Annualized functional change in alzheimer's disease participants and normal controls

The rate of functional change in persons with mild Alzheimer's disease (AD) was compared to that of cognitively normal elderly control subjects. A comparison of annualized rates of change on the Test of Everyday Functional Abilities (TEFA) was carried out, along with a brief measure of instrumental activities of daily living skills, in persons with mild AD (Mini-Mental State Exam score >20) and cognitively normal elderly controls. Persons with AD (N = 30) showed an 8.5 %?(3.5 point) annualized decline in TEFA scores over an average of 1.2 years; there was no decline in a group of elderly normal controls (N = 20) over an average of 1.5 years. Persons with mild AD showed functional changes over the course of a year on a direct measure of instrumental activities of daily living; a comparable group of normally aging persons did not.     

BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls

Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) are common forms of dementia in the elderly. Recent findings have suggested an involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of AD. BDNF is an endogenous protein involved in the maintenance of neuronal function, synaptic plasticity and structural integrity in the adult brain. BDNF serum and cerebrospinal fluid (CSF) concentrations were assessed by a sensitive ELISA in 27 AD patients in comparison to 9 NPH patients and 28 age-matched healthy controls (10 CSF samples). We found a significant decrease of BDNF serum concentration in AD (18.6ng/ml) and NPH patients (18.1ng/ml) as compared to healthy controls (21.3ng/ml; p=0.041/p=0.017). BDNF serum concentrations did not correlate with CSF levels, age or MMSE scores both in AD and NPH patients. In unconcentrated CSF samples, BDNF could be detected in AD patients in 8/27 cases (29.6%; mean of 4.6pg/ml), in NPH patients in 1/9 cases (11.1%; mean of 6.4pg/ml) and in the control subjects in 5/10 cases (50%; mean of 1.6pg/ml) with no significant differences as regards mean concentration and frequency of detectable BDNF in CSF. The decrease of BDNF serum levels in AD and NPH may reflect a lack of trophic support and thus contribute to progressive degeneration in both diseases. In contrast to serum, CSF seems to be no useful source to determine BDNF in AD or NPH because of too low concentrations. Further examinations have to follow to elucidate the potential sources and the meaning of reduced BDNF levels in the blood in AD and NPH.     

Vacuolar change in Alzheimer's disease

A retrospective neuropathologic study of brains from 66 patients with Alzheimer's disease (AD) demonstrated the presence of a vacuolar change (VC) in 50 cases that was virtually indistinguishable histologically from the spongiform change characteristic of Creutzfeldt-Jakob disease (CJD). Indeed, in several instances, there was initial diagnostic confusion with CJD. Unlike the spongiform change in CJD, however, VC was almost entirely restricted to the medial temporal cortex and amygdala. Furthermore, the severity of VC was usually less intense than the spongiform change observed in cases of CJD with severe neurologic impairment. The VC could be readily distinguished from the fine microvacuolation of the upper layers of the isocortex reported in a number of different conditions, including AD. It also differed from the status spongiosus of the cerebral cortex that occurs in advanced AD and CJD as well as in other degenerative diseases. The artifactual rarefaction that occurs in improperly processed paraffin-embedded brain tissue was excluded as a contributory factor to the VC. Since VC does not invariably occur in AD, it conceivably could represent a subtype of this disorder or may represent a variant of the pathologic changes that can occur. Its relationship to CJD or other slow virus disorders is to date unknown but unlikely.     

Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex

Evidence supports a role for epigenetic mechanisms in the pathogenesis of late-onset Alzheimer's disease (LOAD), but little has been done on a genome-wide scale to identify potential sites involved in disease. This study investigates human postmortem frontal cortex genome-wide DNA methylation profiles between 12 LOAD and 12 cognitively normal age- and gender-matched subjects. Quantitative DNA methylation is determined at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Data are analyzed using parallel linear models adjusting for age and gender with empirical Bayes standard error methods. Gene-specific technical and functional validation is performed on an additional 13 matched pair samples, encompassing a wider age range. Analysis reveals 948 CpG sites representing 918 unique genes as potentially associated with LOAD disease status pending confirmation in additional study populations. Across these 948 sites the subtle mean methylation difference between cases and controls is 2.9%. The CpG site with a minimum false discovery rate located in the promoter of the gene Transmembrane Protein 59 (TMEM59) is 7.3% hypomethylated in cases. Methylation at this site is functionally associated with tissue RNA and protein levels of the TMEM59 gene product. The TMEM59 gene identified from our discovery approach was recently implicated in amyloid-β protein precursor post-translational processing, supporting a role for epigenetic change in LOAD pathology. This study demonstrates widespread, modest discordant DNA methylation in LOAD-diseased tissue independent from DNA methylation changes with age. Identification of epigenetic biomarkers of LOAD risk may allow for the development of novel diagnostic and therapeutic targets.     

Neuropsychological functioning in depressed versus nondepressed participants with Alzheimer's disease

Differences in cognitive functioning between participants with Alzheimer's Disease (AD) reporting depressive symptomatology (AD-Dep; n = 37) and a control group of nondepressed participants with AD (AD-Con; n = 98) were investigated based on hypothesized impairments of attention/concentration, psychomotor speed, and simple motor speed. Groups did not differ in age, education, overall severity of dementia, auditory comprehension, or use of psychotropic medications. AD-Dep participants performed significantly more poorly than AD-Con participants on 3 of the 13 measures on which they were hypothesized to exhibit greater impairment (WAIS-R Block Design, WAIS-R Digit Symbol, and speeded motor programming); and there were trends toward poorer performance on four additional measures (WAIS-R Object Assembly, WAIS-R Picture Arrangement, WAIS-R Digit Span-backward, and letter fluency). There was only one significant effect for the 13 measures on which no group differences were hypothesized; the AD-Dep participants unexpectedly obtained better WMS-R Logical Memory delayed recall scores than the AD-Con participants. Finally, AD-Dep participants exhibited an unexpected pattern of greater right hand advantage on the Finger Tapping Test.     

Neurochemical markers in the cerebrospinal fluid of patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and normal controls

Summary Several neurotransmitter markers were investigated in the cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) (n=27), Parkinson's disease (PD) (n=35) and ALS (n=26) and from control subjects (n=34) to compare the possible alterations in the biochemical profiles of these different neurodegenerative diseases. The main proportion of the patients represented an early phase of the illness at the time of the diagnosis. Correlations of the degree of dementia and the stage of the disease with CSF measures were evaluated. The CSF levels of somatostatin like-immunoreactivity (SLI) were significantly reduced in AD patients when compared with those of normals and ALS patients. The CSF concentrations of homovanillic acid (HVA) were significantly decreased for PD patients and the decrease focused on the nondemented patients. A trend of decreasing HVA values towards the most advanced stage of Parkinson's disease assessed by Webster's scale was also displayed. The content of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF was higher for ALS patients than for other groups. The lowest 5-hydroxy-indoleacetic acid (5HIAA) levels were observed in the PD group and the lowest acetylcholinesterase (AChE) activities were found in the PD patients with the most severe disease. Changes in CSF measures were too subtle to be beneficial for diagnostic purposes, but adequate for reflecting the different neurochemical profiles of these three degenerative neurological disorders.     

Neurological findings in Alzheimer's disease and normal aging

To determine the potential value of abnormal neurological findings as markers of Alzheimer's disease (AD) and their relationship to the stage of AD, we compared standardized neurological examinations in 135 community-dwelling patients with AD and 91 nondemented elderly individuals. After correcting for differences in age and education between the two groups, we found that rigidity, stooped posture, graphesthesia, neglect of simultaneous tactile stimuli (face-hand test), and snout, grasp, and glabella reflexes were present significantly more often in patients with AD than in control subjects. These findings increased in prevalence in patients with AD according to the severity of dementia. However, in a multivariate logistic regression model only the grasp reflex, graphesthesia, and the face-hand test were statistically significantly associated with the degree of cognitive impairment. Although abnormal neurological findings occur regularly in AD, they are too infrequent early in the course of AD to serve as diagnostic markers. Prospective studies are needed to determine whether patients with the early onset of extrapyramidal or other findings form a distinct subgroup of AD.     

Tau protein in normal and Alzheimer's disease brain

In 1975, Weingarten and colleagues isolated a protein factor that was able to induce microtubule formation. They called this factor tau (t). Some ten years later a new era of research on this microtubule-associated protein was launched when several groups almost simultaneously discovered that tau was the predominant protein component of the paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) which are characteristic pathological lesions of the Alzheimer's disease brain. Subsequent findings that PHF-tau isolated from Alzheimer's disease brain was phosphorylated to a greater extent than non-PHF tau, led to extensive investigation into the posttranslational modifications (mainly phosphorylation) of tau in normal and Alzheimer's disease brain. The present review highlights the literature concerning the normal functioning and processing of tau protein, and examines the evidence for the involvement of the abnormal posttranslational processing of tau in the pathology of Alzheimer's disease. Finally, speculation as to the relationship between abnormal processing of tau, other subcellular abnormalities seen in Alzheimer's disease, and the pathological causes of the disease are discussed.     

Assessment of functional changes in Alzheimer's disease

Functional difficulties occur in all patients with Alzheimer's disease. Instrumental skills (shopping, handling money) are involved first, then self-care activities (toileting, dressing). Drug trials in intermediate stage Alzheimer's disease should monitor self-care activities with structured diaries and rating scales.     

Temporo‐frontal functional connectivity during auditory change detection is altered in Alzheimer's disease

Cortico‐cortical connections might be disturbed in patients with Alzheimer's disease (AD). This study aimed to investigate the alterations of functional connectivity in AD during auditory change detection processing by measuring the local neuronal activation and functional connectivity between cortical regions. Magnetoencephalographic responses to deviant and standard sounds were recorded in 16 AD patients, 18 young controls and 16 elderly controls. Larger source amplitudes and shorter peak latencies were found in the right temporal magnetic mismatch responses of young controls compared with elderly controls and AD patients. During deviant stimuli, the right theta temporal‐frontal phase synchrony was significantly smaller in AD than in young controls and elderly controls. Moreover, the left temporal‐frontal synchronization at theta and alpha bands was reduced in AD and elderly controls compared with young controls. In conclusion, the loss in temporo‐frontal theta synchronization might be an electrophysiological hallmark of AD. Hum Brain Mapp 35:5565–5577, 2014. © 2014 Wiley Periodicals, Inc.     

Delusions increase functional impairment in Alzheimer's disease

Background/Aims: Delusions in Alzheimer's disease (AD) may be associated with functional impairment. No studies to date have used functional instruments sensitive to changes in frontal executive function, possibly underestimating the impact. Methods: Patients with AD with and without delusions were administered cognitive tests and questionnaires to assess depression and quality of life. Caregivers were administered questionnaires to assess functional impairment, caregiver burden and behavioural symptoms. Results: AD patients with delusions (n = 19) when compared to AD patients without delusions (n = 19) matched for age, education and global cognitive function were significantly more functionally impaired based on performance on the Disability Assessment for Dementia Scale (p < 0.005). Conclusion: AD patients with delusions have significantly worse functional performance.     

Clock tests in depression, Alzheimer's disease, and elderly controls

OBJECTIVE: While clock-drawing tests are commonly used to screen for cognitive impairment in the elderly, little is known about the performance of elderly depressives. METHODS: We compared thirty-three patients with major depression to forty-two Alzheimer's disease and thirty age-matched controls on clock-drawing, copying, and reading. RESULTS: Patients with Alzheimer's disease had significantly lower scores on clock-drawing, copying, and reading than patients with depression or the controls (p < 0.05). Patients with depression did not differ significantly from controls on quantitative scores or qualitative errors. CONCLUSIONS: Clock tests may be useful for identifying depressed patients with underlying dementia.     

Automatic memory processes in normal ageing and Alzheimer's disease

This study examined the contribution of automatic and controlled uses of memory to stem completion in young, middle-aged and older adults, and compared these data with a study involving patients with Alzheimer's disease (AD) who performed the same task (Hudson and Robertson, 2007). In an inclusion task participants aimed to complete three-letter word stems with a previously studied word, in an exclusion task the aim was to avoid using studied words to complete stems. Performances under inclusion and exclusion conditions were contrasted to obtain estimates of controlled and automatic memory processes using process-dissociation calculations (Jacoby, 1991). An age-related decline, evident from middle age was observed for the estimate of controlled processing, whereas the estimate of automatic processing remained invariant across the age groups. This pattern stands in contrast to what is observed in AD, where both controlled and automatic processes have been shown to be impaired. Therefore, the impairment in memory processing on stem completion that is found in AD is qualitatively different from that observed in normal ageing.     

Equivalent spatial-rotation deficits in normal aging and Alzheimer's disease

Two tests of spatial-rotation ability were administered to 17 young normals, 23 aged normals, and 51 patients with diagnoses of Alzheimer's disease (AD). The AD patients consisted of 28 early dementia patients and 23 advanced dementia patients. On a computerized version of the Boston Naming Test, 40 objects were presented for naming, 20 of which were rotated 180 degrees. The subjects' capacity for mental rotation was assessed on the basis of their accuracy of naming of rotated vs. unrotated objects. On Money's Standardized Road Map Test, in which the subject is asked whether turns on a map are to the left or to the right, spatial-rotation ability was assessed on the basis of the subject's left-right orientation on turns with movement away from the subject (requiring no rotation) vs. turns with movement toward the subject (requiring rotation). Performance on both tasks was progressively worse in the young normal, aged normal, early dementia, and advanced dementia groups. Both tasks demonstrated a clear spatial-rotation deficit in the elderly. Although the spatial-rotation effect was superimposed upon deficits in naming and left-right orientation in the demented subjects, the magnitude of the rotation effect did not significantly differ in the aged normal vs. the early dementia group on either task, suggesting that early AD produces no further impairment of spatial-rotation abilities than is produced by normal aging.