Diagnostic Validity of the Smart Aging Serious Game: An Innovative Tool for Digital Phenotyping of Mild Neurocognitive Disorder.

BACKGROUND: The Smart Aging Serious Game (SASG) is an ecologically-based digital platform used in mild neurocognitive disorders. Considering the higher risk of developing dementia for mild cognitive impairment (MCI) and vascular cognitive impairment (VCI), their digital phenotyping is crucial. A new understanding of MCI and VCI aided by digital phenotyping with SASG will challenge current differential diagnosis and open the perspective of tailoring more personalized interventions. OBJECTIVE: To confirm the validity of SASG in detecting MCI from healthy controls (HC) and to evaluate its diagnostic validity in differentiating between VCI and HC. METHODS: 161 subjects (74 HC: 37 males, 75.47±2.66 mean age; 60 MCI: 26 males, 74.20±5.02; 27 VCI: 13 males, 74.22±3.43) underwent a SASG session and a neuropsychological assessment (Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test, Trail Making Test). A multi-modal statistical approach was used: receiver operating characteristic (ROC) curves comparison, random forest (RF), and logistic regression (LR) analysis. RESULTS: SASG well captured the specific cognitive profiles of MCI and VCI, in line with the standard neuropsychological measures. ROC analyses revealed high diagnostic sensitivity and specificity of SASG and MoCA (AUCs > 0.800) in detecting VCI versus HC and MCI versus HC conditions. An acceptable to excellent classification accuracy was found for MCI and VCI (HC versus VCI; RF: 90%, LR: 91%. HC versus MCI; RF: 75%; LR: 87%). CONCLUSION: SASG allows the early assessment of cognitive impairment through ecological tasks and potentially in a self-administered way. These features make this platform suitable for being considered a useful digital phenotyping tool, allowing a non-invasive and valid neuropsychological evaluation, with evident implications for future digital-health trails and rehabilitation.

Classifying Non-Dementia and Alzheimer's Disease/Vascular Dementia Patients Using Kinematic, Time-Based, and Visuospatial Parameters: The Digital Clock Drawing Test.

BACKGROUND: Advantages of digital clock drawing metrics for dementia subtype classification needs examination. OBJECTIVE: To assess how well kinematic, time-based, and visuospatial features extracted from the digital Clock Drawing Test (dCDT) can classify a combined group of Alzheimer's disease/Vascular Dementia patients versus healthy controls (HC), and classify dementia patients with Alzheimer's disease (AD) versus vascular dementia (VaD). METHODS: Healthy, community-dwelling control participants (n = 175), patients diagnosed clinically with Alzheimer's disease (n = 29), and vascular dementia (n = 27) completed the dCDT to command and copy clock drawing conditions. Thirty-seven dCDT command and 37 copy dCDT features were extracted and used with Random Forest classification models. RESULTS: When HC participants were compared to participants with dementia, optimal area under the curve was achieved using models that combined both command and copy dCDT features (AUC = 91.52%). Similarly, when AD versus VaD participants were compared, optimal area under the curve was, achieved with models that combined both command and copy features (AUC = 76.94%). Subsequent follow-up analyses of a corpus of 10 variables of interest determined using a Gini Index found that groups could be dissociated based on kinematic, time-based, and visuospatial features. CONCLUSION: The dCDT is able to operationally define graphomotor output that cannot be measured using traditional paper and pencil test administration in older health controls and participants with dementia. These data suggest that kinematic, time-based, and visuospatial behavior obtained using the dCDT may provide additional neurocognitive biomarkers that may be able to identify and tract dementia syndromes.

Prevalence and subtype distribution of early-onset dementia in Japan.

AIM: People living with early-onset dementia (EOD) have specific social needs. Epidemiological studies are needed to obtain current information and provide appropriate service planning. This study aimed to clarify the current prevalence and subtype distribution of EOD, as well as the services frequently used by individuals with EOD. METHODS: A multisite, population-based, two-step study was conducted. Questionnaires were sent to 26 416 candidate facilities in 12 areas with a target population of 11 630 322 to inquire whether any individuals with EOD had sought services or stayed during the last 12 months (step 1). When "yes" responses were received, additional questionnaires were sent to the facilities both to complete and to distribute to the target individuals with EOD to obtain more detailed information, including the dementia subtype (step 2). RESULTS: In step 1, valid responses were obtained from 16 848 facilities (63.8%), and 4077 cases were identified. In step 2, detailed information was obtained for 1614 cases (39.6%) from the facilities and 530 cases (13.0%) from the individuals. The national EOD prevalence rate was estimated to be 50.9/100 000 population at risk (95% confidence interval: 43.9-57.9; age range, 18-64 years). The number of individuals with EOD was estimated to be 35 700 as of 2018. Alzheimer-type dementia (52.6%) was the most frequent subtype, followed by vascular dementia (17.1%), frontotemporal dementia (9.4%), dementia due to traumatic brain injury (4.2%), dementia with Lewy bodies/Parkinson's disease dementia (4.1%), and dementia due to alcohol-related disorders (2.8%). Individuals with EOD were most frequently identified at medical centers for dementia. CONCLUSION: The prevalence rate estimated in this study was comparable to those in previous studies in Japan. However, the subtype distribution differed, with Alzheimer-type dementia being the most prominent. Based on the case identification frequencies, medical centers for dementia are expected to continue to function as the primary special health service by providing quality diagnosis and post-diagnostic support for individuals with EOD.

The Relationship between the Most Common Subtypes of Dementia and Orthostatic Hypotension in Older Adults.

BACKGROUND: It is crucial to evaluate the causes of morbidity and mortality in elderly patients with dementia, such as orthostatic hypotension (OH), which may affect their daily life activities, reduce the quality of life, and increase the caregiver burden. OBJECTIVE: We aimed to investigate the relationship between OH and the most common subtypes of dementia in detail. METHODS: A total of 268 older adults with dementia diagnosed with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia (VaD), and behavioral variant frontotemporal dementia (bvFTD), and 539 older adults without dementia were included in this prospective study. Comprehensive geriatric assessment including comorbidity, medication evaluation, and the head-up tilt test was also performed. RESULTS: Of the participants, 13.8, 8.3, 6.4, and 4.8% had AD, DLB, bvFTD, and VaD, respectively. After adjusting for age, gender, the presence of comorbidities, and usage of OH-induced drugs; AD, DLB, and VaD were associated with OH (odds ratio [OR]: 2.23 confidence interval [CI] 95% 1.31-3.80; p = 0.003; OR: 3.68 CI 95% 1.98-6.83; p < 0.001, and OR: 3.56 CI 95% 1.46-8.69; p = 0.005, respectively). Furthermore, VaD was independently related to diastolic OH (OR: 4.19 CI 95% 1.66-10.57; p = 0.002), whereas AD and DLB were not. CONCLUSIONS: This study shows that elderly patients with DLB, AD, and VaD often have OH, a disabling autonomic dysfunction feature. Moreover, diastolic OH may play a role in the development of VaD. Therefore, considering potential complications of OH, it is essential to evaluate OH in the follow-up and management of those patients.

Alzheimer's/Vascular Spectrum Dementia: Classification in Addition to Diagnosis.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called 'mixed' dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called 'pure' AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other.

An Algorithm to Characterize a Dementia Population by Disease Subtype.

PURPOSE: Identification of Alzheimer disease and related dementias (ADRD) subtypes is important for pharmacologic treatment and care planning, yet inaccuracies in dementia diagnoses make ADRD subtypes hard to identify and characterize. The objectives of this study were to (1) develop a method to categorize ADRD cases by subtype and (2) characterize and compare the ADRD subtype populations by demographic and other characteristics. METHODS: We identified cases of ADRD occurring during 2008 to 2014 from the OptumLabs Database using diagnosis codes and antidementia medication fills. We developed a categorization algorithm that made use of temporal sequencing of diagnoses and provider type. RESULTS: We identified 36,838 individuals with ADRD. After application of our algorithm, the largest proportion of cases were nonspecific dementia (41.2%), followed by individuals with antidementia medication but no ADRD diagnosis (15.6%). Individuals with Alzheimer disease formed 10.2% of cases. Individuals with vascular dementia had the greatest burden of comorbid disease. Initial documentation of dementia occurred primarily in the office setting (35.1%). DISCUSSION: Our algorithm identified 6 dementia subtypes and three additional categories representing unique diagnostic patterns in the data. Differences and similarities between groups provided support for the approach and offered unique insight into ADRD subtype characteristics.

Biomarkers identify the Binswanger type of vascular cognitive impairment.

Binswanger's disease is a form of subcortical ischemic vascular disease (SIVD-BD) with extensive white matter changes. To test the hypothesis that biomarkers could improve classification of SIVD-BD, we recruited 62 vascular cognitive impairment and dementia (VCID) patients. Multimodal biomarkers were collected at entry into the study based on clinical and neuropsychological testing, multimodal magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. The patients' diagnoses were confirmed by long-term follow-up, and they formed a "training set" to test classification methods, including (1) subcortical ischemic vascular disease score (SIVDS), (2) exploratory factor analysis (EFA), (3) logistic regression (LR), and (4) random forest (RF). A subsequently recruited cohort of 43 VCID patients with provisional diagnoses were used as a "test" set to calculate the probability of SIVD-BD based on biomarkers obtained at entry. We found that N-acetylaspartate (NAA) on proton magnetic resonance spectroscopy (1H-MRS) was the best variable for classification, followed by matrix metalloproteinase-2 in CSF and blood-brain barrier permeability on MRI. Both LR and RF performed better in diagnosing SIVD-BD than either EFA or SIVDS. Two-year follow-up of provisional diagnosis patients confirmed the accuracy of statistically derived classifications. We propose that biomarker-based classification methods could diagnose SIVD-BD patients earlier, facilitating clinical trials.

Multi-Parametric Classification of Vascular Cognitive Impairment and Dementia: The Impact of Diverse Cerebrovascular Injury Biomarkers.

Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood-brain barrier health on cerebrovascular disease trajectory.

A clinicopathological approach to the diagnosis of dementia.

The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes - Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases - with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms.

[Vascular dementia].

Vascular dementia comprises a heterogeneous group of conditions covering a range of clinical and neuropathological presentations of cerebrovascular disease-causing dementia. Vascular dementia is a common occurrence, but many questions regarding the disease remain unanswered. Recently, proposed criteria focus on constructing an overarching disease concept, which captures both pre-dementia stages and the clinical and neuropathological heterogeneity. Future research should focus on identifying subtypes with distinct pathophysiological mechanisms in order to facilitate treatment development.

Vascular parkinsonism--characteristics, pathogenesis and treatment.

Parkinson disease is a primary degenerative disease of the brain, but parkinsonism can also result from a variety of vascular disorders. Vascular parkinsonism (VP) most frequently presents as lower body parkinsonism, a condition that is accompanied by the development of white matter lesions (WMLs) and lacunes in the brain. Patients with lower body parkinsonism exhibit gait impairment and go on to develop urinary incontinence, abnormal pyramidal responses and cognitive decline. However, WMLs and lacunes are also common observations among elderly individuals who do not have parkinsonism, which causes difficulty in determining the pathogenetic mechanisms that lead to VP. In addition, imaging studies suggest that many pathological and clinical features are common to VP and Binswanger disease, a type of small vessel vascular dementia. This Review summarizes current understanding of the clinical characteristics of VP, as well as knowledge gained from neuroimaging and nuclear imaging of the pathological features of VP. The lack of current treatment options, and the emergence of new therapies such as cerebrospinal fluid drainage, are also discussed. Finally, consideration is given to whether the overlap between VP and Binswanger disease means that these two disorders should be considered as part of the same disease entity.

Comparison of vascular cognitive impairment--no dementia by multiple classification methods.

AIMS: To compare vascular cognitive impairment-no dementia (VCI-ND) using different classification methods. METHODS: We recruited 56 patients with VCI-ND between April 2012 and March 2013. We used a battery of neuropsychological tests to classify patients with VCI-ND into different subtypes based on memory and executive function as follows: cognitive screening (Mini-Mental State Examination, MMSE), memory (Auditory Verbal Learning Test, AVLT), executive/attention (Shape Trails Test, STT; Stroop Color-Word Test, SCWT; Reading the Mind in the Eyes, RME; Digit Ordering Test-A, DOT-A; Symbol Digit Modalities Test, SDMT), language (Action Naming Test, ANT; Boston Naming Test, BNT; Famous Face Test, FFT; Similarity Test, ST; Verbal Fluency Test, VFT) and visuospatial function (Complex Figure Test, CFT). RESULTS: The two groups had comparable demographic information (P>0.05). Amnestic VCI-ND (aVCI-ND) patients obtained significantly lower scores compared with individuals with nonamnestic VCI-ND (naVCI-ND) on the AVLT memory test, VFT language test and VFT-alternating executive test (P<0.05). Additionally, executive VCI-ND (eVCI-ND) patients performed significantly longer than nonexecutive VCI-ND (neVCI-ND) patients on the SCWT-C timed executive test. Finally, eVCI-ND patients obtained significantly lower scores compared with neVCI-ND patients on the RME, DOT-A and SDMT-correct executive tests and the ANT, BNT and ST language tests (P<0.05). CONCLUSION: aVCI-ND patients performed poorly compared with naVCI-ND patients in terms of executive and language functions, while eVCI-ND patients performed poorly compared with neVCI-ND patients in terms of language function.

Diagnosis of vascular cognitive impairment and its main categories.

OBJECTIVE: A review of current criteria for the diagnosis of categories related with vascular cognitive impairment, in particular the nomenclature, diagnostic criteria, and differential clinical-radiological findings. DEVELOPMENT: The criteria for the diagnosis of vascular cognitive impairment have evolved, but available criteria were designed basically for differentiating between vascular dementia and dementia due to Alzheimer disease, and for research purposes. Nevertheless, in clinical practice precise elements are required for: 1) Clinical diagnosis of dementia and mild cognitive impairment; 2) Clinical and neuroimaging criteria for identification of the various cerebrovascular lesions associated with cognitive dysfunction, and 3) A formulation of the aetiogenic-pathogenic relationship between cognitive impairment and cerebrovascular lesions. For this reason, a review was carried out on the diagnostic elements of vascular cognitive impairment categories, classification, and their most relevant characteristics. It highlights the characteristic for the diagnosis of multi-infarction dementia, strategic single infarct dementia, small vessel disease with dementia, mixed dementia, and vascular mild cognitive impairment. CONCLUSIONS: Standardisation is required, by a multidisciplinary expert team, as regards nomenclature and criteria for the diagnosis of the full spectrum associated with vascular cognitive impairment and especially for vascular dementia and its categories.

[Effect of AChE and BuChE inhibition by rivastigmin in a group of old-old elderly patients with cerebrovascular impairment (SIVD type)]. / Effecto dell'inibizione AChE e BuChE tramite rivastigmina in un gruppo di soggetti geriatrici old-old affetti da demenza vascolare (SIVD-type).

AIM: Vascular dementia (VaD) is defined as a loss of cognitive function resulting from ischemic, hypoperfusive, or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. The main types of VaD are: Small Vessel Disease Dementia (sVAD), Large vessel disease dementia, hypoperfusive-ischemic dementia and hemorragic dementia. The sVAD is divided into two main categories: subcortical ischemic vascular dementia (SIVD) and cortical dementia. Currently, no drugs are approved for the treatment of VaD. This study aimed to determine whether rivastigmine, a second generation cholinesterase inhibitor with selectivity for the CNS, with capacity to inhibit both acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE), slows the rate of cognitive decline associated with VaD. METHODS: Study subjects were 27 male and 43 female outpatients aged 80.03±6.53 years, with Mini-Mental State Examination (MMSE) score ranging batween 22 and 12, affected by VaD. They were included in the study if they were undergoing pharmacological treatment with acetylsalicylic acid 100 mg for at least six months. Patients were divided into two groups: one group was treated with ASA 100 mg and rivastigmine patch 9.5 mg (Rivastigmine group), the other just with ASA 100 mg (ASA group). All patients were followed for 6 months, with a first evaluation (T0) and a second examination after six mounths of treatment (T1). RESULTS: Statistically data proved as the Rivastigmine group showed constant values at MMSE, compared with patients of the ASA group who experienced decline of their cognitive performances. The same result was found in CDR, ADL, GDS and NPI scales. It is remarkable to underline as Rivastigmine-treated patients had a mean improvement in GDS scales, in comparison with patients of the ASA group who showed a worsening of mood. CONCLUSION: Rivastigmine-therapy improves cognitive performance in elderly with SIVD.

Individual subject classification of mixed dementia from pure subcortical vascular dementia based on subcortical shape analysis.

Subcortical vascular dementia (SVaD), one of common causes of dementia, has concomitant Alzheimer's disease (AD) pathology in over 30%, termed "mixed dementia". Identifying mixed dementia from SVaD is important because potential amyloid-targeted therapies may be effective for treatment in mixed dementia. The purpose of this study was to discriminate mixed dementia from pure SVaD using magnetic resonance imaging (MRI). We measured brain amyloid deposition using the 11C-Pittsburgh compound B positron emission tomography (PiB-PET) in 68 patients with SVaD. A PiB retention ratio greater than 1.5 was considered PiB(+). Hippocampal and amygdalar shape were used in the incremental learning method to discriminate mixed dementia from pure SVaD because these structures are known to be prominently involved by AD pathologies. Among 68 patients, 23 (33.8%) patients were positive for PiB binding. With use of hippocampal shape analysis alone, PiB(+) SVaD could be discriminated from PiB(-) SVaD with 77.9% accuracy (95.7% sensitivity and 68.9% specificity). With use of amygdalar shape, the discrimination accuracy was 75.0% (87.0% sensitivity and 68.9% specificity). When hippocampal and amygdalar shape were analyzed together, accuracy increased to 82.4% (95.7% sensitivity and 75.6% specificity). An incremental learning method using hippocampal and amygdalar shape distinguishes mixed dementia from pure SVaD. Furthermore, our results suggest that amyloid pathology and vascular pathology have different effects on the shape of the hippocampus and amygdala.

Vascular neuropathology and cognitive decline.

Cerebrovascular disease is an important cause of cognitive decline and dementia. Despite numerous epidemiological, clinical, neuroimaging and neuropathological studies, the link between cerebrovascular lesions and their impact on cognition and behavior is still a matter of debate. Cerebrovascular lesions are heterogeneous and most descriptive studies distinguish vessel wall modifications, perivascular space modifications, white matter changes, and infarcts as the main features of vascular dementia. However, to date there is still no consensual criteria for the neuropathological diagnosis of vascular or mixed dementia. The diagnosis of these conditions still relies on both clinical and neuropathological expertise.

Claudin expression profile separates Alzheimer's disease cases from normal aging and from vascular dementia cases.

We have reported earlier that tight-junction proteins are detectable by standard immunohistochemistry in the brain parenchyma, namely in the cell bodies of neurons, astrocytes, and oligodendrocytes. Here we show, by projection to latent structures - discriminate analysis (PLS-DA), that the immunohistochemical detection profile of tight junction proteins clearly distinguishes the AD cases from healthy aging controls and from the cases of dementia with a predominantly vascular pathology underlying the symptoms (vascular dementia, VaD; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL; and cerebral amyloid angiopathy, CAA). Our findings might be valuable in the perspective of developing biomarkers for AD.

Subtypes of dementia: a study from a memory clinic in India.

BACKGROUND: The clinical syndrome of dementia consists of several subtypes that are distinct in their etiology, clinical profile, management, and outcome. Limited specialized services are available for dementia patients in India. We report the profile of dementia subtypes from a clinic-based dementia registry in India. METHODS: Consecutive dementia patients were investigated with clinical evaluation, neuropsychological tests modified for local use, and brain imaging. RESULTS: In 347 consecutive dementia patients, Alzheimer's disease was the most common subtype of dementia (38.3%), followed by a high proportion of vascular dementia (25.4%). Frontotemporal dementia syndromes were not uncommon (18.7%). Dementia with Lewy bodies was encountered in 8.9% of the patients, and mixed dementia was found in 8.6%. The mean age of the group at presentation was 66.3 years, nearly a decade younger than in developed countries. The proportion of patients with early-onset dementia was high (49.9%). CONCLUSIONS: Our results demonstrate that the clinical profiles of dementia subtypes in a clinic population are influenced by the population's demographic profile, cardiovascular risk factor burden, sociocultural attitudes about cognitive impairment, and possibly genetic factors.

The nature of episodic memory deficits in MCI with and without vascular burden.

This study measured episodic memory deficits in individuals with mild cognitive impairment (MCI) as a function of their vascular burden. Vascular burden was determined clinically by computing the number of vascular risk factors and diseases and neuroradiologically by assessing the presence and severity of white matter lesions (WML). Strategic memory processes were measured with free recall and temporal contextual memory tasks requiring self-initiated retrieval. Nonstrategic memory retrieval processes were appraised with a five-choice recognition procedure. Results showed that MCI participants with high vascular burden displayed impairment of strategic memory processes, whereas MCI participants with no vascular burden showed impairment of both strategic and nonstrategic memory processes. A similar pattern was found whether vascular burden was measured using a clinical index of vascular risk profile or whether it was measured neuroradiologically by assessing the extent and severity of subcortical WML. However, the effect of WML on memory differed as function of level of education, used here as a proxy for cognitive reserve. Among participants with MCI, those who had higher education and no WML were the least memory impaired. The study also examined memory as a function of whether patients later progressed to dementia after a three-year follow-up. When examining progressors' performance, strategic and nonstrategic processes were both impaired in progressors with no concomitant vascular conditions, whereas progressors with a high vascular burden showed less impairment of nonstrategic than strategic processes. Overall, results indicate that the presence of vascular burden in MCI is associated with selective impairment of strategic memory processes.