV. These findings highlight the differential distribution and importance of preventable causes of dementia in the young.

<i>Background/Aims:</i> Behavioural and psychological symptoms have a high prevalence amongst patients with dementia and can be a significant source of distress to both patients and carers. The present study explored the relationships between quality of life and behavioural and psychological symptoms in dementia (BPSD) from both patient and carer perspectives. Contextual factors surrounding the occurrence of BPSD were explored. <i>Methods:</i> Forty-six patients and 116 carers completed questionnaire measures of BPSD and quality of life. <i>Results:</i> BPSD were negatively associated with both patient and carer ratings of patient quality of life. The symptoms related to lower quality of life differed between patient and carer ratings: depression and irritability were found to predict lower carer ratings of quality of life, whilst delusions and apathy indicated lower patient ratings. Carers were found to be poor at identifying antecedents and consequences of BPSD. <i>Conclusions:</i> The presence of BPSD is associated with lower quality of life in dementia. Interventions designed to improve the quality of life for patients should focus on the BPSD specifically associated with the patient’s rating of quality of life. Information regarding the role of contextual factors in behaviour management should be made available to carers.

<i>Background/Aims:</i> Subjective memory complaint (SMC) in normal individuals may predict future cognitive decline. The goal of this study was to examine whether the probability of decline increases with growing intensity of complaint. <i>Methods:</i> Normal subjects over the age of 50 years were included in a longitudinal retrospective study (mean follow-up time = 8 years). All subjects (n = 230) underwent cognitive and medical examination at baseline. The presence of SMC was determined based on Global Deterioration Scale staging. A subgroup of 83 participants also received baseline assessment for the intensity of SMC. Logistic regression was used to predict outcome from baseline variables. Three outcome groups were established at the final visit: nondeclining, declining and diagnostically unstable (i.e. the diagnosis changed over time: from normal to mild cognitive impairment, then back to normal). <i>Results:</i> The presence of SMC was a predictor of future decline but also increased the likelihood of the unstable diagnosis. Increasing intensity of SMC did not further raise the risk for decline. High intensity of complaints and more pronounced affective symptoms predicted the unstable clinical diagnosis. <i>Conclusions:</i> The presence of SMC contributes to the risk of future decline, however, the increasing intensity of the perceived impairment does not further enhance the risk.

Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer’s disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using β-amyloid 1–42 (Aβ42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Aβ42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-α, TGF-β₁, MIP-1α) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Aβ42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Aβ42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.

<i>Background/Aims:</i> Increased cerebrospinal fluid (CSF) tau, decreased CSF amyloid-β42 (Aβ42) and the apolipoprotein E gene <i>(APOE) </i>ε<i>4</i> allele predict progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Here, we investigated these markers to assess their predictive value and influence on the rate of disease progression. <i>Methods:</i> Using ELISA, we measured the CSF biomarkers in 47 AD patients, 58 patients with MCI and 35 healthy control subjects. Twenty-eight MCI patients revisited the clinic and half of them progressed to AD during a period of 3–12 years. <i>Results:</i> The expected changes in CSF total (T)-tau, phosphorylated (P)-tau and Aβ42 levels were found in AD, confirming the diagnostic value of these biomarkers. We were also able to corroborate an increased risk for progression from MCI to AD with elevated CSF T-tau and P-tau and with the presence of the <i>APOE </i>ε<i>4/</i>ε<i>4</i> genotype, but not with decreased Aβ42. Finally, for the first time we demonstrated that MCI subjects with high CSF T-tau or P-tau and <i>APOE </i>ε<i>4</i> homozygosity progressed faster from MCI to AD. <i>Conclusions:</i> CSF T-tau and P-tau as well as the <i>APOE </i>ε<i>4/</i>ε<i>4</i> genotype are robust predictors of AD and are also associated with a more rapid progression from MCI to AD.