Risk, Resilience, and the Two-Track Model of Dementia Grief Among Spouses of People Living With Cognitive Decline.

Pre-death grief in the context of dementia caregiving is a significant risk factor for depression, burden, anxiety, and adjustment difficulties. The Two-Track Model of Dementia Grief (TTM-DG) provides a bifocal perspective addressing the nature of the emotional attachment to a loved one living with cognitive impairment, along with a medico-psychiatric perspective associated with stress, trauma, and change in life. The aims of the present study were to empirically validate the components of the model as to identify salutary and risk factors for maladaptive grief responses. Participants were 62 spouses of people living with cognitive impairment, and a control group of 32 spouses. All completed a battery of self-report questionnaires. Structural Equation Modeling yielded six variables consistent with the TTM-DG: partner's behavioral disorders; caregiver's burden; social support; physical health; attachment anxiety; and dementia grief as an outcome measure. Additional findings addressed participants at risk for grief difficulties. The findings provide empirical support for the utility of the TTM-DG in the identification of risk factors associated with maladaptive responses and pre-death grief following a spousal cognitive decline. The TTM-DG can assist in the formulation of evidence-based evaluations and interventions to assist spouses caring for their loved ones living with dementia.

The Two-Track Model of Dementia Grief and spousal response to illness and death.

This cross-sectional study examined the experiences of healthy spouses caring for their partners via the Two-Track Model of Dementia Grief thereby broadening our understanding of the functional and relational aspects of this process. The 122 participating older adults had spouses drawn from four groups: mild to moderate cognitive-impairment; advanced cognitive-impairment; deceased following dementia; and, healthy controls. They completed a battery of self-report measures. Results showed elevated scores on both tracks of the model for all affected groups. Assisting spouses of those living with cognitive-impairment begins with the earliest symptoms of decline and continues after the death of the loved one.

Spousal Mourning for Partners Living with Cognitive Impairment: The Interplay of Attachment and the Two-Track Model of Dementia Grief.

The aim of the present research was to study the interplay of Attachment Theory and the Two-Track Model of Dementia Grief. To examine the research hypotheses, a cross-sectional study was designed and included 122 participants (Mean age = 72.77) drawn from four groups: spouses of people living with mild to moderate cognitive impairment, spouses of people living with advanced cognitive impairment, widowed spouses of deceased dementia patients, and a control group. Participants completed a battery of self-report questionnaires. Results showed that secure attachment constitutes a significant protective factor with regard to bio-psycho-social symptomatology (Track I) as well as difficulties in the relational bond with the spouse and grief over their deterioration (Track II). The results of the research support integrating attachment-based insights into clinical work with spouses coping with the losses accompanying cognitive decline and the grief processes that are operant in these losses.

Familial Early-Onset Alzheimer's Caused by Novel Genetic Variant and APP Duplication: A Cross-Sectional Study.

BACKGROUND: The clinical characteristics of symptomatic and asymptomatic carriers of early- onset autosomal dominant Alzheimer's (EOADAD) due to a yet-undescribed chromosomal rearrangement may add to the available body of knowledge about Alzheimer's disease and may enlighten novel and modifier genes. We report the clinical and genetic characteristics of asymptomatic and symptomatic individuals carrying a novel APP duplication rearrangement. METHODS: Individuals belonging to a seven-generation pedigree with familial cognitive decline or intracerebral hemorrhages were recruited. Participants underwent medical, neurological, and neuropsychological evaluations. The genetic analysis included chromosomal microarray, Karyotype, fluorescence in situ hybridization, and whole genome sequencing. RESULTS: Of 68 individuals, six females presented with dementia, and four males presented with intracerebral hemorrhage. Of these, nine were found to carry Chromosome 21 copy number gain (chr21:27,224,097-27,871,284, GRCh37/hg19) including the APP locus (APP-dup). In seven, Chromosome 5 copy number gain (Chr5: 24,786,234-29,446,070, GRCh37/hg19) (Chr5-CNG) cosegregated with the APP-dup. Both duplications co-localized to chromosome 18q21.1 and segregated in 25 pre-symptomatic carriers. Compared to non-carriers, asymptomatic carriers manifested cognitive decline in their mid-thirties. A third of the affected individuals carried a diagnosis of a dis-immune condition. CONCLUSION: APP extra dosage, even in isolation and when located outside chromosome 21, is pathogenic. The clinical presentation of APP duplication varies and may be gender specific, i.e., ICH in males and cognitive-behavioral deterioration in females. The association with immune disorders is presently unclear but may prove relevant. The implication of Chr5-CNG co-segregation and the surrounding chromosome 18 genetic sequence needs further clarification.

Fronto-striatal connectivity patterns account for the impact of methylphenidate on choice impulsivity among healthy adults.

Choice impulsivity depicts a preference towards smaller-sooner rewards over larger-delayed rewards, and is often assessed using a delay discounting (DD) task. Previous research uncovered the prominent role of dopaminergic signaling within fronto-striatal circuits in mediating choice impulsivity. Administration of methylphenidate (MPH), an indirect dopaminergic agonist, was shown to reduce choice impulsivity in animals and pathological populations, although significant inter-individual variability in these effects was reported. Whether MPH impacts choice impulsivity among healthy individuals, and whether variability in the impact of MPH is related to fronto-striatal activation and connectivity patterns, has yet to be assessed. Here, fifty-seven healthy young adults completed the DD task twice during fMRI scans, after acute administration of either MPH (20 mg) or placebo, in a randomized double-blind placebo-controlled design. Acute MPH administration was found to reduce choice impulsivity at the group level, yet substantial variability in this behavioral response was observed. MPH was also found to increase activation in the bilateral putamen and the right caudate, and to enhance functional connectivity between the left putamen and medial prefrontal cortex (mPFC), particularly during non-impulsive choices. Notably, the more putamen-mPFC functional connectivity increased during non-impulsive choices following MPH administration, the less an individual was likely to make impulsive choices. These findings reveal, for the first time in healthy adults, that acute MPH administration is associated with reduced choice impulsivity and increased striatal activation and fronto-striatal connectivity; and furthermore, that the magnitude of MPH-induced change in fronto-striatal connectivity may account for individual differences in the impact of MPH on impulsive behavior.

Cognitive dysfunction following COVID-19 infection.

The coronavirus (COVID-19) pandemic is still evolving, causing hundreds of millions of infections around the world. The long-term sequelae of COVID-19 and neurologic syndromes post COVID remain poorly understood. The present study aims to characterize cognitive performance in patients experiencing cognitive symptoms post-COVID infection. Patients evaluated at a post COVID clinic in Northern Israel who endorsed cognitive symptoms were referred for neurologic consultation. The neurologic work-up included detailed medical history, symptom inventory, neurological examination, the Montreal Cognitive Assessment (MoCA), laboratory tests and brain CT or MRI. Between December 2020 and June 2021, 46 patients were referred for neurological consultation (65% female), mean age 49.5 (19-72 years). On the MoCA test, executive functions, particularly phonemic fluency, and attention, were impaired. In contrast, the total MoCA score, and memory and orientation subscores did not differ from expected ranges. Disease severity, premorbid condition, pulmonary function tests and hypoxia did not contribute to cognitive performance. Cognitive decline may affect otherwise healthy patients post-COVID, independent of disease severity. Our examination identified abnormalities in executive function, attention, and phonemic fluency. These findings occurred despite normal laboratory tests and imaging findings.

Alzheimer's disease research progress in the Mediterranean region: The Alzheimer's Association International Conference Satellite Symposium.

As research and services in the Mediterranean region continue to increase, so do opportunities for global collaboration. To support such collaborations, the Alzheimer's Association was due to hold its seventh Alzheimer's Association International Conference Satellite Symposium in Athens, Greece in 2021. Due to the COVID-19 pandemic, the meeting was held virtually, which enabled attendees from around the world to hear about research efforts in Greece and the surrounding Mediterranean countries. Research updates spanned understanding the biology of, treatments for, and care of people with Alzheimer's disease (AD_ and other dementias. Researchers in the Mediterranean region have outlined the local epidemiology of AD and dementia, and have identified regional populations that may expedite genetic studies. Development of biomarkers is expected to aid early and accurate diagnosis. Numerous efforts have been made to develop culturally specific interventions to both reduce risk of dementia, and to improve quality of life for people living with dementia.

The First Word Recalled Measure - A Potential Addition to Clinical Exams.

Characterizing episodic memory abilities is highly important in the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI), and usually includes wordlist learning and recall tasks. Clinical evaluations typically focus on the number of words recalled, ignoring additional information, like serial position. Here, we tested the potential value of two serial positioning measures for clinical diagnosis - how retrieval is initiated, as measured by the first word recalled, and how it proceeds - using data from patients with AD and MCI that completed a wordlist learning and recall task. Our results show that during the early stages of learning, patients with AD are less prone to retrieve the first word from the wordlist, manifested as lower primacy effect in the first word recalled, compared with MCI patients. The first word recalled measure adds to the differentiation between the groups over and above the total number of words learned. Thus, the first word recalled during word list learning and recall tasks may be used as a simple complementary measure to distinguish between MCI and AD during standard neuropsychological evaluations.

Extracellular Vesicles of Alzheimer's Disease Patients as a Biomarker for Disease Progression.

Alzheimer's disease (AD) is a progressive neurodegenerative brain pathology and the most common form of dementia. Evidence suggests that extracellular vesicles (EVs) containing cytokines and microRNA are involved in inflammation regulation. The current study aimed to explore a potential impact of AD patients' EVs on disease progression. Blood samples were collected after obtaining signed informed consent (No. 0462-14-RMB) from 42 AD patients at three stages of disease severity and from 19 healthy controls (HC). EV size and concentration were studied by nanotracking analysis. EV membrane antigens were defined by flow cytometry and Western blot; EV protein contents were screened by protein array; the miRNA content was screened by nanostring technology and validated by RT-PCR. HC and AD patients' EVs consisted of a mixture of small (< 100 nm) and larger vesicles. The myelin oligodendrocyte glycoprotein (MOG) expression on EVs correlated with disease severity. EVs of patients with moderate and severe AD had significantly higher levels of MOG, compared with mild AD patients. Levels of EVs expressing the axonal glycoprotein CD171 were significantly higher in severe AD patients than in HC. Increase in endothelial EVs was observed in AD patients. An above twofold increase was found in the content of inflammatory cytokines and > 50% decrease in growth factors in AD patients' EVs compared with HC-EVs. Levels of let-7g-5p, miR126-3p, miR142-3p, miR-146a-5p, and mir223-3p correlated with disease severity. Neural damage, specific miRNA downregulation, and inflammatory cytokine upregulation, found in patients' EVs, might be used as a biomarker reflecting AD severity.

The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Precise cannabis treatment dosing remains a major challenge, leading to physicians' reluctance to prescribe medical cannabis. OBJECTIVE: To test the pharmacokinetics, analgesic effect, cognitive performance and safety effects of an innovative medical device that enables the delivery of inhaled therapeutic doses of Δ9 -Tetrahydrocannabinol (THC) in patients with chronic pain. METHODS: In a randomized, three-arms, double-blinded, placebo-controlled, cross-over trial, 27 patients received a single inhalation of Δ9 -THC: 0.5mg, 1mg, or a placebo. Δ9 -THC plasma levels were measured at baseline and up to 150-min post-inhalation. Pain intensity and safety parameters were recorded on a 10-cm visual analogue scale (VAS) at pre-defined time points. The cognitive performance was evaluated using the selective sub-tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Following inhalation of 0.5 mg or 1mg, Δ9 -THC plasma Cmax  ± SD were 14.3 ± 7.7 and 33.8 ± 25.7 ng/ml. Tmax  ± SD were 3.7 ± 1.4 and 4.4 ± 2.1 min, and AUC0  â†’ infinity ±SD were 300 ± 144 and 769 ± 331 ng*min/ml, respectively. Both doses, but not the placebo, demonstrated a significant reduction in pain intensity compared with baseline and remained stable for 150-min. The 1-mg dose showed a significant pain decrease compared to the placebo. Adverse events were mostly mild and resolved spontaneously. There was no evidence of consistent impairments in cognitive performance. CONCLUSION: This feasibility trial demonstrated that a metered-dose cannabis inhaler delivered precise and low THC doses, produced a dose-dependent and safe analgesic effect in patients with neuropathic pain/ complex-regional pain syndrome (CRPS). Thus, it enables individualization of medical cannabis regimens that can be evaluated pharmacokinetically and pharmacodynamically by accepted pharmaceutical models. SIGNIFICANCE: Evidence suggests that cannabis-based medicines are an effective treatment for chronic pain in adults. The pharmacokinetics of THC varies as a function of its route of administration. Pulmonary assimilation of inhaled THC causes rapid onset of analgesia. However, currently used routes of cannabinoids delivery provide unknown doses, making it impossible to implement a pharmaceutical standard treatment plan. A novel selective-dose cannabis inhaler delivers significantly low and precise doses of THC, thus allowing the administration of inhaled cannabis-based medicines according to high pharmaceutical standards. These low doses of THC can produce safe and effective analgesia in patients with chronic pain.

Ethnic Differences in Attending a Tertiary Dementia Clinic in Israel.

Introduction: Variations in lifestyle, socioeconomic status and general health likely account for differences in dementia disparities across racial groups. Our aim was to evaluate the characteristics of Arab (AS) and Jewish (JS) subjects attending a tertiary dementia clinic in Israel. Methods: Retrospective data regarding subjects attending the Cognitive Neurology Institute at Rambam Health Care Campus between April 1, 2010, and April 31, 2016, for complaints of cognitive decline were collected from the institutional registry. AS and consecutive JS, aged ≥50 years without a previous history of structural brain disease, were included. Results: The records of 6,175 visits were found; 3,246 subjects were ≥50 years at the initial visit. One hundred and ninety-nine AS and consecutive JS cases were reviewed. Mean age at first visit was 68.4 ± 8.8 for AS and 74.3 for JS (p < 0.0001). Mean education was 7.7 ± 4.8 years for AS and 11.3 years for JS (p < 0.0001). Mean duration of cognitive complaints prior to first visit did not differ between the groups. Initial complaints of both ethnicities were failing memory (97%) and behavioral changes (59%). Functional impairment was reported by 59% of AS and 45% of JS (p = 0.005). MMSE on first evaluation was 19.2 ± 7 for AS and 23.1 ± 5.9 for JS; p = 0.001. Alzheimer's disease was diagnosed in 32% AS and 23% JS, mild cognitive impairment in 12% AS and 21% JS. Normal cognition was diagnosed in 2% AS and 9% JS; p = 0.0001. Conclusions: Compared to JS, AS attend a tertiary clinic when their cognitive impairment already affects their functional abilities providing a comprehensive benchmark for social health care interventions to reduce disparities.

The Effect of a 30-Min Water-Pipe Smoking Session on Cognitive Measures and Cardio-Pulmonary Parameters.

INTRODUCTION: One session of water-pipe tobacco smoking (WPS) can increase carboxyhemoglobin (COHb) to levels comparable to those reported in carbon monoxide poisoning, which may cause memory impairment and confusion. METHODS: A prospective study evaluating healthy volunteers pre- and post-30 min of WPS session. Primary outcome parameters were executive cognitive measures [digit span test and Paced Auditory Serial Addition Test (PASAT)]. The effect of repeated cognitive testing 30 min apart without WPS was evaluated in age- and sex-matched healthy volunteers. Secondary outcome parameters included cardio-pulmonary, COHb, serum nicotine, and cytokine changes. RESULTS: Thirty-five subjects aged 25.6 ± 4.5 years smoked water-pipe for a 30-min session. Control group included 20 subjects aged 25.2 ± 5.1 years. Digit span test median score decreased after WPS (16 and 15, respectively, p = .003), insignificant decrease in controls. Median PASAT score increased after WPS (49 and 52, respectively, p = .009); however, a much larger significant increase was observed in controls (p ≤ .001). One WPS session resulted in significant increases in heart and respiratory rates and significant decrease in FEF25-75%. Post WPS, median COHb levels increased (from 2.2% to 10.7%, p < .0001) as did median serum nicotine levels (from 1.2 to 26.8 ng/mL, p < .0001). Serum cytokines levels: IL-2 and IL-6 increased (p < .0001 for each), and IL-10 and IL-5 decreased (p < .0001 and p = .04, respectively). CONCLUSIONS: One session of WPS resulted in significant negative effects on cognitive executive measures, significant increases in COHb and serum nicotine levels, and significant changes in serum cytokines. Our findings call for increasing awareness towards the possible consequences of cognitive alterations following a 30-min session of WPS. IMPLICATIONS: One 30-min session of water-pipe smoking resulted in negative effects on executive cognitive measures, increased carboxyhemoglobin and serum nicotine, and significant changes in serum cytokine levels. This study adds to the accumulating evidence on the harmful effects of water-pipe smoking, a growing epidemic, and calls for awareness of its possible consequences of acute cognitive alterations.

[ADHD IN THE AGING POPULATION: A NEW DIFFERENTIAL DIAGNOSIS?]

INTRODUCTION: During midlife and aging, subjective reports regarding cognitive decline increase in frequency. Age-associated cognitive impairment, mild cognitive impairment and dementia, increase in prevalence and are frequently diagnosed. Background medical conditions and risk factors are often regarded as contributing to the cognitive decline. The contribution of prior undiagnosed ADHD (Attention Deficit Hyperactive Disorder) is seldom considered. The aim of the current study was to examine whether childhood or adult ADHD should be considered relevant in the differential diagnosis of cognitive complaints during midlife and aging. METHODS: Thirty-six subjects, aged 50-70 years, diagnosed with probable ADHD (pADHD) and 29 controls participated in the present study. The pADHD group included 12 individuals self-referred due to self-complaints regarding cognitive decline or memory impairment, previously undiagnosed with ADHD (ADHD-A) but with lifelong symptomatology of ADHD and fulfilling ADHD criteria and 24 individuals, parents of diagnosed ADHD children and reporting ADHD symptoms (ADHD-B) , without complaints regarding recent cognitive decline. The neuropsychological evaluation included the Conners' Adult ADHD Rating Scale-SL, Beck Depression Inventory, and the following cognitive tests: logical memory subscale (LM- WMS), California Verbal study was conducted at the Cognitive Neurology Clinic - Rambam Health Care Campus and was granted the approval of the local IRB committee. RESULTS: ADHD-A were impaired on attention parameters while memory and executive functions were intact. ADHD-B did not present measurable attention or other neuropsychological deficits as compared to the control group. Neither group fulfilled criteria for MCI or dementia. CONCLUSIONS: ADHD should be considered as a new/additional entity in the differential diagnosis of subjective cognitive complaints among middle-aged and older persons. The recognition of the specific cognitive and behavioral profiles of ADHD should contribute to the ability to reach optimal differentiation from pre-dementia conditions in order to tailor appropriate therapies. The pathophysiology and future trajectory of the emerging ADHD symptomatology in older patients fulfilling lifelong ADHD symptomatology remains to be clarified. When examining older adults, ADHD should be considered as a differential diagnosis.

Cannabis-related cognitive impairment: a prospective evaluation of possible influences on patients with cancer during chemotherapy treatment as a pilot study.

OBJECTIVES: In patients with cancer, the use of medical cannabis has increased significantly during the recent years. There is evidence that cannabis consumption may affect cognitive performance; however, this potential effect has not been investigated prospectively in patients with cancer to date. We aimed to evaluate the effect of cannabis consumption on cognitive abilities as well as on symptom relief in patients with cancer during chemotherapy treatment. PATIENTS AND METHODS: A prospective study was carried out on a group of 17 patients on cannabis treatment (case) who were compared with 17 patients not on cannabis treatment (control). Participants completed self-reported questionnaires (the Hospital Anxiety and Depression Scale, Brief Fatigue Inventory, European Organization of Research and Treatment of Cancer core questions on the Quality of Life Questionnaire) and underwent the following neurocognitive tests: Montreal Cognitive Assessment, Digit Symbol Substitution subtest (WAIS III) and Digital-Finger Tapping Test. The evaluation was conducted before the initiation of cannabis consumption and 3 months later during the period of cannabis use. RESULTS: Improvement in executive functioning was demonstrated in the case group. In aspects of symptoms, improvement in fatigue, appetite and sleep disorder was demonstrated after cannabis consumption. Patients consuming cannabis did not differ from the control group in cognitive functioning over 3 months of use. No significant cognitive decline was observed in either group over time. CONCLUSION: These preliminary findings suggest that the short-term use of cannabis during chemotherapy treatment improved disease-related symptoms and did not affect cognitive skills in patients with cancer.

Cognitive impairment in hodgkin lymphoma survivors.

Cancer-related cognitive impairment (CRCI) is commonly reported post-chemotherapy in adults with solid tumours. Hodgkin lymphoma (HL) mostly affects young adults. Data regarding CRCI in HL survivors (HLS) are scarce. The current study aimed to objectively assess CRCI incidence and characteristics in HLS. HLS, who completed first-line (chemotherapy ± radiation) therapy and remained in complete remission for 6 months to 5 years from therapy end, were evaluated. Age- and education-matched healthy individuals served as controls (n = 14). Test results were compared to population norms and healthy controls. Study participants completed self-reported questionnaires evaluating fatigue, depression, anxiety, quality of life and cognitive function. Subjects underwent neurocognitive evaluation, assessing processing speed, memory, attention, executive functions and intelligence domains. The present study included 51 HLS with a median age of 28 years, mean education of 14·5 ± 2·5 years. Complaints related to cognitive deterioration and fatigue were significantly more severe and frequent in HLS compared to healthy controls. Objective neurocognitive evaluation demonstrated that 30% of HLS were impaired in ≥2 cognitive domains. In conclusion, the present study demonstrates that fatigue and cognitive impairment, predominantly in executive functions and memory, constitute frequent and alarming findings in HLS. These adverse effects can persist and exert an impact on all aspects of life.

Long-term effects of brief hypoxia due to cardiac arrest: Hippocampal reductions and memory deficits.

OBJECTIVE: To examine the effects of brief hypoxia (<7 min) due to cardiac arrest on the integrity of the brain and performance on memory and executive functions tasks. METHODS: Patients after out-of-hospital cardiac arrest (CA) (n = 9), who were deemed neurologically intact on discharge, were compared to matched patients with myocardial infarction (MI) (n = 9). A battery of clinical and experimental memory and executive functions neuropsychological tests were administered and MRI scans for all patients were collected. Measures of subcortical and cortical volumes and cortical thickness were obtained using FreeSurfer. Manual segmentations of the hippocampus were also performed. APACHE-II scores were calculated based on metrics collected at admission to ICCU for all patients. RESULTS: Significant differences between the two groups were observed on several verbal memory tests. Both hippocampi were significantly reduced (p < 0.05) in the CA patients, relative to MI patients. Hippocampal subfields segmentation showed significantly reduced presubiculum volumes bilaterally. CA patients had on average 10% reduction in volumes bilaterally across hippocampal subfields. No cortical thickness differences survived correction. Significant correlations were observed in the CA group only between the hippocampal volumes and performance on verbal memory tasks, including recollection. Hippocampal volumes and several memory measures (but not other cognitive domains) were strongly correlated with APACHE-II scores on admission in the CA group, but not in the MI group CONCLUSIONS: Chronic patients with cardiac arrest who were discharged from hospital in "good neurological condition" showed an average of 10% reduction in hippocampal volume bilaterally and significant verbal memory deficits relative to matched controls with myocardial infarction, suggesting even brief hypoxic periods suffice to lead to specific hippocampal damage.

Closed-loop auditory feedback for the improvement of gait in patients with Parkinson's disease.

OBJECTIVE: To study the effects of closed-loop auditory feedback cues, corresponding to patient self-motion, on the walking abilities of patients with Parkinson's disease, in comparison to the effects of open-loop (metronome-like) auditory cues. METHODS: Sixteen patients on their regular medication schedule participated. A device which translates patient steps into a clicking cue sounded by earphones provides auditory feedback for gait pattern correction. Walking speed and stride length are measured. Device-on performance is compared to device-off performance and to baseline performance, and short-term residual performance following 15 min rest is compared to baseline performance. RESULTS: Device-on performance was found to represent, on average, 10.72%±19.53% improvement in walking speed and 6.77%±6.57% improvement in stride length with respect to device-off performance, and an average improvement of 12.37%±18.37% in walking speed and 4.30%±3.64% in stride length with respect to baseline performance, with 87.5% and 81.25% of the patients improving their walking speed and stride length, respectively. Average short-term residual performance showed 9.09%±6.34% improvement in walking speed and 6.52%±4.36% improvement in stride length, compared to baseline performance, with 85.71% of the patients improving in both walking speed and stride length. CONCLUSIONS: Closed-loop auditory feedback improves walking speed and stride length in patients with Parkinson's disease. Improvement in walking speed is more pronounced than improvement in stride length. Yet, in contrast to previously studied open-loop auditory cues, training with closed-loop auditory feedback results in non-negligible on-line improvement in stride length. Moreover, in contrast to previously reported results of open-loop auditory cuing, training with closed-loop auditory feedback has residual effects, which suggest the examination of this approach in a comprehensive therapy program.

Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer's Disease Biomarkers.

Biomarkers for Alzheimer's disease (AD) are vital for disease detection in the clinical setting. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation and linked to cognitive functions. Here, we revealed that blood borne expression of ADNP and its paralog ADNP2 is correlated with premorbid intelligence, AD pathology, and clinical stage. Age adjustment showed significant associations between: 1) higher premorbid intelligence and greater serum ADNP, and 2) greater cortical amyloid and lower ADNP and ADNP2 mRNAs. Significant increases in ADNP mRNA levels were observed in patients ranging from mild cognitive impairment (MCI) to AD dementia. ADNP2 transcripts showed high correlation with ADNP transcripts, especially in AD dementia lymphocytes. ADNP plasma/serum and lymphocyte mRNA levels discriminated well between cognitively normal elderly, MCI, and AD dementia participants. Measuring ADNP blood-borne levels could bring us a step closer to effectively screening and tracking AD.

Early Age-Related Functional Connectivity Decline in High-Order Cognitive Networks.

As the world ages, it becomes urgent to unravel the mechanisms underlying brain aging and find ways of intervening with them. While for decades cognitive aging has been related to localized brain changes, growing attention is now being paid to alterations in distributed brain networks. Functional connectivity magnetic resonance imaging (fcMRI) has become a particularly useful tool to explore large-scale brain networks; yet, the temporal course of connectivity lifetime changes has not been established. Here, an extensive cross-sectional sample (21-85 years old, N = 887) from a public fcMRI database was used to characterize adult lifespan connectivity dynamics within and between seven brain networks: the default mode, salience, dorsal attention, fronto-parietal control, auditory, visual and motor networks. The entire cohort was divided into young (21-40 years, mean ± SD: 25.5 ± 4.8, n = 543); middle-aged (41-60 years, 50.6 ± 5.4, n = 238); and old (61 years and above, 69.0 ± 6.3, n = 106) subgroups. Correlation matrices as well as a mixed model analysis of covariance indicated that within high-order cognitive networks a considerable connectivity decline is already evident by middle adulthood. In contrast, a motor network shows increased connectivity in middle adulthood and a subsequent decline. Additionally, alterations in inter-network interactions are noticeable primarily in the transition between young and middle adulthood. These results provide evidence that aging-related neural changes start early in adult life.

Memory, Decision-Making, and the Ventromedial Prefrontal Cortex (vmPFC): The Roles of Subcallosal and Posterior Orbitofrontal Cortices in Monitoring and Control Processes.

The ventromedial prefrontal cortex (vmPFC) prominently and separately features in neurobiological models of decision-making (e.g., value-encoding) and of memory (e.g., automatic veracity-monitoring). Recent decision-making models propose value judgments that inherently comprise of second-order confidence estimates. These demonstrate quadratic relationships with first-order judgments and are automatically encoded in vmPFC activity. Memory studies use Quantity-Accuracy Profiles to capture similar first-order and second-order meta-mnemonic processes, suggesting convergence across domains. Patients with PFC damage answered general knowledge questionnaires under 2 conditions. During forced report, they chose an answer and rated the probability of it being correct (first-order "monitoring"). During free report, they could choose to volunteer or withhold their previous answers (second-order "control") to maximize performance. We found quadratic relationships between first-order and second-order meta-mnemonic processes; voxel-based lesion-symptom mapping demonstrated that vmPFC damage diminished that relationship. Furthermore, damage to subcallosal vmPFC was specifically associated with impaired monitoring and additional damage to posterior orbitofrontal cortex led to deficient control. In decision-making, these regions typically support valuation and choice, respectively. Persistent spontaneous confabulation (false memory production) confirmed the clinical relevance of these dissociations. Compared with patients with no confabulation history, patients who currently confabulate were impaired on both monitoring and control, whereas former confabulators demonstrated impaired monitoring but intact control.