Howard Chertkow

Working memory and control of attention in persons with Alzheimer's disease and mild cognitive impairment.

The goal of the present study was to assess 3 attentional control processes--divided attention, manipulation capacities, and inhibition--in persons with mild cognitive impairment (MCI) and with mild Alzheimers disease (AD). Manipulation capacities were tested by comparing immediate serial recall with alphabetical-order recall of words. Divided attention was tested with the Brown-Peterson procedure, in which participants divide their attention between simple addition tasks and consonant trigrams over delays. Inhibition was tested with the Hayling procedure, in which participants complete sentences with words irrelevant to their context. Persons with AD showed severe impairment on the 3 attentional control components. Persons with MCI exhibited impaired performance on the Brown-Peterson procedure but normal performance on the other 2 tasks. With AD and MCI participants, there was a negative correlation between general cognitive deficits and impairment on attentional control tasks, indicating that attentional control deficits increase in the MCI/AD continuum. When separating MCI with and without significant subsequent decline, those with subsequent decline showed impaired performance on both the Brown-Peterson procedure and manipulation task. These data suggest that control of attention tasks can track AD at a preclinical stage and that impairment increases gradually during the preclinical phase of AD.

The Neural Substrate of Picture Naming

A PET study of 10 normal males was carried out using the bolus H215O intravenous injection technique to examine the effects of picture naming and semantic judgment on blood flow. In a series of conditions, subjects (1) passively viewed flashing plus signs, (2) noted the occurrence of abstract patterns, (3) named animal pictures, or (4) carried out a semantic judgment on animal pictures. Anticipatory scans were carried out after the subjects were presented with the instructions but before they began the cognitive task, as they were passively viewing plus signs. Our results serve to clarify a number of current controversies regarding the neural substrate of picture naming. The results indicate that the fusiform gyrus is unlikely to be the region where low-level perceptual processing such as shape analysis is undertaken. In fact, our evidence suggests that activation of the fusiform gyrus is most likely related to visual perceptual semantic processing. In addition, the inferior/middle frontal lobe activity observed while performing the picture naming and semantic judgment tasks does not appear to be due to the effects of anticipation or preparation. Furthermore, there appears to be a set of regions (a semantic network) that becomes activated regardless of whether the subjects perform a picture naming or semantic judgment task. Finally, picture naming of animals did not activate either parietal regions or anterior inferior left temporal regions, regardless of what subtraction baseline was used.

Anticipation causes increased blood flow to the anterior cingulate cortex.

Increased cerebral blood flow in the anterior cingulate cortex (ACC) has been noted in a range of cognitively demanding tasks studied with PET. A PET study of 10 normal males was carried out using the bolus H213O intravenous injection technique to examine the effects of anticipation on blood flow to the ACC. In a series of conditions, subjects 1) passively viewed flashing plus signs, 2) noted the occurrence of abstract patterns, 3) named animal pictures, 4) or carried out a semantic judgement on animal pictures. Anticipatory scans were carried out after the subjects were presented with the instructions but before they began the cognitive task, as they were passively viewing plus signs. Significantly increased cerebral blood flow to the ACC was found in all three cognitive tasks when compared with baseline. More importantly, a similar increase was observed in each of the anticipatory states when compared with baseline. When the anticipation scan served as the subtracted baseline for the cognitive task, the increase in blood flow was not significant. This pattern of activity suggests that receiving instructions, preparation, and anticipation of the cognitive task, rather than task‐related processing itself, may be responsible for the increased blood flow in the ACC noted in many PET studies of simple cognitive tasks.

Constraining theories of semantic memory processing: Evidence from Dementia

Abstract In this paper we analyse the performance of ten patients with Dementia of the Alzheimers Type (D.A.T.) who show a pattern of performance suggesting a deficit at the level of semantic memory in the face of normal visual perceptual processing. We use the results of their performance on probe questions for pictures and words to evaluate several hypotheses arising from recent theories concerning semantic memory. We assess whether these patients demonstrate better performance on pictures than words (they do), and whether this can be explained away as a by-product of the perceptual nature of the items tested; pictures whose items have many discernible object parts would tend to contact more residual information in semantic memory, thus producing apparent superior performance from pictures. In fact, we find no support for this explanation. Rather, we are able to demonstrate, in the semantic category of animals, that it is only the items that are correctly identified (as a whole) that will give rise to ...

Magnetization transfer ratio in mild cognitive impairment and dementia of Alzheimer's type.

Almost half of the elderly subjects that are diagnosed with mild cognitive impairment (MCI) go on to develop dementia of Alzheimers type (DAT) over a 5-year follow-up. MCI and DAT subjects show regional decreases in the volume of brain structures, which correlate with the cognitive decline among these groups. Volumetric changes are found more consistently in the DAT group than in the MCI group. Since not all MCI subjects demonstrate volumetric decline, we propose that the underlying changes in the structural integrity of the brain, measured using magnetization transfer ratio (MTR), may be used as an additional predictor for abnormal cognitive decline in the elderly. Magnetic resonance (MR) images were obtained in 15 DAT, MCI, and elderly control subjects. Using automatic tissue classification, the brain region of each MR volume was segmented into gray matter and white matter. Mean and standard error of the mean MTR measured within the gray matter was found to be significantly lower in the MCI (30.77 +/-0.29; P = 0.037) and the DAT (29.37 +/-0.41; P = 0.000) group compared to the control group (32.11 +/-0.20). The MTR of white matter was significantly lower only in the DAT group. The gray matter volume was significantly lower (P = 0.000) in the DAT (387.29 +/-26.04 cm(3)) group compared to controls (532.93 +/-20.53 cm(3)) and MCI (464.64 +/-16.93 cm(3)). No significant differences were found in the white matter volume between the three groups. We conclude that changes in MTR are measurable even in the absence of detectable volumetric changes in gray and white matter in the MCI group. Furthermore, MTR changes may present a novel MRI measure for the early diagnosis of dementia of Alzheimers type.

Increased semantic priming in patients with dementia of the Alzheimer's type

Semantic priming on a lexical decision task(LDT) was examined in 50 patients with mild to moderate dementia of the Alzheimers Type(DAT), and 25 normal age-matched controls. DAT patients were slower in their responses, and showed significantly greater priming effects (mean 54 ms vs. 27 ms in controls). The size of the priming effect correlated with the speed of response on the LDT task for the individual DAT patients but not for controls. Twenty of the DAT patients (vs. one control) showed priming greater than 60 ms. This subgroup of DAT patients with hyperpriming was slower than the nonhyperpriming group on yes responses to targets preceded by unassociated prime words and more impaired on tests of clock drawing and verbal fluency. Slowing of responses alone, however, seems unable to account for the presence of increased priming in DAT patients. Its presence may reflect semantic memory deficits, as well as impaired attentional processing and supervisory control systems. The exact mechanism of this increased priming remains to be established.

Increased microRNA-34c abundance in Alzheimer's disease circulating blood plasma

Circulating microRNAs, present either in the cellular component, peripheral blood mononuclear cells (PBMC), or in cell-free plasma, have emerged as biomarkers for age-dependent systemic, disease-associated changes in many organs. Previously, we have shown that microRNA (miR)-34a is increased in circulating PBMC of Alzheimers disease (AD) patients. In the present study, we show that this microRNAs sister, miR-34c, exhibits even greater increase in both cellular and plasma components of AD circulating blood samples, compared to normal age-matched controls. Statistical analysis shows the accuracy of levels of miR-34c assayed by receiver operating characteristic (ROC) analysis: the area under the curve is 0.99 (p < 0.0001) and the 95% confidence level extends from 0.97 to 1. Pearson correlation between miR-34c levels and mild and moderate AD, as defined by the mini-mental state examination (MMSE), shows an r-value of −0.7, suggesting a relatively strong inverse relationship between the two parameters. These data show that plasma levels of microRNA 34c are much more prominent in AD than those of its sister, miR-34a, or than its own level in PBMC. Transfection studies show that miR-34c, as does its sister miR-34a, represses the expression of several selected genes involved in cell survival and oxidative defense pathways, such as Bcl2, SIRT1, and others, in cultured cells. Taken together, our results indicate that increased levels of miR-34c in both PBMC and plasma may reflect changes in circulating blood samples in AD patients, compared to age-matched normal controls.

Regional magnetization transfer ratio changes in mild cognitive impairment

Reduction in temporal lobe volume is consistently found in dementia of Alzheimers type (DAT). However, due to the lack of a consistent association between brain volume and cognitive decline in mild cognitive impairment (MCI), volumetric measures are not a reliable predictor for the progression of the disease. In our study, we hypothesized that changes in the magnetization transfer ratio (MTR) may reflect underlying brain pathology in the absence of quantifiable volumetric changes. Such a measure may be used as a predictor for abnormal cognitive decline in elderly subjects. The study was carried out on 15 normal elderly controls, 11 subjects with DAT, and 12 subjects with MCI. We used MTRs with magnetic resonance imaging (MRI) to detect tissue changes in the four lobes of each hemisphere, and compared that to the volumetric changes in the same regions. Our results indicate that the MTR of both temporal lobes is significantly reduced in subjects with MCI in the absence of significant volumetric changes. In comparison, DAT subjects have significantly reduced temporal lobe volumes and MTR. We conclude that changes in MTR have the potential to mark the progression of MCI to DAT, before volumetric changes are detected on conventional MRI scans.

Montreal Cognitive Assessment (MoCA): Concept and Clinical Review

The Montreal Cognitive Assessment (MoCA) is a cognitive screening instrument developed to detect mild cognitive impairment (MCI). It is a simple 10 minute paper and pencil test that assesses multiple cognitive domains including memory, language, executive functions, visuospatial skills, calculation, abstraction, attention, concentration, and orientation. Its validity has been established to detect mild cognitive impairment in patients with Alzheimer’s disease and other pathologies in cognitively impaired subjects who scored in the normal range on the MMSE. MoCA’s sensitivity and specificity to detect subjects with MCI due to Alzheimer’s disease and distinguish them from healthy controls are excellent. MoCA is also sensitive to detect cognitive impairment in cerebrovascular disease and Parkinson’s disease, Huntington’s disease, brain tumors, systemic lupus erythematosus, substance use disorders, idiopathic rapid eye movement sleep behaviour disorder, obstructive sleep apnoea, risk of falling, rehabilitation outcome, and epilepsy. There are several features in MoCA’s design that likely explain its superior sensitivity for detecting MCI. The MoCA’s memory testing involves more words, fewer learning trials, and a longer delay before recall than the MMSE. Executive functions, higher-level language abilities, and complex visuospatial processing can also be mildly impaired in MCI participants of various etiologies and are assessed by the MoCA with more numerous and demanding tasks than the MMSE. MoCA was developed in a memory clinic setting and normed in a highly educated population. Norms in lesser educated, community based, multi-cultural samples will hopefully be available to help first line healthcare providers better assess subjects presenting with cognitive complaints. The MoCA is freely accessible for clinical and educational purposes (www.mocatest.org), and is available in 36 languages and dialects.

Executive Functions in Frontotemporal Dementia and Lewy Body Dementia

Diagnosis of different types of dementia is often based on clinical symptomatology rather than underlying pathology; therefore, accurate diagnosis depends on a thorough description of cognitive functioning in different dementias. Furthermore, direct comparison of cognitive functions between different types of dementia is necessary for differential diagnosis. Executive dysfunction is common in several types of dementia, including frontotemporal dementia (FTD) and Lewy body dementia (LBD); however, FTD and LBD patients have never been directly compared on measures of executive functioning. The authors compared the performance of 17 FTD and 15 LBD patients on 6 measures of executive functioning in terms of statistical group differences, mean severity of clinical impairment in comparison to normal controls, and frequency of impairment. Results indicated a remarkably similar pattern of performance across all areas examined in terms of mean performance, as well as degree and frequency of impairment. Only the Stroop test produced results that could potentially differentiate the patient groups. These findings suggest that both FTD and LBD should be considered disorders involving executive dysfunction.