Matteo De Marco

Paradigm shift: semantic memory decline as a biomarker of preclinical Alzheimer's disease

Uncovering the presence of Alzheimer’s disease (AD) in routine neurological management of middle-aged/elderly adults, and differentiating its combination of symptoms from those induced by the processes of normal aging, neurovascular disease or psychiatric conditions (e.g., depression), are challenges of primary importance. Usually, it is the onset of behavioral symptoms that encourages patients with AD and caregivers to seek medical attention for the first time. Research evidence, however, shows that the earliest changes triggered by the disease on the biology of the brain occur several decades prior to any behavioral change of clinical relevance [1]. Based on this large preclinicalstage/symptomatic-stage temporal discrepancy, it is of paramount importance to identify biomarkers that are more effective than those currently used in clinical practice. An ideal biomarker should be of as early diagnostic help as possible in the disease-progression timeline, as well as highly sensitive and specific. On this note, the use of cognitive tests is among the most proficient sources of clinical information in the early phases of AD, due to their validity, reliability and simplicity/immediateness. A skillful interpretation of neuropsychological performance may offer an indirect, yet fruitful view of the pathological processes affecting the nervous system, which could be the result of incipient AD. Although episodic memory impairment has been classically recognized as the main symptom of the prodromal AD stage characterized by mild cognitive impairment (MCI) [2], a temporally parallel decline of semantic memory has also been described [3,4]. The basic clinical disadvantage associated with episodic memory is that a qualitatively (but certainly not quantitatively) similar memory decline is also ‘physiologically’ visible in the absence of any pathologies in the general population of elderly adults. In contrast, semantic memory remains fairly stable across the lifespan, and aspects of lexical-semantic abilities even appear to improve with age [5]. Based on this, using the same logic argument that sustains all differential diagnoses, measuring semantic memory can be discriminative in separating healthy and pathological aging. Nevertheless, the most recent criteria for the detection of the earliest clinical manifestation of AD [6,7] persist in highlighting the sole role of measures of episodic retrieval. A major reason behind the choice of episodic memory as the cognitive subdomain ‘of reference’ lies in the fact that prodromal, earlysymptomatic AD (manifesting in the form of MCI) corresponds to the pathophysiological moment in which the neurofibrillary pathology intensifies within the hippocampal complex [8]. This mediotemporal structure sustains the neocortical circuitry responsible for context-associated, episodic memory [9]. Based on this, the theoretical convergence of peptidic accumulation of hypephosphorylated TAU protein within hippocampal cells, Paradigm shift: semantic memory decline as a biomarker of preclinical Alzheimer’s disease

Cognitive stimulation of the default-mode network modulates functional connectivity in healthy aging.

A cognitive-stimulation tool was created to regulate functional connectivity within the brain Default-Mode Network (DMN). Computerized exercises were designed based on the hypothesis that repeated task-dependent coactivation of multiple DMN regions would translate into regulation of resting-state network connectivity. Forty seniors (mean age: 65.90 years; SD: 8.53) were recruited and assigned either to an experimental group (n=21) who received one month of intensive cognitive stimulation, or to a control group (n=19) who maintained a regime of daily-life activities explicitly focused on social interactions. An MRI protocol and a battery of neuropsychological tests were administered at baseline and at the end of the study. Changes in the DMN (measured via functional connectivity of posterior-cingulate seeds), in brain volumes, and in cognitive performance were measured with mixed models assessing group-by-timepoint interactions. Moreover, regression models were run to test gray-matter correlates of the various stimulation tasks. Significant associations were found between task performance and gray-matter volume of multiple DMN core regions. Training-dependent up-regulation of functional connectivity was found in the posterior DMN component. This interaction was driven by a pattern of increased connectivity in the training group, while little or no up-regulation was seen in the control group. Minimal changes in brain volumes were found, but there was no change in cognitive performance. The training-dependent regulation of functional connectivity within the posterior DMN component suggests that this stimulation program might exert a beneficial impact in the prevention and treatment of early AD neurodegeneration, in which this neurofunctional pathway is progressively affected by the disease.

Apolipoprotein E ε4 Allele Modulates the Immediate Impact of Acute Exercise on Prefrontal Function

The difference between Apolipoprotein E ε4 carriers and non-carriers in response to single exercise sessions was tested. Stroop and Posner tasks were administered to young untrained women immediately after walking sessions or moderately heavy exercise. Exercise had a significantly more profound impact on the Stroop effect than on the Posner effect, suggesting selective involvement of prefrontal function. A significant genotype-by-exercise interaction indicated differences in response to exercise between ε4 carriers and non-carriers. Carriers showed facilitation triggered by exercise. The transient executive down-regulation was construed as due to exercise-dependent hypofrontality. The facilitation observed in carriers was interpreted as better management of prefrontal metabolic resources, and explained within the antagonistic pleiotropy hypothesis framework. The findings have implications for the interpretation of differences between ε4 carriers and non-carriers in the benefits triggered by long-term exercise that might depend, at least partially, on mechanisms of metabolic response to physical activity.

Cognitive Stimulation: The Evidence Base for its Application in Neurodegenerative Disease

Multiple modalities of cognitive stimulation (CS) have been designed and tested in samples of patients with probable Alzheimers disease (AD). Despite the substantial inter-study variability, an overall positive impact of CS is reported. This impact has been especially observed in general measures of cognition. The mechanisms by which cognitive exercises would be beneficial for high-order cortical functions are still largely undetermined, however. When CS has been applied to patients with mild cognitive impairment (who are at the prodromal stage of AD) more stringent methodological criteria and designs were used and studies have been of greater clinical and research relevance. At this disease stage, a positive impact of CS has been reported in a range of different cognitive domains, and even at a neuro-computational level by the measurement of test-retest modifications of brain function. The effects of CS in healthy adults have also been studied. This population allows researchers to explore and test specific neural mechanisms possibly underlying the effect of pen-and-paper or computerised exercises. The evidence from these studies and those contributing to a better understanding of the pathophysiology of AD has led to devising forms of CS as preventive and therapeutical measures for neurodegenerative diseases based on novel frameworks of brain structure, function and connectivity. An extensive review of the literature was carried out to clarify whether CS is effective in AD and mild cognitive impairment and, together with the evidence from studies in healthy participants, to identify the relevant mechanisms that might sustain this effectiveness.

Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer’s Disease in Humans

BACKGROUND There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimers disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans. OBJECTIVE We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls. METHODS Structural and resting state functional MRI scans, and neuropsychological scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested. RESULTS VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD. CONCLUSION Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration.

Morphometric correlates of dysarthric deficit in amyotrophic lateral sclerosis

Our objective was to investigate the volumetric correlates of speech in amyotrophic lateral sclerosis (ALS). Twenty-three ALS patients had a structural 3D MRI scan, neuropsychological, linguistic and speech assessments. Twenty-three healthy adults of comparable age, education, white-matter hyperintensity load and intracranial volumes were also recruited. Between-group differences in grey matter and white matter (WM) were examined to characterize ALS patients accurately. The association between residual speech and volumetric maps was studied in these patients. Results demonstrated that ALS patients showed a pattern of WM reduction, which was located in peri-cortical motor/premotor fibres bilaterally, and in a large volume extending from the pons/midbrain to the cerebellum. A speech composite score was computed, and this was positively associated with premotor/supplementary-motor WM bilaterally, and right cerebellar WM. Since premotor associations were found in volumes where ALS patients showed WM reduction, this region is believed to be directly involved in speech execution in this group. Since cerebellar associations were instead found in volumes free from shrinkage, this region is interpreted as playing a modulatory role, compensating for the impact of ALS pathology.

Integration of Cognitive Tests and Resting State fMRI for the Individual Identification of Mild Cognitive Impairment

WARM among the subjects of two sets of PET data from, respectively, 31 patients with dementia of Alzheimer’s type, and 28 healthy volunteers, compared to a conventional Standard Uptake Value Ratio (SUVR) index. Results: The discriminatory powers of binding potential (BP) and sCBF measures determined withWARM exceeded the power of SUVR. Estimated as the area under the curves (AUC) of the ROC of ten brain regions, the sCBFmeasure had the AUC closest to unity (Table). The discriminatory power of a measure ranges from AUC 0.5 (no discrimination) to AUC 1 (complete discrimination). The differences between the two groups, both of PIB retention and surrogate CBF index, were highly significant (P< 0.001), with the CBF index providing the greatest degree of discrimination between patients and healthy volunteers (Table). Conclusions: We conclude that WARM yields two important variables that independently discriminate among patients with Alzheimer’s disease and healthy volunteers with operating characteristics that are superior to conventional methods of analysis. Gjedde A, Aanerud J, Braendgaard H, Rodell A (2013) Front Aging Neurosci. http://dx.doi.org/10.3389/fnagi.2013.00070 Rodell A, Aanerud J, Braendgaard H, Gjedde A (2013) Front Aging Neurosci. http://dx.doi. org/10.3389/fnagi.2013.00045.

White Matter Hyperintensity Load Modulates Brain Morphometry and Brain Connectivity in Healthy Adults: A Neuroplastic Mechanism?

White matter hyperintensities (WMHs) are acquired lesions that accumulate and disrupt neuron-to-neuron connectivity. We tested the associations between WMH load and (1) regional grey matter volumes and (2) functional connectivity of resting-state networks, in a sample of 51 healthy adults. Specifically, we focused on the positive associations (more damage, more volume/connectivity) to investigate a potential route of adaptive plasticity. WMHs were quantified with an automated procedure. Voxel-based morphometry was carried out to model grey matter. An independent component analysis was run to extract the anterior and posterior default-mode network, the salience network, the left and right frontoparietal networks, and the visual network. Each model was corrected for age, global levels of atrophy, and indices of brain and cognitive reserve. Positive associations were found with morphometry and functional connectivity of the anterior default-mode network and salience network. Within the anterior default-mode network, an association was found in the left mediotemporal-limbic complex. Within the salience network, an association was found in the right parietal cortex. The findings support the suggestion that, even in the absence of overt disease, the brain actuates a compensatory (neuroplastic) response to the accumulation of WMH, leading to increases in regional grey matter and modified functional connectivity.

ApoE ε4 Allele Related Alterations in Hippocampal Connectivity in Early Alzheimer’s Disease Support Memory Performance

BACKGROUND Whether the presence of the Apolipoprotein E ε4 allele modulates hippocampal connectivity networks in abnormal ageing has yet to be fully clarified. OBJECTIVE Allele-dependent differences in this pattern of functional connectivity were investigated in patients with very mild neurodegeneration of the Alzheimers type, carriers and non-carriers of the ε4 allele. METHOD A seed-based connectivity approach was used. The two groups were similar in demographics, volumetric measures of brain structure, and cognitive profiles. RESULTS ε4-carriers had increased connectivity between the seed area in the left hippocampus and 1) a left insular/lateral prefrontal region and 2) the contralateral right parietal cortex. Moreover, hippocampus- to-parietal connectivity in the group of ε4 carriers was positively associated with memory performance, indicating that the between-group difference reflects compensatory processes. Retrospective analyses of functional connectivity based on patients from the ADNI initiative confirmed this pattern. CONCLUSION We suggest that increased connectivity with areas external to the Default Mode Network (DMN) reflects both compensatory recruitment of additional areas, and pathological interwining between the DMN and the salience network as part of a global ε4-dependent circuital disruption. These differences indicate that the ε4 allele is associated with a more profound degree of DMN network breakdown even in the prodromal stage of neurodegeneration.

The network substrate of confabulatory tendencies in Alzheimer's disease

Confabulatory phenomena are rare in the early stage of Alzheimers disease (AD), are often provoked and are triggered by questions or in response to neuropsychological testing. In this retrospective study functional connectivity alterations were investigated for the first time in a group of patients with early AD who had shown evidence of verbal and non-verbal confabulatory tendencies. Resting-state functional magnetic resonance imaging (fMRI) scans of 18 confabulating patients were compared with those of 18 non confabulators. The finding showed that confabulators had decreased connectivity between a seed region in the right inferolateral frontal cortex and right mediotemporal and insular regions, and increased connectivity with frontal areas and a homologous region on the left. The seed control region in the left inferolateral frontal cortex showed increased connectivity with midline frontal and anterior cingulate regions, while a decrease was found in temporal areas. Confabulatory tendencies appear in early AD as a result of disconnection between crucial computational hubs in frontal and mediotemporal regions. This disconnection is coupled with the presence of up-regulation of frontal activity, and especially of midline and anterior cingulate regions, which might disrupt efficient output monitoring in confabulators.