Current Alzheimer Research (v.14, #9)

Meet Our Editorial Board Member by Giulio Maria Pasinetti (913-913).

Modulation of Retinal Arteriolar Central Reflection by APOE Genotype by Shaun Frost, Alauddin Bhuiyan, David Offerman, James D. Doecke, S. Lance Macaulay, Hamid R. Sohrabi, David Ames, Colin Masters, Ralph N. Martins, Yogesan Kanagasingam, AIBL Research Group (916-923).
Objective: This study investigated the retinal arteriolar central reflex (CR, the central reflection observed in photographs of retinal vessels), which may provide information about micro-vascular health in the retina and also the brain, due to the homology between these vascular networks. The study also describes a novel computer based semi-automated technique that accurately quantifies retinal arteriolar CR and vessel width, and calculates the CR to vessel width ratio (CRR) from digital retinal photographs. <P></P> Methods: Digital retinal photographs were collected from participants in the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL), including 25 participants diagnosed with Alzheimer’s disease (AD) (age 72.4 ± 7.5 yrs, 12 male, 13 female) and 123 elderly participants without dementia (cognitively normals: CN) (age 71.6 ± 5.6 yrs, 55 male, 68 female). Using a sub-cohort of 144 (22 AD, 122 CN) with the novel CRR measures, we identified significantly higher CRR levels in AD participants (mean CRR 0.253 (SD 0.04)) as compared with CN’s (mean CRR 0.231 (SD 0.04), p = 0.025). Adjustment for <i>APOE</i> ε4 allele status however, reduced the significance (p = 0.081). CRR was significantly higher in <i>APOE</i> ε4 allele carriers (mean CRR 0.254 (SD 0.03) as compared with non-carriers (mean CRR 0.224 (SD 0.05), p < 0.0001). <P></P> Results: These data indicate that CRR is strongly linked to <i>APOE</i> ε4 status and exhibits a weaker, independent trend with AD diagnosis. The retina may be useful as a novel model for non-invasive monitoring of the effects of <i>APOE</i> ε4 on the central nervous system, particularly in cerebrovascular disease.

Spatio-Temporal Fluctuations of Neural Dynamics in Mild Cognitive Impairment and Alzheimer's Disease by Jesús Poza, Carlos Gómez, María García, Miguel A. Tola-Arribas, Alicia Carreres, Mónica Cano, Roberto Hornero (924-936).
Background: An accurate characterization of neural dynamics in mild cognitive impairment (MCI) is of paramount importance to gain further insights into the underlying neural mechanisms in Alzheimer’s disease (AD). Nevertheless, there has been relatively little research on brain dynamics in prodromal AD. As a consequence, its neural substrates remain unclear. <P></P> Methods: In the present research, electroencephalographic (EEG) recordings from patients with dementia due to AD, subjects with MCI due to AD and healthy controls (HC) were analyzed using relative power (RP) in conventional EEG frequency bands and a novel parameter useful to explore the spatio-temporal fluctuations of neural dynamics: the spectral flux (SF). <P></P> Results: Our results suggest that dementia due to AD is associated with a significant slowing of EEG activity and several significant alterations in spectral fluctuations at low (i.e. theta) and high (i.e. beta and gamma) frequency bands compared to HC (p < 0.05). Furthermore, subjects with MCI due to AD exhibited a specific frequency-dependent pattern of spatio-temporal abnormalities, which can help identify neural mechanisms involved in cognitive impairment preceding AD. Classification analyses using linear discriminant analysis with a leave-one-out cross-validation procedure showed that the combination of RP and within-electrode SF at the beta band was useful to obtain a 77.3 % of accuracy to discriminate between HC and AD patients. In the case of comparison between HC and MCI subjects, the classification accuracy reached a value of 79.2 %, combining within-electrode SF at beta and gamma bands. SF has proven to be a useful measure to obtain an original description of brain dynamics at different stages of AD. <P></P> Conclusion: Consequently, SF may contribute to gain a more comprehensive understanding into neural substrates underlying MCI, as well as to develop potential early AD biomarkers.

Differentiated Effective Connectivity Patterns of the Executive Control Network in Progressive MCI: A Potential Biomarker for Predicting AD by Suping Cai, Yanlin Peng, Tao Chong, Yun Zhang, Karen M. von Deneen, Liyu Huang, Alzheimer&apos;s Disease Neuroimaging Initiative (937-950).
Objective: Mild cognitive impairment (MCI) is often a transitional state between normal aging and Alzheimer’s disease (AD). When observed longitudinally, some MCI patients convert to AD, while a considerable portion either remains MCI or revert to a normal functioning state. This divergence has provided some enlightenment on a potential biomarker to be represented in the resting state brain activities of MCI patients with different post-hoc labels. Recent studies have shown impaired executive functions, other than typically explicated memory impairment with AD/MCI patients. This observation raises the question that whether or not the executive control network (ECN) was impaired, which pivotally supports the central executive functions. Given the fact that effective connectivity is a sufficient index in detecting resting brain abnormalities in AD/MCI, the current study specifically asks a question whether the effective connectivity patterns are differentiated in MCI patients with different post-hoc labels. <P></P> Methods: We divided the MCI subjects into three groups depending on their progressive state obtained longitudinally: 1) 15 MCI-R subjects: MCI reverted to the normal functioning state and stabilized to the normal state in 24 months; 2) 35 MCI-S subjects: MCI patients maintained this disease in a stable state for 24 months; 3) 22 MCI-P subjects: MCI progressed to AD and stabilized to AD in 24 months, and 4) 39 age-matched normal control subjects (NC). We conducted a Granger causality analysis after identifying the core nodes of ECN in all of the subjects using Independent Component Analysis. Our findings revealed that different MCI groups presented different effective connectivity patterns within the ECN compared to the NC group. Specifically, (1) dorsolateral prefrontal cortex (dLPFC) and medial prefrontal cortex (mPFC) were the core nodes in the ECN network that exhibited different connecting patterns; (2) an effective connection circuit “R.dLPFC&rarr; right caudate&rarr; left thalamus&rarr;R.dLPFC” in the ECN showed different levels of damage; and (3) there were four pathways between the R.dLPFC and L.LP, and these four pathways were also different. <P></P> Results: Our results would help to understand the potential central mechanism of MCI patients. The differentiated effective connectivity of ECN may serve as a potential biomarker for early detection of AD, which may also provide a reference for clinical researchers to manipulate active but distinctive interventions for MCI patients who have different risks.

Motif Discovery in Speech: Application to Monitoring Alzheimer's Disease by Peter Garrard, Vanda Nemes, Dragana Nikolic, Anna Barney (951-959).
Background: Perseveration - repetition of words, phrases or questions in speech - is commonly described in Alzheimer’s disease (AD). Measuring perseveration is difficult, but may index cognitive performance, aiding diagnosis and disease monitoring. Continuous recording of speech would produce a large quantity of data requiring painstaking manual analysis, and risk violating patients’ and others’ privacy. A secure record and an automated approach to analysis are required. <P></P> Objectives: To record bone-conducted acoustic energy fluctuations from a subject’s vocal apparatus using an accelerometer, to describe the recording and analysis stages in detail, and demonstrate that the approach is feasible in AD. <P></P> Methods: Speech-related vibration was captured by an accelerometer, affixed above the temporomandibular joint. Healthy subjects read a script with embedded repetitions. Features were extracted from recorded signals and combined using Principal Component Analysis to obtain a one-dimensional representation of the feature vector. Motif discovery techniques were used to detect repeated segments. The equipment was tested in AD patients to determine device acceptability and recording quality. <P></P> Results: Comparison with the known location of embedded motifs suggests that, with appropriate parameter tuning, the motif discovery method can detect repetitions. The device was acceptable to patients and produced adequate signal quality in their home environments. <P></P> Conclusion: We established that continuously recording bone-conducted speech and detecting perseverative patterns were both possible. In future studies we plan to associate the frequency of verbal repetitions with stage, progression and type of dementia. It is possible that the method could contribute to the assessment of disease-modifying treatments.

Kinematic and Pressure Features of Handwriting and Drawing: Preliminary Results Between Patients with Mild Cognitive Impairment, Alzheimer Disease and Healthy Controls by Josep Garre-Olmo, Marcos Faúndez-Zanuy, Karmele López-de-Ipiña, Laia Calvó-Perxas, Oriol Turró-Garriga (960-968).
Background: Alzheimer’s disease (AD) is the most common neurodegenerative dementia of old age, and the leading chronic disease contributor to disability and dependence among older people worldwide. Clinically, AD is characterized by a progressive cognitive decline that interferes with the ability to perform the activities of daily living. Handwriting and drawing are complex human activities that entail an intricate blend of cognitive, kinesthetic, and perceptual-motor features. <P></P> Objective: To compare the kinematic characteristics of handwriting and drawing between patients with AD, patients with mild cognitive impairment (MCI) and healthy controls. <P></P> Methods: We used a cross-sectional and observational design to assess the kinematic and pressure features of handwriting and drawing using a computerized system. Participants were asked to copy one sentence, write a dictated sentence and an own sentence, copy two and-three dimensions drawings, and to execute the clock drawing test. By means of discriminant analyses, we explored the value of several kinematic features in order to classify participants depending on their degree of cognitive functioning. <P></P> Results: The sample consisted of 52 participants (23 AD, 12 MCI, and 17 healthy controls) with a mean age of 69.7 years (SD=8.11). The degree of correct classification was largely dependent on the nature of the groups to be classified and the specific task, and ranged between 63.5% and 100%. Diagnostic accuracy based on kinematic measures showed higher specificity values for distinguishing between normal and impaired cognition (MCI and AD), and higher sensitivity was obtained when distinguishing between impaired cognition levels (MCI <i>vs</i>. AD). <P></P> Conclusion: The kinematic features of writing and drawing procedures, rather than the final product, may be a useful and objective complement to the clinical assessment of patients with cognitive impairment.

The Ultimate Outlier: Transitional Care for Persons with Dementia and BPSD by Jiska Cohen-Mansfield, Colleen A. Ray, Tasmia Hai, Cristina Marcu, Brandy L. Callahan, Morris Freedman (969-977).
Background: Transitional care units aim to assist caregivers who cannot manage the care for persons with dementia who manifest behavioral and psychological symptoms of dementia (BPSD). However, there is a dearth of research on such care units. <P></P> Objective: The current study reviewed one specialized transitional unit to better understand the characteristics of the persons with dementia and behavioral symptoms entering such unit. The study also looked at the change in terms of (a) BPSD, (b) use of psychotropic medications and (c) function of the patients in this unit. <P></P> Method: A retrospective chart review of 73 residents of a transitional care unit was conducted. Background and outcome information were collected on electronic data entry sheets. <P></P> Results: Patients had an average age of 75.0 years, 74.0% were men. Mean Cognitive Performance Scale score was 4.7. Comparing admission to discharge, there was a significant decrease in BPSD, and a significant increase in number of central nervous system medications. There were no significant changes in cognition or ability to perform activities of daily living. <P></P> Conclusion: Patient characteristics differed from those of other long term care settings. This unique population requires further study to optimize the outcomes.

Association between Periodontal Health Status and Cognitive Abilitie s. The Role of Cytokine Profile and Systemic Inflammation by Marta Sochocka, Maciej Sobczyński, Aleksandra Sender-Janeczek, Katarzyna Zwolińska, Olga Błachowicz, Tomasz Tomczyk, Marek Ziętek, Jerzy Leszek (978-990).
Background: Contemporary neurobiology, periodontal medicine, and immunology are now focusing on the relationship between chronic periodontitis and systemic diseases, which also include Alzheimer’s disease (AD). However a causative relationship between dementia and periodontitis has yet to be confirmed. <P></P> Objective: The aim of the study was to determine whether periodontal health status and cognitive abilities are correlated with the relative changes in systemic measures of pro- and anti-inflammatory cytokines as a reflection of systemic inflammation. We hypothesized that poor periodontal health status may be associated with cognitive impairment and dementia <i>via</i> the exacerbation of systemic inflammation. <P></P> Methods: Based on the periodontal and psychiatric examinations and the cytokine levels produced by unstimulated and LPS-stimulated PBL isolated from 128 participants, we have examined if the coexisting of these two clinically described conditions may have influence on the systemic inflammation. Mini- Mental State Examination (MMSE) and Bleeding on Probing (BoP) test results were combined into the one mathematical function <i>U</i>, which determines the severity of specific condition, called <i>Cognitive and periodontal impairment state</i>. Similarly, the levels of cytokines were combined into the one mathematical function V, whose value determines the level of <i>Inflammatory state</i>. The correlation between <i>U</i> and <i>V</i> was determined. <P></P> Results: These results confirm that the presence of cognitive decline and the additional source of proinflammatory mediators, like periodontal health problems, aggravate the systemic inflammation. Conclusion: It is most likely that the comorbidity of these two disorders may deepen the cognitive impairment, and neurodegenerative lesions and advance to dementia and AD.

White Matter Integrity in Subcortical Vascular Cognitive Impairment: A Multimodal Structural MRI Study by Yao Wang, Wenwei Cao, Yawen Sun, Xue Chen, Weina Ding, Qun Xu, Yan Zhou, Jianrong Xu, Shiteng Suo (991-999).
Objective: To investigate the disruption of white matter (WM) integrity in patients with subcortical vascular cognitive impairment (SVCI) with multimodal structural magnetic resonance imaging (MRI), and to explore the relationships between WM damage, structural network disruptions, and general cognitive function decline. <P></P> Methods: Twenty-eight patients with SVCI and twenty control subjects underwent structural MRI scans and neuropsychological assessment. WM volume (WMV), WM hyperintensities (WMH), lacunar infarcts (LI), diffusion tensor imaging parameters and structural network characteristics were compared between two groups. Correlations between these parameters and general cognitive function were calculated. <P></P> Results: WMV, WMH load, LI number, mean fractional anisotropy (FA), peak height and peak location of mean diffusivity (MD) of normal-appearing WM (NAWM) and structural network characteristics were significantly different between the two groups. Disruption of WM microstructure and network characteristics was widespread. WMV, WMH load, mean FA and peak location of MD of NAWM explained about 70% of the variance in structural network characteristics. Shortest path length with LI number explained 47.5% of the variance in z-scores. <P></P> Conclusion: SVCI was associated with widespread disruptions of WM integrity in the brain. Network characteristics may be a comprehensive reflection of WM integrity and a superior predictor of general cognitive function, while LI was an independent predictor of cognitive impairment.

Diagnostic and Prognostic Potential of Retinal Biomarkers in Early On-Set Alzheimer's Disease by Sahar Shariflou, Dana Georgevsky, Hussein Mansour, Mahdie Rezaeian, Nafiseh Hosseini, Fathima Gani, Vivek Gupta, Nady Braidy, S. Mojtaba Golzan (1000-1007).
Objective: Accumulating evidence suggests that the eye can be used in the assessment of early on-set Alzheimer’s disease (AD). The eye offers a natural window to the brain through the retina. The retina and brain share common developmental origins and patho-physiological origins and mechanisms, having been sequestered from it during early development, but retaining its connections with the brain <i>via</i> the optic nerve. Therefore, it is well understood that neurological abnormalities have a direct profound impact on the retina. Recent studies suggest an array of physiological and pathological changes in the retina in dementia and specifically in AD. There are also reports on imaging the two hallmark proteins of the disease, extracellular amyloid beta peptides and intracellular hyper phosphorylated tau protein, as a proxy to neuroimaging. <P></P> Results: In this review, we summarise retinal structural, functional and vascular changes reported to be associated with AD. We also review techniques employed to image these two major hall mark proteins of AD and their relevance for early detection of AD.

Optimizing ADAS-Cog Worksheets: A Survey of Clinical Trial Rater s' Perceptions by Stephen M. Meyer, Kristina A. Bertzos, Magdalena Perez, Donald J. Connor, Kimberly Schafer, Sarah Walter (1008-1016).
Background: The Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADASCog) remains the most widely used test of longitudinal cognitive functioning in Alzheimer’s disease (AD) clinical trials. Unlike most neuropsychological tests, the ADAS-Cog source documentation worksheets are not uniform across clinical trials, and vary by document layout, inclusion of administration and/or scoring instructions, and documentation of subtest scoring (<i>e.g</i>., recording correct <i>versus</i> incorrect scores), among other differences. Many ADAS-Cog test administrators (raters) participate in multiple AD trials and switching between different ADAS-Cog worksheets may increase the likelihood of administration and/or scoring mistakes that lessen the reliability of the instrument. An anonymous online survey sought raters’ experiences with ADAS-Cog worksheets and their opinions on the design and content of the worksheets. <P></P> Results: Results of the survey indicated preference for structure and standardization of the ADASCog worksheets, which has been considered in the development of a standard ADAS-Cog source document by the Alzheimer’s Disease Cooperative Study (ADCS) Working Group.