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Souza, Leonardo Cruz de, Maxime Bertoux, Aurélie Funkiewiez, Dalila Samri, Carole Azuar, Marie-Odile Habert, Aurélie Kas, Foudil Lamari, Marie Sarazin, and Bruno Dubois. "Frontal presentation of Alzheimer's disease: A series of patients with biological evidence by CSF biomarkers." Dementia & Neuropsychologia 7, no. 1 (March 2013): 66–74. http://dx.doi.org/10.1590/s1980-57642013dn70100011.
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ABSTRACT Besides its typical amnesic presentation, focal atypical presentations of Alzheimer's disease (AD) have been described in neuropathological studies. These phenotypical variants of AD (so-called "atypical AD") do not follow the typical amnestic pattern and include non-amnestic focal cortical syndromes, such as posterior cortical atrophy and frontal variant AD. These variants exhibit characteristic histological lesions of Alzheimer pathology at post-mortem exam. By using physiopathological markers, such as cerebrospinal fluid markers, it is now possible to establish in vivo a biological diagnosis of AD in these focal cortical syndromes. We report a series of eight patients who were diagnosed with behavioural variant frontotemporal dementia based on their clinical, neuropsychological and neuroimaging findings, while CSF biomarkers showed an AD biological profile, thus supporting a diagnosis of frontal variant of AD.
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Aguilar-Navarro, Sara G., Itzel I. Gonzalez-Aparicio, José Alberto Avila-Funes, Teresa Juárez-Cedillo, Teresa Tusié-Luna, and Alberto Jose Mimenza-Alvarado. "Association between ApoE ε4 Carrier Status and Cardiovascular Risk Factors on Mild Cognitive Impairment among Mexican Older Adults." Brain Sciences 11, no. 1 (January 7, 2021): 68. http://dx.doi.org/10.3390/brainsci11010068.
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Mild cognitive impairment (MCI) (amnestic or non-amnestic) has different clinical and neuropsychological characteristics, and its evolution is heterogeneous. Cardiovascular risk factors (CVRF), such as hypertension, diabetes, or dyslipidemia, and the presence of the Apolipoprotein E ε4 (ApoE ε4) polymorphism have been associated with an increased risk of developing Alzheimer’s disease (AD) and other dementias but the relationship is inconsistent worldwide. We aimed to establish the association between the ApoE ε4 carrier status and CVRF on MCI subtypes (amnestic and non-amnestic) in Mexican older adults. Cross-sectional study including 137 older adults (n = 63 with normal cognition (NC), n = 24 with amnesic, and n = 50 with non-amnesic MCI). Multinomial logistic regression models were performed in order to determine the association between ApoE ε4 polymorphism carrier and CVRF on amnestic and non-amnestic-MCI. ApoE ε4 carrier status was present in 28.8% participants. The models showed that ApoE ε4 carrier status was not associated neither aMCI nor naMCI condition. The interaction term ApoE ε4 × CVRF was not statistically significant for both types of MCI. However, CVRF were associated with both types of MCI and the association remained statistically significant after adjustment by sex, age, and education level. The carrier status of the ApoE genotype does not contribute to this risk.
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Putcha, Deepti, Nicole Carvalho, Sheena Dev, Scott M. McGinnis, Bradford C. Dickerson, and Bonnie Wong. "Verbal Encoding Deficits Impact Recognition Memory in Atypical “Non-Amnestic” Alzheimer’s Disease." Brain Sciences 12, no. 7 (June 28, 2022): 843. http://dx.doi.org/10.3390/brainsci12070843.
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Memory encoding and retrieval deficits have been identified in atypical Alzheimer’s disease (AD), including posterior cortical atrophy (PCA) and logopenic variant primary progressive aphasia (lvPPA), despite these groups being referred to as “non-amnestic”. There is a critical need to better understand recognition memory in atypical AD. We investigated performance on the California Verbal Learning Test (CVLT-II-SF) in 23 amyloid-positive, tau-positive, and neurodegeneration-positive participants with atypical “non-amnestic” variants of AD (14 PCA, 9 lvPPA) and 14 amnestic AD participants. Recognition memory performance was poor across AD subgroups but trended toward worse in the amnestic group. Encoding was related to recognition memory in non-amnestic but not in amnestic AD. We also observed cortical atrophy in dissociable subregions of the distributed memory network related to encoding (left middle temporal and angular gyri, posterior cingulate and precuneus) compared to recognition memory (anterior medial temporal cortex). We conclude that recognition memory is not spared in all patients with atypical variants of AD traditionally thought to be “non-amnestic”. The non-amnestic AD patients with poor recognition memory were those who struggled to encode the material during the learning trials. In contrast, the amnestic AD group had poor recognition memory regardless of encoding ability.
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Bergeron, David, Jean-Mathieu Beauregard, Jean-Guimond, Jean-Paul Soucy, Louis Verret, Stéphane Poulin, Jordi A. Matias-Guiu, María Nieves Cabrera-Martín, Rémi W. Bouchard, and Robert Laforce. "Posterior Cingulate Cortex Hypometabolism in Non-Amnestic Variants of Alzheimer’s Disease." Journal of Alzheimer's Disease 77, no. 4 (October 13, 2020): 1569–77. http://dx.doi.org/10.3233/jad-200567.
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Background: Hypometabolism of the posterior cingulate cortex (PCC) is an important diagnostic feature of late-onset, amnestic Alzheimer’s disease (AD) measured with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, it is unclear whether PCC hypometabolism has diagnostic value in young-onset, non-amnestic variants of AD, which exhibit less pathology in the hippocampus and default mode network. Objective: Evaluate the prevalence and diagnostic value of PCC hypometabolism in non-amnestic variants of AD. Methods: We retrospectively identified 60 patients with young-onset, atypical dementia who have undergone a detailed clinical evaluation, FDG-PET, and an amyloid biomarker (amyloid-PET or cerebrospinal fluid analysis). We quantitatively analyzed regional hypometabolism in 70 regions of interest (ROI) using the MIMneuro® software. Results: Based on a cut-off of z-score < –1.5 for significant PCC hypometabolism, the prevalence of PCC hypometabolism in non-amnestic variants of AD was 65% compared to 28% in clinical variants of frontotemporal dementia (FTD). The ROI with the maximal hypometabolism was the dominant middle temporal gyrus in the language variant of AD (mean z score –2.28), middle occipital gyrus in PCA (–3.24), middle temporal gyrus in frontal AD (–2.70), and angular gyrus in corticobasal syndrome due to AD (–2.31). The PCC was not among the 10 most discriminant regions between non-amnestic variants of AD versus clinical variants of FTD. Conclusion: We conclude that PCC hypometabolism is not a discriminant feature to distinguish non-amnestic variants of AD from clinical variants of FTD—and should be interpreted with caution in patients with young-onset, non-amnestic dementia.
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Becker, James T., Olurotimi Bajulaiye, and Christine Smith. "Longitudinal analysis of a two-component model of the memory deficit in Alzheimer's disease." Psychological Medicine 22, no. 2 (May 1992): 437–45. http://dx.doi.org/10.1017/s0033291700030385.
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SYNOPSISThe memory deficit in Alzheimer's disease (AD) has been characterized as consisting of multiple components. The purpose of this study was to confirm the utility of a two-process model, and to examine changes in the nature and extent of the neuropsychological deficits after a one-year interval. The results replicate the initial observation that the memory loss in AD can be described as consisting of a focal amnesic syndrome and a dysexecutive syndrome characterized by failure of rapid information processing and search of both episodic and semantic memory. One year after the initial observation, all dysexecutive patients and the majority of the amnesic patients had become non-focal. No patient developed a dysexecutive syndrome, but 18 patients developed amnesic syndromes. These results suggest that, like other aspects of the cognitive deficits of AD, the memory loss is multifactorial. These results have implications for understanding the pathophysiology of AD, and for designing pharmacotherapeutic intervention.
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Andrejeva, Nadeshda, Maren Knebel, Vasco Dos Santos, Janna Schmidt, Christina Josefa Herold, Ruxandra Tudoran, Petra Wetzel, et al. "Neurocognitive Deficits and Effects of Cognitive Reserve in Mild Cognitive Impairment." Dementia and Geriatric Cognitive Disorders 41, no. 3-4 (2016): 199–209. http://dx.doi.org/10.1159/000443791.
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Background/Aims: Mild cognitive impairment (MCI) is a frequent syndrome in the older population, which involves an increased risk to develop Alzheimer's disease (AD). The latter can be modified by the cognitive reserve, which can be operationalized by the length of school education. MCI can be differentiated into four subtypes according to the cognitive domains involved: amnestic MCI, multiple-domain amnestic MCI, non-amnestic MCI and multiple-domain non-amnestic MCI. While neurocognitive deficits are a constituent of the diagnosis of these subtypes, the question of how they refer to the cognitive reserve still needs to be clarified. Methods: We examined neuropsychological deficits in healthy controls, patients with MCI and patients with mild AD (n = 485) derived from a memory clinic. To reduce the number of neuropsychological variables, a factor analysis with varimax rotation was calculated. In a second step, diagnostic groups including MCI subtypes were compared with respect to their clinical and neuropsychological characteristics including cognitive reserve. Results: Most MCI patients showed the amnestic multiple-domain subtype followed by the pure amnestic subtype, while the non-amnestic subtypes were rare. The amnestic subtype displayed a significantly higher level of cognitive reserve and higher MMSE scores than the amnestic multiple-domain subtype, which was in most cases characterized by additional psychomotor and executive deficits. Conclusions: These findings confirm earlier reports revealing that the amnestic multiple-domain subtype is the most frequent one and indicating that a high cognitive reserve may primarily prevent psychomotor and executive deficits in MCI.
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Jungwirth, S., S. Zehetmayer, M. Hinterberger, K. H. Tragl, and P. Fischer. "The validity of amnestic MCI and non-amnestic MCI at age 75 in the prediction of Alzheimer's dementia and vascular dementia." International Psychogeriatrics 24, no. 6 (February 3, 2012): 959–66. http://dx.doi.org/10.1017/s1041610211002870.
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ABSTRACTBackground: Clinical subtypes of mild cognitive impairment (MCI) were assigned as potential prodromes to various types of dementia. Amnestic MCI (aMCI) is said to have a high likelihood of progressing to Alzheimer's dementia (AD) and non-amnestic MCI (naMCI) subtypes are assumed to have a higher likelihood of progressing to non-AD dementia. The aim of this study was to investigate the prognostic accuracy of aMCI and naMCI for the development of AD, vascular dementia (VaD), and mixed dementia.Methods: In this longitudinal study, 487 subjects without dementia (cognitively healthy: n = 387; MCI cases: n = 115) aged 75 years at baseline, who participated in a population-based cohort study (Vienna Transdanube Aging study), were available for analysis. The observation period was 90 months. The diagnoses of the clinical MCI subtypes were made according to common criteria. The outcome (AD, VaD, mixed dementia) was described for both MCI subtypes. Diagnostic values of aMCI and naMCI according to incident AD, VaD, and mixed dementia were determined.Results: AD was the most common type of dementia following both MCI subtypes. Participants with aMCI were more likely to progress to AD than participants with naMCI. The proportion of incident VaD and mixed dementia did not differ concerning the MCI subtypes. The positive predictive value for both MCI subtypes was low (range: 1%–46%), whereas the negative predictive value was high (range: 86%–99%).Conclusions: The increased risk of clinical MCI subtypes for a particular type of dementia could only be confirmed for aMCI and incident AD.
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Smith, Alphonso, James E. Eaton, and Richard R. Darby. "A-252 A Suspected Case Of Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE) in an Older Adult." Archives of Clinical Neuropsychology 37, no. 6 (August 17, 2022): 1396. http://dx.doi.org/10.1093/arclin/acac060.252.
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Abstract Objective: LATE is a common but underrecognized neuropathology that causes a progressive amnestic syndrome in older adults which mimics an Alzheimer’s disease (AD) clinical profile. Method: A 75-year-old female with a history of progressive cognitive impairment presented to a multidisciplinary neurology clinic. Neurocognitive screening during her neurological exam showed an amnestic memory profile. A work-up for medical causes for her cognitive impairment was negative. She had prominent hippocampal atrophy on MRI with a negative amyloid PET scan, raising concerns for LATE. She was referred for a comprehensive neuropsychological evaluation. Results: Neuropsychological testing confirmed an amnestic mild dementia profile in the context of her other cognitive skills (e.g., attention, executive functioning, processing speed, word finding, and visuospatial abilities) being largely preserved. On self-report questionnaires, the patient denied having any significant symptoms of depression or anxiety. Conclusions: LATE is described as causing a primarily amnestic neurocognitive profile with associated hippocampal atrophy and this was well demonstrated in our patient. While the diagnosis of LATE cannot be definitively made until autopsy, the absence of amyloid on her PET scan highly suggests a non-AD pathology like LATE. A limitation of the evaluation is that tau biomarker tests were not performed, making primary age-related tauopathy (PART) another possible pathology or co-pathology. Overall, this case study illustrates the importance of multidisciplinary assessment to help facilitate differential diagnosis for neurodegenerative conditions associated with amnestic cognitive impairment, especially when a non-AD pathology is suspected.
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Voskou, Panagiota. "501 - Prediction of Mild Cognitive Impairment (MCI) progression to Alzheimer Disease (AD) or Dementia with Lewy Bodies (DLB): Is this possible neuropsychologically?" International Psychogeriatrics 33, S1 (October 2021): 55–56. http://dx.doi.org/10.1017/s1041610221001964.
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Objective:Aim of the present review study was to describe and compare the neurocognitive features of MCI which could predict its progression to DLB vs AD.Background:Progression of MCI to AD or DLB is a relatively recent field of study with emphasis on the clinical or neuropsychological features of MCI which could potentially predict its progression to specific types of dementia.Methods:A literature review in the Pubmed database has been made, after the year 2005, using the key- words: neuropsychological assessment; MCI; AD; DLB; progression to dementia. Seventeen relevant articles have been found.Results:Data from most studies supports that, in MCI, impairment in executive, attentional and visuospatial functions, as well as letter fluency and fluctuating concentration are mainly related to progression to DLB. In contrast, prominent episodic and recognition memory deficits are mostly found in MCI which progresses in AD. Furthermore, non-amnestic MCI has been related most often to progression in DLB, whereas the amnestic type to AD, although memory loss may not necessarily predict the development of AD. Nevertheless, fewer studies suggest that MCI-DLB is related to cognitive profile similar to that of MCI-AD, while cognitive scoring alone does not accurately predict MCI-DLB vs MCI-AD. Interestingly, quantitative electroencephalogram has been found to help in predicting the progression of MCI to DLB, while preservation of hippocampal volume is associated with increased risk of DLB vs AD, especially in non-amnestic MCI. Moreover, specific patterns on neuroimaging MCI may predict progression to AD in contrast to DLB.Conclusions:Predicting the progression of MCI to AD or DLB based on neuropsychological profiles is challenging and useful for early therapeutic interventions. More studies are needed, since there are some conflicting findings and, at present, the combination of clinical symptoms with neurocognitive assessment and neuroimaging is the ideal method for the prediction of MCI progression to various types of dementia.
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Collins, Kathleen, Brittany Rohl, Sarah Morgan, Edward D. Huey, Elan D. Louis, and Stephanie Cosentino. "Mild Cognitive Impairment Subtypes in a Cohort of Elderly Essential Tremor Cases." Journal of the International Neuropsychological Society 23, no. 5 (April 3, 2017): 390–99. http://dx.doi.org/10.1017/s1355617717000170.
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AbstractObjectivesIndividuals with essential tremor (ET) exhibit a range of cognitive deficits generally conceptualized as “dysexecutive” or “fronto-subcortical,” and thought to reflect disrupted cortico-cerebellar networks. In light of emerging evidence that ET increases risk for Alzheimer’s disease (AD), it is critical to more closely examine the nature of specific cognitive deficits in ET, with particular attention to amnestic deficits that may signal early AD.MethodsWe performed a cross-sectional analysis of baseline data from 128 ET cases (age 80.4±9.5 years) enrolled in a longitudinal, clinical-pathological study. Cases underwent a comprehensive battery of motor-free neuropsychological tests and a functional assessment to inform clinical diagnoses of normal cognition (ET-NC), mild cognitive impairment (MCI) (ET-MCI), or dementia (ET-D). ET-MCI was subdivided into subtypes including: amnestic single-domain (a-MCI), amnestic multi-domain (a-MCI+), non-amnestic single-domain (na-MCI), or non-amnestic multi-domain (na-MCI+).ResultsNinety-one (71.1%) cases were ET-NC, 24 (18.8%) were ET-MCI, and 13 (10.2%) were ET-D. Within MCI, the a-MCI+ subtype was the most common (13/24; 54.2%) followed by a-MCI (4/24; 16.7%), na-MCI+ (4/24; 16.7%), and na-MCI (3/24; 12.5%). Cases with amnestic MCI demonstrated lower recognition memoryZ-scores (−2.4±1.7) than non-amnestic groups (−0.9±1.2) (p=.042).ConclusionsAmnestic MCI, defined by impaired memory recall but associated with lower memory storage scores, was the most frequent MCI subtype in our study. Such impairment has not been explicitly discussed in the context of ET and may be an early hallmark of AD. Results have implications for the prognosis of specific cognitive deficits in ET. (JINS, 2017,23, 390–399)
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Souza, Leonardo Cruz de, Luciano Inácio Mariano, Renata Freire de Moraes, and Paulo Caramelli. "Behavioral variant of frontotemporal dementia or frontal variant of Alzheimer's disease? A case study." Dementia & Neuropsychologia 13, no. 3 (September 2019): 356–60. http://dx.doi.org/10.1590/1980-57642018dn13-030015.
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ABSTRACT Alzheimer's disease (AD) has heterogeneous clinical presentations. Amnestic progressive disorder leading to dementia is the most typical, but non-amnestic presentations are also recognized. Here we report a case of frontal variant of AD. A right-handed woman, aged 68 years, was referred for progressive behavioral disorders and personality changes. She had a corroborated history of dietary changes, hyperorality, impulsivity, affective indifference and apathy, with functional impairment. Cognitive assessment yielded severe executive deficits. Positron emission tomography with fluorodeoxyglucose showed marked hypometabolism in frontotemporal regions, with relative preservation of parietal regions. CSF AD biomarkers showed low Aβ42, high Tau and high P-Tau. The patient fulfilled criteria for probable behavioral variant frontotemporal dementia. However, considering the AD pathophysiological signature on CSF biomarkers, a diagnosis of frontal variant of AD was established. In the perspective of disease-modifying therapies, it is important to identify atypical Alzheimer presentations, as these patients may be candidates for specific treatments.
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Biundo, Roberta, Simona Gardini, Paolo Caffarra, Letizia Concari, Davide Martorana, Tauro Maria Neri, Michael F. Shanks, and Annalena Venneri. "Influence of APOE Status on Lexical–Semantic Skills in Mild Cognitive Impairment." Journal of the International Neuropsychological Society 17, no. 3 (March 17, 2011): 423–30. http://dx.doi.org/10.1017/s135561771100021x.
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AbstractThis study characterized the relationship between apolipoprotein E (APOE) status and residual semantic abilities in amnestic mild cognitive impairment (MCI). APOE status (ε4 carrier/non ε4 carrier) was determined in 30 amnestic MCIs and in 22 healthy matched non ε4 carrier controls. The lexical characteristics (age of acquisition, typicality, familiarity) of words produced in a category fluency task were determined. MCIs produced fewer words than controls and these were also earlier acquired and more familiar. The words produced by MCI ε4 carriers were earlier acquired than those of non ε4 carriers. Analyses limited to the first 10 words produced by patients and controls showed similar findings and also revealed that MCI subgroups retrieved first more typical words than controls. Follow up showed higher conversion to Alzheimer's disease (AD) in MCI ε4 carriers than in non ε4 carriers. These findings show that a significant proportion of phenotype variability in performance on category fluency in people at increased AD risk is influenced by genetic factors. These findings explain why category fluency deficits, together with episodic memory deficits, are the only consistent early deficits in MCI patients who convert to AD. (JINS, 2011, 17, 423–430)
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Weston, PSJ, RW Paterson, M. Lehmann, M. Modat, JB Bomanji, I. Kayani, J. Dickson, et al. "USING FLORBETAPIR PET TO INCREASE DIAGNOSTIC CERTAINTY IN ATYPICAL DEMENTIAS." Journal of Neurology, Neurosurgery & Psychiatry 86, no. 11 (October 14, 2015): e4.112-e4. http://dx.doi.org/10.1136/jnnp-2015-312379.24.
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Amyloid PET or CSF can be used to determine Alzheimer pathology in vivo. Few studies have assessed the additional value of amyloid imaging where CSF results are equivocal. We recruited 20 cognitive patients (65.5+/–7.6 y) with MRI, neuropsychology, and CSF Aβ1–42 and tau measured during their diagnostic assessment. Individuals were selected to have a range of CSF results; ten had amnestic and ten non-amnestic presentations. Following the investigations, the treating neurologist gave a diagnosis (AD or non-AD). Four controls (63+/–7.0y) also had CSF examination. All subjects had Florbetapir PET imaging, reported as positive/negative. The clinicians were given the PET results and asked to review their diagnoses. Eighteen patients had positive Florbetapir scans; two patients and all controls were Florbetapir negative. Following initial investigations, thirteen patients were diagnosed with AD, and seven with non-AD pathology. Providing the Florbetapir result led to a change in diagnosis in seven patients, five of whom had atypical phenotypes. For all seven the CSF results were close to or in a “grey” area, where results overlapped for positive and negative PET scans. Even in individuals with CSF measures of Aβ1–42, and tau, Florbetapir PET imaging may have diagnostic utility, particularly in atypical cases and/or equivocal CSF results.
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Paraskevas, George P., Vasilios C. Constantinides, Fotini Boufidou, Ioanna Tsantzali, Efstratios-Stylianos Pyrgelis, Georgios Liakakis, and Elisabeth Kapaki. "Recognizing Atypical Presentations of Alzheimer’s Disease: The Importance of CSF Biomarkers in Clinical Practice." Diagnostics 12, no. 12 (December 1, 2022): 3011. http://dx.doi.org/10.3390/diagnostics12123011.
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Besides the typical amnestic presentation, neuropathological studies indicate that Alzheimer’s disease (AD) may present with atypical clinical pictures. The relative frequencies of typical and atypical or mixed presentations within the entire spectrum of AD remain unclear, while some mixed or atypical presentations may have not received adequate attention for them to be included in diagnostic criteria. We investigated the spectrum of clinical presentations in patients with the AD CSF biomarker profile (high tau and phospho-tau, low Aβ42 levels), hospitalized in a tertiary academic center. Among 98 patients with the CSF AD profile, 46% of patients had the typical presentation of “hippocampal” amnestic dementia. Additionally, 23.5% and 15.3% fulfilled the criteria of mixed or atypical presentations, respectively, as described in the IWG-2 criteria. The remaining 15.3% had unusual presentations, including non-logopenic (semantic and non-fluent agrammatic) primary progressive aphasia, corticobasal syndrome, and Richardson syndrome, or could be diagnosed with normal pressure hydrocephalus. Despite selection bias (academic center), atypical clinical presentations of AD may be more common than previously thought. CSF biomarkers seem to be a useful tool for antemortem identification of such patients, which is likely to affect therapeutic decisions. Some of the unusual presentations described above should be incorporated in diagnostic criteria.
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Dolphin, H., A. Fallon, C. McHale, J. Dookhy, D. O'Neill, T. Coughlan, S. Coveney, S. O'Dowd, and S. P. Kennelly. "89 CSF BIOMARKER UTILITY IN SUPPORTING ALZHEIMER’S DISEASE DIAGNOSIS: CLINICAL PERSPECTIVES FROM AN IRISH REGIONAL SPECIALIST MEMORY SERVICE." Age and Ageing 50, Supplement_3 (November 2021): ii9—ii41. http://dx.doi.org/10.1093/ageing/afab219.89.
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Abstract Background CSF (cerebrospinal fluid) biomarkers [amyloid- beta-42 (AB-42), phosphorylated tau (p-tau)] are increasingly used in supporting clinical diagnosis of Alzheimer’s Disease (AD). Both elevated CSF p-tau and reduced AB-42 are necessary for pathological diagnosis of AD. The aim of this study is to apply recent international recommendations to patients attending a regional specialist memory service, evaluating consistency with detailed clinical, neuroimaging, and neuropsychological ad-phenotype profiling. Methods All patients age < 80, with mild/subjective cognitive and/or atypical neurobehavioral symptoms, non-significant vascular burden on neuroimaging, and without contraindication to lumbar puncture are offered CSF analysis. Clinical diagnosis was ascribed on the basis of specialist multi-disciplinary consensus review. We undertook a case-note and database retrospective review of those who had ad-biomarker CSF analysis, collecting demographic, clinical phenotype diagnosis, and neuropsychological performance. Data was extracted and analysed using SPSS v.25. Results One-hundred-sixteen patients underwent CSF biomarker testing. Forty-nine patients (42%) had positive AD-CSF biomarkers, 41/49 (84%) of whom presented with common ad phenotypes (Amnestic/Logopenic PPA/PCA). Twenty patients (17%) had negative ad-CSF (elevated AB-42, and low p-tau) studies, and half of those (10/20, 50%) had a consistent atypical non-AD clinical phenotype. Patients with negative ad-CSF were younger and tended to have non-amnestic neuropsychological profile. Therefore there was a mismatch in 18/69 (26%) people in these groups with definitive +/− ad biomarker results and ad/Non-ad clinical phenotype. A further forty seven (40%) patients had indeterminate CSF studies with one or other changes in AB-42 or p-tau, but not both as is necessary for definitive diagnosis. Conclusion Incorporation of CSF biomarker analysis is quickly being established as a key component of the neurocognitive/dementia diagnostic pathway. However, there are challenges and limitations arising as they are applied in clinical settings, and further research is warranted to explore variations between pathological results and clinical phenotype presentation.
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Tahmasebi, R., S. Zehetmayer, G. Pusswald, G. Kovacs, E. Stögmann, and J. Lehrner. "Identification of odors, faces, cities and naming of objects in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer´s disease: a longitudinal study." International Psychogeriatrics 31, no. 04 (September 21, 2018): 537–49. http://dx.doi.org/10.1017/s1041610218001114.
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ABSTRACTObjective:Recent studies have tried to find a reliable way of predicting the development of Alzheimer´s Disease (AD) among patients with mild cognitive impairment (MCI), often focusing on olfactory dysfunction or semantic memory. Our study aimed to validate these findings while also comparing the predictive accuracy of olfactory and semantic assessments for this purpose.Method:Six hundred fifty patients (median age 68, 58% females) including controls, SCD (subjective cognitive decline), non-amnestic MCI (naMCI), amnestic MCI (aMCI), and AD patients were tested for olfactory dysfunction by means of odor identification testing and semantic memory. Of those 650 patients, 120 participants with SCD, naMCI, or aMCI at baseline underwent a follow-up examination after two years on average. Of these 120 patients, 12% had developed AD at follow-up (converters), while 88% did not develop AD at follow-up (non-converters).Results:Analysis showed a significant difference only for initial olfactory identification between converters and non-converters. Sensitivity of impairment of olfactory identification for AD prediction was low at 46.2%, although specificity was high at 81.9%. Semantic memory impairment at baseline was not significantly related to AD conversion, although, when naming objects, significant differences were found between AD patients and all other groups and between naMCI and aMCI patients compared to controls and SCD patients.Conclusions:Objective olfactory assessments are promising instruments for predicting the conversion to AD among MCI patients. However, due to their low sensitivity and high specificity, a combination with other neuropsychological tests might lead to an improved predictive accuracy. Further longitudinal studies with more participants are required to investigate the usefulness of semantic memory tests in this case.
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Schaefer, Sydney Y., Michael Malek-Ahmadi, Andrew Hooyman, Jace B. King, and Kevin Duff. "Association Between Motor Task Performance and Hippocampal Atrophy Across Cognitively Unimpaired, Amnestic Mild Cognitive Impairment, and Alzheimer’s Disease Individuals." Journal of Alzheimer's Disease 85, no. 4 (February 15, 2022): 1411–17. http://dx.doi.org/10.3233/jad-210665.
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Hippocampal atrophy is a widely used biomarker for Alzheimer’s disease (AD), but the cost, time, and contraindications associated with magnetic resonance imaging (MRI) limit its use. Recent work has shown that a low-cost upper extremity motor task has potential in identifying AD risk. Fifty-four older adults (15 cognitively unimpaired, 24 amnestic mild cognitive impairment, and 15 AD) completed six motor task trials and a structural MRI. Several measures of motor task performance significantly predicted bilateral hippocampal volume, controlling for age, sex, education, and memory. Thus, this motor task may be an affordable, non-invasive screen for AD risk and progression.
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Balthazar, Marcio Luiz Figueredo, and Benito Pereira Damasceno. "Dysexecutive mild cognitive impairment associated to frontal atrophy: Case report." Dementia & Neuropsychologia 2, no. 1 (March 2008): 76–79. http://dx.doi.org/10.1590/s1980-57642009dn20100015.
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Abstract Non-amnestic mild cognitive impairment (MCI) evolving to neurodegenerative diseases other than Alzheimer's disease (AD) is rarely well documented. We report a case of a 49 year-old woman who presented a slowly progressive attentional/dysexecutive syndrome sparing other cognitive domains and without significant impairment of daily life activities. Her mother had Parkinsonism and her brother, a psychotic syndrome. Brain CT/MRI showed frontal atrophy while brain SPECT showed moderate cortical hypoperfusion, mainly in the frontal lobes. Our case is an example of non-memory MCI whose neuropsychological data and brain imaging indicating high likelihood of progression to a non-AD dementia.
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Sundermann, Erin E., Lisa L. Barnes, Mark W. Bondi, David A. Bennett, David P. Salmon, and Pauline M. Maki. "Improving Detection of Amnestic Mild Cognitive Impairment with Sex-Specific Cognitive Norms." Journal of Alzheimer's Disease 84, no. 4 (December 7, 2021): 1763–70. http://dx.doi.org/10.3233/jad-215260.
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Background Despite a female advantage in verbal memory, normative data for verbal memory tests used to diagnose Alzheimer’s disease (AD) dementia and amnestic mild cognitive impairment (aMCI) often are not sex-adjusted. Objective To determine whether sex-adjusted norms improve aMCI diagnostic accuracy when accuracy was evaluated by progression to AD dementia over time. Methods Non-sex-specific and sex-specific verbal memory test norms were incorporated into Jak/Bondi aMCI criteria and applied to older (age 65–90) non-demented women (N = 1,036) and men (N = 355) from the Rush Memory and Aging Project. Using sex-specific aMCI diagnosis as the “true” condition versus non-sex-specific aMCI diagnosis as the “predicted” condition, we identified True Positives, False Positives, True Negatives, and False Negatives and compared AD dementia risk over 10 years among groups. Results Rates of aMCI were higher in men versus women (χ2 = 15.39, p < 0.001) when determined based on typical diagnostic criteria, but this difference reversed when using sex-specific diagnostic criteria (χ2 = 8.38, p = 0.004). We identified 8%of women as False Negatives and 12%of men as False Positives. Risk of incident AD dementia in False Positive men was significantly lower than in True Positive men (HR = 0.26, 95%CI = 0.12–0.58, p = 0.001). Risk of incident AD dementia in False Negative women was substantially higher than in True Negative women (HR = 3.11, 95%CI = 2.09–4.63, p < 0.001). Conclusion Results suggest that previous reports of higher aMCI rates in men versus women may be an artifact of non-sex-adjusted norms/cut-scores. Incorporation of sex-specific norms/cut-scores for verbal memory impairment into aMCI diagnostic criteria may improve diagnostic accuracy and avoid diagnostic errors in approximately 20%.
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Meilan, Juan J. G., Francisco Martinez-Sanchez, Juan Carro, Nuria Carcavilla, and Olga Ivanova. "Voice Markers of Lexical Access in Mild Cognitive Impairment and Alzheimer's Disease." Current Alzheimer Research 15, no. 2 (January 3, 2018): 111–19. http://dx.doi.org/10.2174/1567205014666170829112439.
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Background: Recent studies have identified the correlation between dementia and certain vocal features, such as voice and speech changes. Vocal features may act as early markers of Alzheimer's disease (AD). Despite being present in non-pathological senescence and Mild Cognitive Impairment, especially in its amnesic subtype (aMCI), these voice- and speech-related symptoms are the first signs of AD. The purpose of this study is to verify whether these signs are related to deficits in lexical access, which appear early in AD. Method: Anomic deficits in persons with MCI and AD are assessed through tests on verbal memory, denomination by confrontation, and verbal fluency. In addition, an acoustic analysis of speech is conducted in a reading task to identify the acoustic parameters associated with the groups analyzed, and their relation to the degree of anomic impairment observed in each one of them. Results and Conclusions: The results show a direct relationship between the different acoustic parameters present in AD and the verbal fluency tests results.
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Vandiver, Richard, Michael J. Lyons, and Kristy Cuthbert. "RELATION BETWEEN ERECTILE DYSFUNCTION AND AMNESTIC MILD COGNITIVE IMPAIRMENT ACROSS TWO TIME POINTS." Innovation in Aging 3, Supplement_1 (November 2019): S958. http://dx.doi.org/10.1093/geroni/igz038.3476.
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Abstract Previous research by the Vietnam Era Twin Study of Aging (VETSA) demonstrated an association between erectile dysfunction (ED) and cognitive functioning. That finding supports a hypothesis that cardiovascular dysfunction may underlie both ED and problems in cognitive functioning. The purpose of the current research was to extend these findings by investigating a putative association between ED and amnestic and non-amnestic mild cognitive impairment (MCI). MCI is of particular interest because of its relationship with Alzheimer’s disease and other dementing illnesses. VETSA is a longitudinal study of twins who served in the US military during the Vietnam conflict (N= 960) consisting of data collected at age 20 (enlistment), age 55 (VETSA 1), and 61 (VETSA 2). The results of the current analyses show that ED is related to both amnestic MCI (p=.032) and non-amnestic MCI (p=.009) at VETSA 1. At VETSA 2, however, the relationship between ED and non-amnestic MCI was no longer significant (p=.751) while the relationship between ED and amnestic MCI was stronger (p=.001). These results are consistent with ED and MCI sharing, to some extent, a common etiology. Vascular dysfunction, which is associated with both ED and MCI, is a plausible mechanism responsible for the observed relationship. These results also highlight the potential role that may be played by ED as an early indicator of cognitive impairment and, perhaps, pre-symptomatic AD.
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Forlenza, Orestes Vicente, Breno Satler Diniz, Paula Villela Nunes, Claudia Maia Memória, Monica Sanches Yassuda, and Wagner Farid Gattaz. "Diagnostic transitions in mild cognitive impairment subtypes." International Psychogeriatrics 21, no. 6 (August 20, 2009): 1088–95. http://dx.doi.org/10.1017/s1041610209990792.
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ABSTRACTBackground: At least for a subset of patients, the clinical diagnosis of mild cognitive impairment (MCI) may represent an intermediate stage between normal aging and dementia. Nevertheless, the patterns of transition of cognitive states between normal cognitive aging and MCI to dementia are not well established. In this study we address the pattern of transitions between cognitive states in patients with MCI and healthy controls, prior to the conversion to dementia.Methods: 139 subjects (78% women, mean age, 68.5 ± 6.1 years; mean educational level, 11.7 ± 5.4 years) were consecutively assessed in a memory clinic with a standardized clinical and neuropsychological protocol, and classified as cognitively healthy (normal controls) or with MCI (including subtypes) at baseline. These subjects underwent annual reassessments (mean duration of follow-up: 2.7 ± 1.1 years), in which cognitive state was ascertained independently of prior diagnoses. The pattern of transitions of the cognitive state was determined by Markov chain analysis.Results: The transitions from one cognitive state to another varied substantially between MCI subtypes. Single-domain MCI (amnestic and non-amnestic) more frequently returned to normal cognitive state upon follow-up (22.5% and 21%, respectively). Among subjects who progressed to Alzheimer's disease (AD), the most common diagnosis immediately prior conversion was multiple-domain MCI (85%).Conclusion: The clinical diagnosis of MCI and its subtypes yields groups of patients with heterogeneous patterns of transitions between one given cognitive state to another. The presence of more severe and widespread cognitive deficits, as indicated by the group of multiple-domain amnestic MCI may be a better predictor of AD than single-domain amnestic or non-amnestic deficits. These higher-risk individuals could probably be the best candidates for the development of preventive strategies and early treatment for the disease.
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Kim, Heeyoung, Sungmin Jun, Bum Soo Kim, and In-Joo Kim. "Serum Adiponectin in Alzheimer’s Disease (AD): Association with AD Biomarkers and Cognitive Outcome." Journal of Alzheimer's Disease 84, no. 3 (November 23, 2021): 1163–72. http://dx.doi.org/10.3233/jad-210722.
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Background: The association between dementia and serum adiponectin has been evaluated in many studies; however, conclusions remain mixed. Objective: We investigated the cross-sectional associations of adiponectin with cognitive function and Alzheimer’s disease (AD) biomarkers and whether serum adiponectin levels can predict cognitive outcomes. Methods: This study included 496 participants from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI1) with available serum adiponectin levels at baseline and ≥65 years of age. Subjects were stratified based on sex and apolipoprotein ɛ4 (APOE4) carrier status to determine associations between adiponectin and cognitive function. The linear mixed model was used to analyze associations between adiponectin level and cognitive outcome in amnestic mild cognitive impairment (aMCI) patients. Results: Serum adiponectin levels were higher in aMCI and AD than in CN subjects among APOE4 non-carrier males (adiponectin in CN, aMCI, and AD: 0.54±0.24, 0.74±0.25, and 0.85±0.25, respectively, p < 0.001). In this group, serum adiponectin levels were associated with age (p = 0.001), ADAS13 (p < 0.001), memory function (p < 0.001), executive function (p < 0.001), total tau (p < 0.001), and phosphorylated tau (p < 0.001) measures in cerebrospinal fluid (CSF). Higher adiponectin level was not associated with cognitive outcome in aMCI patients in the linear mixed model analysis over 5.3±2.6 years of mean follow-up. Conclusion: Serum adiponectin level was associated with cognitive function and CSF AD biomarkers among APOE4 non-carrier males. However, serum adiponectin level was not associated with longitudinal cognitive function outcome in aMCI.
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Cerman, Jiri, Ross Andel, Jan Laczo, Martin Vyhnalek, Zuzana Nedelska, Ivana Mokrisova, Katerina Sheardova, and Jakub Hort. "Subjective Spatial Navigation Complaints - A Frequent Symptom Reported by Patients with Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease." Current Alzheimer Research 15, no. 3 (January 23, 2018): 219–28. http://dx.doi.org/10.2174/1567205014666171120145349.
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Background: Great effort has been put into developing simple and feasible tools capable to detect Alzheimer's disease (AD) in its early clinical stage. Spatial navigation impairment occurs very early in AD and is detectable even in the stage of mild cognitive impairment (MCI). Objective: The aim was to describe the frequency of self-reported spatial navigation complaints in patients with subjective cognitive decline (SCD), amnestic and non-amnestic MCI (aMCI, naMCI) and AD dementia and to assess whether a simple questionnaire based on these complaints may be used to detect early AD. Method: In total 184 subjects: patients with aMCI (n=61), naMCI (n=27), SCD (n=63), dementia due to AD (n=20) and normal controls (n=13) were recruited. The subjects underwent neuropsychological examination and were administered a questionnaire addressing spatial navigation complaints. Responses to the 15 items questionnaire were scaled into four categories (no, minor, moderate and major complaints). Results: 55% of patients with aMCI, 64% with naMCI, 68% with SCD and 72% with AD complained about their spatial navigation. 38-61% of these complaints were moderate or major. Only 33% normal controls expressed complaints and none was ranked as moderate or major. The SCD, aMCI and AD dementia patients were more likely to express complaints than normal controls (p's<0.050) after adjusting for age, education, sex, depressive symptoms (OR for SCD=4.00, aMCI=3.90, AD dementia=7.02) or anxiety (OR for SCD=3.59, aMCI=3.64, AD dementia=6.41). Conclusion: Spatial navigation complaints are a frequent symptom not only in AD, but also in SCD and aMCI and can potentially be detected by a simple and inexpensive questionnaire.
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Paraskevas, George P., and Elisabeth Kapaki. "Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments." Brain Sciences 11, no. 10 (September 23, 2021): 1258. http://dx.doi.org/10.3390/brainsci11101258.
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Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction in CSF β-amyloid (marker of amyloid plaque burden), although compatible with Alzheimer’s pathological change, may also be observed in other dementing disorders, including vascular cognitive disorders due to subcortical small-vessel disease, dementia with Lewy bodies and normal-pressure hydrocephalus. Thus, for the diagnosis of AD, an abnormal result of CSF β-amyloid may not be sufficient, and an increase in phospho-tau (marker of tangle pathology) is also required in order to confirm AD diagnosis in patients with a typical amnestic presentation and reveal underlying AD in patients with atypical or mixed and diagnostically confusing clinical presentations.
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Lee, Sun Hyung, Jun Ho Lee, Min Soo Byun, Dahyun Yi, Gijung Jung, Jee Eun Park, and Dong Young Lee. "Comparison of Amyloid Positivity Rate and Accumulation Pattern between Amnestic and Non-Amnestic Type Mild Cognitive Impairment." Psychiatry Investigation 17, no. 6 (June 15, 2020): 603–7. http://dx.doi.org/10.30773/pi.2020.0063.
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Objective We aimed to compare cerebral beta-amyloid protein (Aβ) positivity rate and amyloid accumulation pattern on amyloid positron emission tomography (PET) between mild cognitive impairment (MCI) subtypes, i.e. amnestic mild cognitive impairment (aMCI) and non-amnestic mild cognitive impairment (naMCI).Methods The study participants were 34 naMCI patients and age-, sex- and education-matched 68 aMCI patients (1:2 ratio) who visited the Dementia and Age-Associated Cognitive Decline Clinic of the Seoul National University Hospital. All participants received comprehensive clinical and neuropsychological assessments and [<sup>18</sup>F] florbetaben PET.Results Aβ positivity rate of naMCI group (26.5%) was significantly lower than that of aMCI group (64.7%). Among Aβ positive individuals, there was no difference in Aβ accumulation pattern between naMCI and aMCI.Conclusion The findings suggest that MCI subtypes based on impaired cognitive domains have a differential association with brain Aβ deposition, a core pathology of AD. Amnestic subtype of MCI are more closely associated with cerebral Aβ deposition compared to nonamnestic subtype. In contrast, the pattern of amyloid deposition does not appear to have any difference between the subtypes.
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H., Veena, Narendranath S., and Shashikala G. H. "A comparative study between cilnidipine and amlodipine on learning and memory in albino mice." International Journal of Basic & Clinical Pharmacology 9, no. 5 (April 23, 2020): 726. http://dx.doi.org/10.18203/2319-2003.ijbcp20201747.
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Background: Alzheimer’s disease (AD) is the leading cause of dementia, followed by vascular dementia (VaD). Animal studies have shown that amlodipine improves learning and memory. Since, cilnidipine produces lesser side effects than amlodipine, and animal studies have shown that it has neuroprotective action, this study was conducted to evaluate the effect of cilnidipine on learning and memory and its comparison with amlodipine in alprazolam induced amnesic albino mice.Methods: This study was carried out on albino mice, divided into three groups of six animals each. Amnesia was induced by intraperitoneal injection of alprazolam in all the three groups from day 1 to 14. In addition, group 1, 2 and 3 received normal saline as a control, amlodipine and cilnidipine as test drugs respectively, by same route for the same duration. Then, learning and memory of the animals was assessed using elevated plus maze and cook’s pole climbing models. Results were compared among the groups using one-way ANOVA followed by post hoc Tukey’s test.Results: In both the model’s amlodipine and cilnidipine groups showed statistically significant reduction in transfer latency and conditioned avoidance response duration in comparison with normal saline. But no difference was found between amlodipine and cilnidipine groups.Conclusions: Cilnidipine and amlodipine showed a non-inferiority response on learning and memory enhancing effect in this study. Since, cilnidipine has lesser side effects than amlodipine, it can be taken up for evaluating its effect on cognitive improvement in dementia patients.
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Aldaco, Juan Pablo Hernandez, Winter Olmos, Abril Baez, Tanner O'Brien, Jordan Kozuki, Loren Alving, David Lent, and Ellen Woo. "A-105 The Utility of Subjective Reports in Predicting Objective Prospective Memory Outcomes in Amnestic and Non-Amnestic Mild Cognitive Impairment." Archives of Clinical Neuropsychology 37, no. 6 (August 17, 2022): 1257. http://dx.doi.org/10.1093/arclin/acac060.105.
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Abstract Objective: Prospective memory (PM) involves remembering to carry out an intended action in the future and is impacted in Mild Cognitive Impairment (MCI) and Alzheimer’s disease (ad). Subjective ratings have been used in reporting patient PM outcomes. This study examined the utility of subjective reports in predicting objective PM in individuals with amnestic mild cognitive impairment (aMCI), non-amnestic mild cognitive impairment (naMCI) and healthy older adults. Methods: Participants included 58 healthy controls (HC), 37 persons with aMCI, and 28 individuals with naMCI. Subjective reports were assessed using caregiver and participant ratings on the Prospective-Retrospective Memory Questionnaire. An objective PM measure was used during the neuropsychological assessment. Simple PM involves remembering to request any pill after a task. Complex PM involves remembering to request the correct number of pills after each task. Results: Linear regression analyses revealed that subjective caregiver and participant ratings predicted simple PM performance for only the HC group, where caregiver reports were unique predictors. Subjective caregiver and participant ratings were not predictive of complex PM performance in any of the groups. Conclusion: Results indicate that subjective caregiver reports were only predictive of healthy participants’ objective simple PM outcomes. This indicates that generally overall subjective ratings are not a substitute for actual PM outcomes in ad and MCI groups. In conclusion, researchers and clinicians should not rely solely on subjective reports in predicting objective outcomes.
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Balthazar, Márcio Luiz Figueredo, Fernando Cendes, and Benito Pereira Damasceno. "Category verbal fluency performance may be impaired in amnestic mild cognitive impairment." Dementia & Neuropsychologia 1, no. 2 (June 2007): 161–65. http://dx.doi.org/10.1590/s1980-57642008dn10200008.
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Abstract To study category verbal fluency (VF) for animals in patients with amnestic mild cognitive impairment (aMCI), mild Alzheimer disease (AD) and normal controls. Method: Fifteen mild AD, 15 aMCI, and 15 normal control subjects were included. Diagnosis of AD was based on DSM-IV and NINCDS-ADRDA criteria, while aMCI was based on the criteria of the International Working Group on Mild Cognitive Impairment, using CDR 0.5 for aMCI and CDR 1 for mild AD. All subjects underwent testing of category VF for animals, lexical semantic function (Boston Naming-BNT, CAMCOG Similarities item), WAIS-R forward and backward digit span, Rey Auditory Verbal Learning (RAVLT), Mini-Mental Status Examination (MMSE), and other task relevant functions such as visual perception, attention, and mood state (with Cornell Scale for Depression in Dementia). Data analysis used ANOVA and a post-hoc Tukey test for intergroup comparisons, and Pearson's coefficient for correlations of memory and FV tests with other task relevant functions (statistical significance level was p<0.05). Results: aMCI patients had lower performance than controls on category VF for animals and on the backward digit span subtest of WAIS-R but higher scores compared with mild AD patients. Mild AD patients scored significantly worse than aMCI and controls across all tests. Conclusion: aMCI patients may have poor performance in some non-memory tests, specifically category VF for animals in our study, where this could be attributable to the influence of working memory.
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Oh, Yoon-Sang, Sang-Won Yoo, Chul Hyoung Lyoo, Ji-Yeon Yoo, Hyukjin Yoon, Seunggyun Ha, Kwang-Soo Lee, and Joong-Seok Kim. "The Association of β-Amyloid with Cognition and Striatal Dopamine in Early, Non-Demented Parkinson’s Disease." Journal of Parkinson's Disease 11, no. 2 (April 13, 2021): 605–13. http://dx.doi.org/10.3233/jpd-202496.
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Background: Co-occurrence of β-amyloid (Aβ) pathology has been reported in Parkinson’s disease (PD), and Aβ deposition in the brain may contribute to cognitive decline in patients with PD. Whether striatal dopamine uptake and cognitive status differ with amyloid deposition has been reported in only a few studies. Objective: The purpose of this study was to investigate the association among striatal dopaminergic availability, Aβ-positivity, and motor and cognitive status in early and non-demented PD. Methods: A total of 98 newly-diagnosed, non-medicated, and non-demented patients with PD were included in this study. Cognitive status was assessed using neuropsychological testing. Patients with mild cognitive impairment (MCI) were stratified into two groups: amnestic MCI (aMCI) and non-amnestic MCI (naMCI). Patient motor status was examined using the Unified Parkinson’s Disease Rating Scale (UPDRS) and positron emission tomography (PET) with 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (18F-FP-CIT). All patients also underwent 18F-florbetaben (18F-FBB) PET and were divided based on the results into Aβ-positive and Aβ-negative groups. Results: Eighteen patients had Aβ-positivity in 18F-FBB PET and 67 had MCI. Sixteen of 18 with Aβ-positive patients had MCI. The Aβ-positive group had higher frequency of MCI, especially amnestic-type, and lower dopaminergic activities in the left ventral striatum, but not with UPDRS motor score. Conclusion: Amyloid pathology was associated with MCI, especially amnestic-subtype, in early and non-demented PD patients and with low dopaminergic activities in the left ventral striatum. This finding suggests that PD patients with Aβ-positivity have AD-related cognitive pathophysiology in PD and associated impaired dopaminergic availability in the ventral striatum can affect the pathophysiology in various ways.
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Senturk, Gulben, Basar Bilgic, Ali Bilgin Arslan, Ali Bayram, Hasmet Hanagasi, Hakan Gurvit, and Murat Emre. "Cognitive and anatomical correlates of anosognosia in amnestic mild cognitive impairment and early-stage Alzheimer's disease." International Psychogeriatrics 29, no. 2 (October 26, 2016): 293–302. http://dx.doi.org/10.1017/s1041610216001812.
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ABSTRACTBackground:Anosognosia is a common feature in Alzheimer's disease (AD). The brain substrates of anosognosia are not fully understood, and less is known about the cognitive substrates of anosognosia in prodromal and early stages of AD.Methods:Fourty-seven patients with amnestic-type mild cognitive impairment (aMCI) (n = 26) and early-stage AD (n = 21) were included, and Clinical Insight Rating Scale and Anosognosia Questionnaire for Dementia (AQ-D) were used to assess anosognosia. A detailed neuropsychological battery was administered; each patient underwent a structural magnetic resonance imaging (MRI). Correlation between anosognosia and performance in individual cognitive domains as well as correlation between anosognosia and cortical thickness values in regions of interest were assessed.Results:Performance of the anosognosic patients in Digit Ordering Test (DOT), Digit Span Backwards, and Clock Drawing Test (CDT) was significantly worse compared to non-anosognosic patients in the total study population and in the aMCI subgroup but not in AD group. AQ-D scores negatively correlated with Mini-Mental State Examination (MMSE), California Verbal Learning Test (CVLT), Digit Span Backwards and CDT scores in total group and MMSE, CVLT, DOT, and Digit Span Backwards scores in the aMCI group. No significant correlations were found between cortical thickness measurements and AQ-D scores in any of the patient populations.Conclusions:Anosognosia was associated with episodic memory, working memory, and executive functions in the total population and aMCI group, but no association was found in early-stage AD patients. Anosognosia in the early stages of AD may be related with non-structural changes such as hypoconnectivity rather than structural changes.
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Binaco, Russell, Nicholas Calzaretto, Jacob Epifano, Sean McGuire, Muhammad Umer, Sheina Emrani, Victor Wasserman, David J. Libon, and Robi Polikar. "Machine Learning Analysis of Digital Clock Drawing Test Performance for Differential Classification of Mild Cognitive Impairment Subtypes Versus Alzheimer’s Disease." Journal of the International Neuropsychological Society 26, no. 7 (March 23, 2020): 690–700. http://dx.doi.org/10.1017/s1355617720000144.
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AbstractObjective:To determine how well machine learning algorithms can classify mild cognitive impairment (MCI) subtypes and Alzheimer’s disease (AD) using features obtained from the digital Clock Drawing Test (dCDT).Methods:dCDT protocols were administered to 163 patients diagnosed with AD(n = 59), amnestic MCI (aMCI; n = 26), combined mixed/dysexecutive MCI (mixed/dys MCI; n = 43), and patients without MCI (non-MCI; n = 35) using standard clock drawing command and copy procedures, that is, draw the face of the clock, put in all of the numbers, and set the hands for “10 after 11.” A digital pen and custom software recorded patient’s drawings. Three hundred and fifty features were evaluated for maximum information/minimum redundancy. The best subset of features was used to train classification models to determine diagnostic accuracy.Results:Neural network employing information theoretic feature selection approaches achieved the best 2-group classification results with 10-fold cross validation accuracies at or above 83%, that is, AD versus non-MCI = 91.42%; AD versus aMCI = 91.49%; AD versus mixed/dys MCI = 84.05%; aMCI versus mixed/dys MCI = 84.11%; aMCI versus non-MCI = 83.44%; and mixed/dys MCI versus non-MCI = 85.42%. A follow-up two-group non-MCI versus all MCI patients analysis yielded comparable results (83.69%). Two-group classification analyses were achieved with 25–125 dCDT features depending on group classification. Three- and four-group analyses yielded lower but still promising levels of classification accuracy.Conclusion:Early identification of emergent neurodegenerative illness is criterial for better disease management. Applying machine learning to standard neuropsychological tests promises to be an effective first line screening method for classification of non-MCI and MCI subtypes.
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Cardoso, Sandra, Dina Silva, Luísa Alves, Manuela Guerreiro, and Alexandre de Mendonça. "The Outcome of Patients with Amyloid-Negative Amnestic Mild Cognitive Impairment." Journal of Alzheimer's Disease 86, no. 2 (March 22, 2022): 629–40. http://dx.doi.org/10.3233/jad-215465.
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Background: Patients with amnestic mild cognitive impairment (aMCI) are usually at an initial stage of Alzheimer’s disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology characteristic of AD. The significance of amyloid-negative aMCI is not presently clear. Objective: To know the etiology and prognosis of amyloid-negative aMCI. Methods: Patients who fulfilled criteria for aMCI and were amyloid negative were selected from a large cohort of non-demented patients with cognitive complaints and were followed with clinical and neuropsychological assessments. Results: Few amyloid-negative aMCI had evidence of neurodegeneration at the baseline, as reflected in cerebrospinal fluid elevated tau protein levels. About half of the patients remained essentially stable for long periods of time. Others manifested a psychiatric disorder that was not apparent at baseline, namely major depression or bipolar disorder. Remarkably, about a quarter of patients developed neurodegenerative disorders other than AD, mostly frontotemporal dementia or Lewy body disease. Conclusion: Amyloid-negative aMCI is a heterogeneous condition. Many patients remain clinically stable, but others may later manifest psychiatric conditions or evolve to neurodegenerative disorders. Prudence is needed when communicating to the patient and family the results of biomarkers, and clinical follow-up should be advised.
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Loewenstein, David A., Rosie E. Curiel, Steven DeKosky, Russell M. Bauer, Monica Rosselli, Salvador M. Guinjoan, Malek Adjouadi, et al. "Utilizing semantic intrusions to identify amyloid positivity in mild cognitive impairment." Neurology 91, no. 10 (August 3, 2018): e976-e984. http://dx.doi.org/10.1212/wnl.0000000000006128.
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ObjectiveSemantic intrusion (SI) errors may highlight specific breakdowns in memory associated with preclinical Alzheimer disease (AD); however, there have been no investigations to determine whether SI errors occur with greater frequency in persons with amnestic mild cognitive impairment (aMCI) confirmed as amyloid positive (Amy+) vs those who have clinical symptoms of aMCI-AD with negative amyloid scans (suspected non-AD pathology [SNAP]) or persons who are diagnosed with other brain disorders affecting cognition.MethodsEighty-eight participants with aMCI underwent brain amyloid PET and MRI scans and were classified as early AD (Amy+), SNAP (Amy−), or other neurological/psychiatric diagnosis (Amy−). We focused on SI on the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) targeting proactive semantic interference (PSI; old semantic learning interferes with new semantic learning), failure to recover from PSI after an additional learning trial (frPSI), and retroactive semantic interference (new semantic learning interferes with memory for old semantic learning).ResultsSIs on measures of PSI and frPSI distinguished between Amy+ AD and SNAP and other non-AD cases. PSI and frPSI intrusions evidenced moderately high associations with reduced volumes in the entorhinal cortex, superior temporal regions, and supramarginal gyrus. No such associations were observed in cases with SNAP.ConclusionsSIs on the LASSI-L related to PSI and frPSI uniquely differentiated Amy+ and Amy− participants with aMCI and likely reflect deficits with inhibition and source memory in preclinical AD not captured by traditional cognitive measures. This may represent a specific, noninvasive test successful at distinguishing cases with true AD from those with SNAP.
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Villain, Nicolas, and Bruno Dubois. "Alzheimer's Disease Including Focal Presentations." Seminars in Neurology 39, no. 02 (March 29, 2019): 213–26. http://dx.doi.org/10.1055/s-0039-1681041.
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AbstractAlzheimer's disease (AD) is the commonest neurodegenerative disease and the most frequent cause of dementia. It affects 30 million people worldwide. Current research criteria focus on biomarkers' status for amyloid and tau using positron emission tomography and cerebrospinal fluid analysis, independent of clinical status. Current epidemiological data, which mostly rely on biomarker-undetermined AD cases, have highlighted ApoE4 and age as the main risk factors. Rare autosomal dominant mutations also account for a small fraction of early-onset AD. The main clinical phenotype at presentation is the amnestic phenotype targeting episodic memory. This is followed by rarer phenotypes such as posterior cortical atrophy, logopenic variant of primary progressive aphasia, frontal variant AD, corticobasal syndrome, and other even rarer presentations mimicking language variants of frontotemporal dementia. Main differential diagnoses include hippocampal sclerosis with TDP-43, primary age-related tauopathy, argyrophilic grain disease, frontotemporal lobar degeneration, Lewy body disease, chronic traumatic encephalopathy as well as nondegenerative disorders such as cerebrovascular disease, chronic alcohol consumption, limbic encephalitis, medial temporal lobe epilepsy, and others. Co-occurrence of AD pathology with other neurodegenerative and vascular diseases is common and increases with age. This presents a challenge in current clinical practice due to a lack of reliable biomarkers for non-AD neurodegenerative diseases.
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Quattrini, Giulia, Moira Marizzoni, Francesca B. Pizzini, Ilaria Boscolo Galazzo, Marco Aiello, Mira Didic, Andrea Soricelli, et al. "Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients." Journal of Alzheimer's Disease 82, no. 4 (August 17, 2021): 1797–808. http://dx.doi.org/10.3233/jad-210531.
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Background: Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer’s disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL). Objective: To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI. Methods: We collected core AD markers (amyloid-β 42 [Aβ42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks’ perfusion, cerebellar volume, and processing speed. Results: Perfusion was reduced in the DMN (F = 5.486, p = 0.039) and LIN (F = 12.678, p = 0.004) in APOE ɛ4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aβ42 levels (r = 0.678, p = 0.022) and memory impairment (PAL, number of errors, r = –0.779, p = 0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features. Conclusion: Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ɛ4, and memory impairment.
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Lehrner, Johann, Sandra Kogler, Claus Lamm, Doris Moser, Stefanie Klug, Gisela Pusswald, Peter Dal-Bianco, Walter Pirker, and Eduard Auff. "Awareness of memory deficits in subjective cognitive decline, mild cognitive impairment, Alzheimer's disease and Parkinson's disease." International Psychogeriatrics 27, no. 3 (November 10, 2014): 357–66. http://dx.doi.org/10.1017/s1041610214002245.
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ABSTRACTBackground:Impaired awareness of memory deficits has been recognized as a common phenomenon in Alzheimer's disease (AD) and research is now increasingly focusing on awareness in groups at risk for future dementia. This study aimed to determine whether levels of awareness differ among healthy elderly people and patients with subjective cognitive decline (SCD), amnestic and non-amnestic subtypes of mild cognitive impairment (aMCI, naMCI), Alzheimer's disease (AD) and Parkinson's disease (PD), to explore correlates of awareness and to establish frequencies of memory over- and underestimation within each diagnostic group.Methods:756 consecutive outpatients of a memory clinic and 211 healthy controls underwent thorough neuropsychological testing. Impairment of awareness was measured as the difference between subjective memory appraisals (16-item questionnaire on current memory-related problems in everyday life) and objective memory performance (15-item delayed recall task). Subgroups of over- and underestimators were classified using percentile ranks of controls.Results:At group level, awareness significantly decreased along the naMCI→aMCI→AD continuum, with naMCI patients showing a tendency towards overestimation of memory dysfunction. PD patients showed accurate self-appraisals as long as memory function was largely unaffected. However, there was a considerable between-group overlap in awareness scores. Furthermore, different correlates of awareness were observed depending on the diagnostic group. In general, unawareness seems to be associated with decreased cognitive performance in various domains (especially memory), higher age and lower levels of depression and self-reported functional impairment.Conclusion:Impaired awareness is an important symptom in aMCI. Yet, given the considerable variability in awareness scores, longitudinal studies are required to evaluate their predictive power.
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Sheng, Can, Mingrui Xia, Zhongjie Hu, and Ying Han. "P1-248: DECREASED RESTING-STATE FUNCTIONAL CONNECTIVITY STRENGTH IN AMNESTIC MCI-TO-AD CONVERTERS AND NON-CONVERTERS." Alzheimer's & Dementia 10 (July 2014): P397. http://dx.doi.org/10.1016/j.jalz.2014.05.487.
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Coutinho, Gabriel, Cláudia Drummond, Ricardo de Oliveira-Souza, Jorge Moll, Fernanda Tovar-Moll, and Paulo Mattos. "Immediate story recall in elderly individuals with memory complaints: how much does it contribute to memory assessment?" International Psychogeriatrics 27, no. 10 (March 13, 2015): 1679–86. http://dx.doi.org/10.1017/s1041610215000307.
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ABSTRACTBackground:Prose memory tests exhibit ecological validity, but the influence of non-memory functions on immediate recall in elderly subjects with memory complaints has not been fully investigated. This study examined (1) whether the ability to immediately recall a story can distinguish among clinical controls, amnesic mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) and (2) which cognitive functions contribute to immediate recall performance.Methods:A total of 73 consecutive volunteers (50 women and 23 men) aged 47–88 (mean age = 71.85 ± 9.41) and with a mean schooling level of 12.51 (SD = 4.09) participated in the experiment. All individuals were seeking specialized evaluation because of memory complaints. Diagnoses were made by considering clinical, neuropsychological, and MRI assessments collected by a multidisciplinary team of neurologists, neuropsychologists, and speech-language therapists. A total of 26 individuals were classified as clinical controls; 27 as MCI patients; and 20 as having AD dementia. All individuals in the AD group had a Clinical Dementia Rating (CDR) ≤ 1.Results:Immediate recall was only able to distinguish AD subjects from MCI patients and clinical controls (p > 0.05). Stepwise multiple linear regression analysis revealed that mental status (MMSE), semantic memory (WAIS-III vocabulary) and episodic memory (RAVLT primacy) explained approximately 62% of the variance in immediate recall.Conclusions:Understanding the value and limitations of immediate story recall in distinguishing between MCI and AD may help clinicians in better choosing cognitive tests to diagnose MCI.
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Pusswald, G., D. Moser, M. Pflüger, A. Gleiss, E. Auff, E. Stögmann, P. Dal-Bianco, and J. Lehrner. "The impact of depressive symptoms on health-related quality of life in patients with subjective cognitive decline, mild cognitive impairment, and Alzheimer's disease." International Psychogeriatrics 28, no. 12 (August 31, 2016): 2045–54. http://dx.doi.org/10.1017/s1041610216001289.
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ABSTRACTBackground:Health-related quality of life (HRQOL) is an important issue in the context of dementia care. The purpose of this study was to investigate the association between HRQOL and depressive symptoms in patients with subjective cognitive decline (SCD) and subtypes of mild cognitive impairment (MCI) and Alzheimer´s disease (AD).Methods:In this cross-sectional, observational study, a control group and four experimental groups (SCD, non-amnestic MCI, amnesticMCI, AD) were compared. Neuropsychological measurers (NTBV) and psychological questionnaires were used for data collection.Results:The control group scored higher than patients with SCD, naMCI, aMCI, or AD for the Mental Health Component Score (MHCS) of the Short Form of the Health Survey (SF-36). The Physical Health Component Score (PHCS) of the SF-36 differed only between some groups. Furthermore, cognitive variables were more strongly associated with the physical aspects of HRQOL, whereas depressive symptoms were more strongly related with the mental aspects of HRQOL.Conclusions:HRQOL and depressive symptoms are closely related in patients with cognitive impairments. Therefore, it is of great importance to assess patients with subjective impairment carefully in terms of depressive symptoms.
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Udeh-Momoh, Chinedu T., Tamlyn Watermeyer, Geraint Price, Celeste A. de Jager Loots, Natalia Reglinska-Matveyev, Michael Ropacki, Nzeera Ketter, et al. "Protocol of the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy." BMJ Open 11, no. 6 (June 2021): e043114. http://dx.doi.org/10.1136/bmjopen-2020-043114.
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IntroductionThe Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy (CPSS), sponsored by Janssen Pharmaceutical Research & Development LLC, is an Alzheimer’s disease (AD) biomarker enriched observational study that began 3 July 2015 CPSS aims to identify and validate determinants of AD, alongside cognitive, functional and biological changes in older adults with or without detectable evidence of AD pathology at baseline.Methods and analysisCPSS is a dual-site longitudinal cohort (3.5 years) assessed quarterly. Cognitively normal participants (60–85 years) were recruited across Greater London and Edinburgh. Participants are classified as high, medium (amnestic or non-amnestic) or low risk for developing mild cognitive impairment–Alzheimer’s disease based on their Repeatable Battery for the Assessment of Neuropsychological Status performance at screening. Additional AD-related assessments include: a novel cognitive composite, the Global Preclinical Alzheimer’s Cognitive Composite, brain MRI and positron emission tomography and cerebrospinal fluid analysis. Lifestyle, other cognitive and functional data, as well as biosamples (blood, urine, and saliva) are collected. Primarily, study analyses will evaluate longitudinal change in cognitive and functional outcomes. Annual interim analyses for descriptive data occur throughout the course of the study, although inferential statistics are conducted as required.Ethics and disseminationCPSS received ethical approvals from the London—Central Research Ethics Committee (15/LO/0711) and the Administration of Radioactive Substances Advisory Committee (RPC 630/3764/33110) The study is at the forefront of global AD prevention efforts, with frequent and robust sampling of the well-characterised cohort, allowing for detection of incipient pathophysiological, cognitive and functional changes that could inform therapeutic strategies to prevent and/or delay cognitive impairment and dementia. Dissemination of results will target the scientific community, research participants, volunteer community, public, industry, regulatory authorities and policymakers. On study completion, and following a predetermined embargo period, CPSS data are planned to be made accessible for analysis to facilitate further research into the determinants of AD pathology, onset of symptomatology and progression.Trial registration numberThe CHARIOT:PRO SubStudy is registered with clinicaltrials.gov (NCT02114372). Notices of protocol modifications will be made available through this trial registry.
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Ruggiero, Gennaro, Alessandro Iavarone, and Tina Iachini. "Allocentric to Egocentric Spatial Switching: Impairment in aMCI and Alzheimer's Disease Patients?" Current Alzheimer Research 15, no. 3 (January 23, 2018): 229–36. http://dx.doi.org/10.2174/1567205014666171030114821.
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Objective: Deficits in egocentric (subject-to-object) and allocentric (object-to-object) spatial representations, with a mainly allocentric impairment, characterize the first stages of the Alzheimer's disease (AD). Methods: To identify early cognitive signs of AD conversion, some studies focused on amnestic-Mild Cognitive Impairment (aMCI) by reporting alterations in both reference frames, especially the allocentric ones. However, spatial environments in which we move need the cooperation of both reference frames. Such cooperating processes imply that we constantly switch from allocentric to egocentric frames and vice versa. This raises the question of whether alterations of switching abilities might also characterize an early cognitive marker of AD, potentially suitable to detect the conversion from aMCI to dementia. Here, we compared AD and aMCI patients with Normal Controls (NC) on the Ego-Allo- Switching spatial memory task. The task assessed the capacity to use switching (Ego-Allo, Allo-Ego) and non-switching (Ego-Ego, Allo-Allo) verbal judgments about relative distances between memorized stimuli. Results: The novel finding of this study is the neat impairment shown by aMCI and AD in switching from allocentric to egocentric reference frames. Interestingly, in aMCI when the first reference frame was egocentric, the allocentric deficit appeared attenuated. Conclusion: This led us to conclude that allocentric deficits are not always clinically detectable in aMCI since the impairments could be masked when the first reference frame was body-centred. Alongside, AD and aMCI also revealed allocentric deficits in the non-switching condition. These findings suggest that switching alterations would emerge from impairments in hippocampal and posteromedial areas and from concurrent dysregulations in the locus coeruleus-noradrenaline system or pre-frontal cortex.
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Martorelli, Marina, Larissa Hartle, Gabriel Coutinho, Daniel Correa Mograbi, Daniel Chaves, Claudia Silberman, and Helenice Charchat-Fichman. "Diagnostic accuracy of early cognitive indicators in mild cognitive impairment." Dementia & Neuropsychologia 14, no. 4 (December 2020): 358–65. http://dx.doi.org/10.1590/1980-57642020dn14-040005.
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ABSTRACT The aging of the population leads to an increase in the prevalence of dementia and mild cognitive impairment (MCI). Alzheimer's disease (AD) is the most common cause of dementia. Recent studies highlight the early non-amnestic deficits in AD and MCI. The European Union report shows the importance of thoroughly assessing cognitive aspects that have been poorly evaluated, such as processing speed (PS), which could represent early indicators of cognitive decline. Objective: To analyze the diagnostic accuracy of PS measures in older adults with MCI, AD, and those who are cognitively-healthy. Methods: A cross-sectional study was conducted by performing an extensive neuropsychological assessment in three samples: 26 control participants, 22 individuals with MCI, and 21 individuals with AD. Analysis of variance (ANOVA) was employed to test the relationship between dependent variables and the clinical group. Post hoc tests (Bonferroni test) were used when a significant ANOVA result was found. Finally, the Receiver Operating Characteristic (ROC) curve for PS measures was performed in older adults with MCI and AD compared with cognitively-healthy older adults. Results: The results showed that deficits in PS measures can be early indicators of cognitive decline in cases of MCI, even when executive functions (EFs) and functionality are preserved. Conversely, AD versus MCI presented differences in PS, EFs, and functionality. Conclusions: The ROC analyses showed that PS measures had discriminative capacities to differentiate individuals with MCI, AD, and cognitively-healthy older adults.
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Invernizzi, Sandra, Isabelle Simoes Loureiro, Kendra G. Kandana Arachchige, and Laurent Lefebvre. "Late-Life Depression, Cognitive Impairment, and Relationship with Alzheimer’s Disease." Dementia and Geriatric Cognitive Disorders 50, no. 5 (2021): 414–24. http://dx.doi.org/10.1159/000519453.
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This narrative review aimed to explore the existing knowledge in order to examine the multiple forms of late-life depression (LLD) within a non-neurodegenerative or a neurodegenerative context, in particular Alzheimer’s disease (AD). This review will first provide information about different pathogenic hypotheses proposed to describe LLD when it is not linked to a neurodegenerative context. Within the presentation of these syndromes, the literature reports thymic and cognitive specific features and highlights a common preponderance of cognitive impairment, and particularly executive. This review will also report data from research works that have addressed the role of depressive symptoms (DSs) in incidence of AD and mild cognitive impairment (MCI) conversion to AD. These findings support the claim that the relationship between DS (or LLD) and the cognitive decline encountered in AD can be of 2 types: (1) risk factor or (2) prodrome. They also support the hypothesis that the effect of DS on the incidence of AD can be identified between specific characteristics of these symptoms such as a very first apparition late in life, an increasing severity of DS, and a poor response to medical treatment. Finally, longitudinal and cross-sectional research will be presented, aiming to identify the predictive value of DS (or LLD) on AD incidence and/or conversion of MCI (and specifically amnestic MCI). This final section shows that specific features of LLD, such as being of early- or late-onset, can be considered as indices of AD incidence.
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Clark, Lindsay R., Lisa Delano-Wood, David J. Libon, Carrie R. McDonald, Daniel A. Nation, Katherine J. Bangen, Amy J. Jak, Rhoda Au, David P. Salmon, and Mark W. Bondi. "Are Empirically-Derived Subtypes of Mild Cognitive Impairment Consistent with Conventional Subtypes?" Journal of the International Neuropsychological Society 19, no. 6 (April 3, 2013): 635–45. http://dx.doi.org/10.1017/s1355617713000313.
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AbstractGiven the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimer's disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up. (JINS, 2013, 19, 1–11)
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Park, Jung Eun, Tamil Iniyan Gunasekaran, Yeong Hee Cho, Seong-Min Choi, Min-Kyung Song, Soo Hyun Cho, Jahae Kim, et al. "Diagnostic Blood Biomarkers in Alzheimer’s Disease." Biomedicines 10, no. 1 (January 13, 2022): 169. http://dx.doi.org/10.3390/biomedicines10010169.
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Potential biomarkers for Alzheimer’s disease (AD) include amyloid β1–42 (Aβ1–42), t-Tau, p-Tau181, neurofilament light chain (NFL), and neuroimaging biomarkers. Their combined use is useful for diagnosing and monitoring the progress of AD. Therefore, further development of a combination of these biomarkers is essential. We investigated whether plasma NFL/Aβ1–42 can serve as a plasma-based primary screening biomarker reflecting brain neurodegeneration and amyloid pathology in AD for monitoring disease progression and early diagnosis. We measured the NFL and Aβ1–42 concentrations in the CSF and plasma samples and performed correlation analysis to evaluate the utility of these biomarkers in the early diagnosis and monitoring of AD spectrum disease progression. Pearson’s correlation analysis was used to analyse the associations between the fluid biomarkers and neuroimaging data. The study included 136 participants, classified into five groups: 28 cognitively normal individuals, 23 patients with preclinical AD, 22 amyloid-negative patients with amnestic mild cognitive impairment, 32 patients with prodromal AD, and 31 patients with AD dementia. With disease progression, the NFL concentrations increased and Aβ1–42 concentrations decreased. The plasma and CSF NFL/Aβ1–42 were strongly correlated (r = 0.558). Plasma NFL/Aβ1–42 was strongly correlated with hippocampal volume/intracranial volume (r = 0.409). In early AD, plasma NFL/Aβ1–42 was associated with higher diagnostic accuracy than the individual biomarkers. Moreover, in preclinical AD, plasma NFL/Aβ1–42 changed more rapidly than the CSF t-Tau or p-Tau181 concentrations. Our findings highlight the utility of plasma NFL/Aβ1–42 as a non-invasive plasma-based biomarker for early diagnosis and monitoring of AD spectrum disease progression.
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Pereira Vatanabe, Izabela, Rafaela Peron, Marina Mantellatto Grigoli, Silvia Pelucchi, Giulia De Cesare, Thamires Magalhães, Patricia Regina Manzine, et al. "ADAM10 Plasma and CSF Levels Are Increased in Mild Alzheimer’s Disease." International Journal of Molecular Sciences 22, no. 5 (February 28, 2021): 2416. http://dx.doi.org/10.3390/ijms22052416.
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ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity as a protease. In this study, we investigated ADAM10 activity in plasma and CSF samples of patients with amnestic mild cognitive impairment (aMCI) and mild AD compared with cognitively healthy controls. Our results indicated that plasma levels of soluble ADAM10 were significantly increased in the mild AD group, and that in these samples the protease was inactive, as determined by activity assays. The same results were observed in CSF samples, indicating that the increased plasma ADAM10 levels reflect the levels found in the central nervous system. In SH-SY5Y neuroblastoma cells, ADAM10 achieves its major protease activity in the fraction obtained from plasma membrane lysis, where the mature form of the enzyme is detected, confirming the importance of ADAM10 localization for its activity. Taken together, our results demonstrate the potential of plasma ADAM10 to act as a biomarker for AD, highlighting its advantages as a less invasive, easier, faster, and lower-cost processing procedure, compared to existing biomarkers.
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Nagata, Tomoyuki, Shunichiro Shinagawa, Yusuke Ochiai, Ryo Aoki, Hiroo Kasahara, Kazutaka Nukariya, and Kazuhiko Nakayama. "Association between executive dysfunction and hippocampal volume in Alzheimer's disease." International Psychogeriatrics 23, no. 5 (November 25, 2010): 764–71. http://dx.doi.org/10.1017/s1041610210002164.
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ABSTRACTBackground: Some previous research has hypothesized that executive dysfunction in patients with early Alzheimer's disease (AD) occurs as a result of a disconnection between different cerebral areas. The aim of the present study was to evaluate how the hippocampal volume influences executive function as a non-memory cognitive function.Methods: From 157 consecutive patients with AD or amnestic mild cognitive impairment (A-MCI), we recruited 107 subjects who had a global Clinical Dementia Rating (CDR) of 0.5 or 1.0 and whose degree of hippocampal atrophy had been measured using magnetic resonance imaging (MRI); the severity of atrophy was assessed using the voxel-based specific regional analysis for Alzheimer's disease (VSRAD) system. We divided the subjects into three groups: mild atrophy, 0 < Z-score < 1.0 (N = 21); moderate atrophy, 1.0 ≤ Z-score < 2.0 (N = 46); or severe atrophy, 2.0 ≤ Z-score < 4.0 (N = 40) according to the Z-score and compared the Frontal Assessment Battery (FAB) and its subtest scores between each atrophy group.Results: The results demonstrated that age, sex ratio, duration of illness, education years, MMSE score, Behave-AD score, and proportion of atrophy area in total brain (%) were not significantly different among the three groups. Only the go/no-go score among the six subtests was significantly lower for increasing atrophy severity (P < 0.05). Furthermore, hippocampal atrophy significantly influenced the go/no-go score independently of interactions from whether the diagnosis was early AD or A-MCI (P < 0.05).Conclusion: These results support a significant association between hippocampal atrophy and executive dysfunction as a non-memory cognitive impairment in patients with early AD and A-MCI.
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Camarda, Cecilia, Paola Torelli, Carmela Pipia, Gianluca Sottile, Giovanna Cilluffo, and Rosolino Camarda. "APOE Genotypes and Brain Imaging Classes in Normal Cognition, Mild Cognitive Impairment, and Alzheimer’s Disease: A Longitudinal Study." Current Alzheimer Research 17, no. 8 (December 24, 2020): 766–80. http://dx.doi.org/10.2174/1567205017666201109093314.
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Objective: To evaluate in 419 stroke-free cognitively normal subjects (CN) aged 45-82 years covering during a long prospective study (11.54 ± 1.47 years) the preclinical to dementia spectrum: 1) the distribution of small vessel disease (V) and brain atrophy (A) aggregated as following: V−/A−, V−/A+, V+/A−, V+/A+; 2) the relationship of these imaging classes with individual apolipoprotein E (APOE) genotypes; 3) the risk of progression to Alzheimer Disease (AD) of the individual APOE genotypes. Methods: Participants underwent one baseline (t0), and 4 clinical and neuropsychological assessments (t1,t2,t3, and t4). Brain MRI was performed in all subjects at t0, t2, t3 and t4.. White matter hyperintensities were assessed through two visual rating scales. Lacunes were also rated. Subcortical and global brain atrophy were determined through the bicaudate ratio and the lateral ventricle to brain ratio, respectively. APOE genotypes were determined at t0 in all subjects. Cox proportional hazard model was used to evaluate the risk of progression to AD. Results: The imaging class of mixed type was very common in AD, and in non amnestic mild cognitive impaired APOE ε4 non carriers. In these subjects, frontal and parieto-occipital regions were most affected by small vessel disease. Conclusion: Our findings suggest that the APOE ε3 allele is probably linked to the brain vascular pathology.
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Abner, Erin L., Richard J. Kryscio, Gregory E. Cooper, David W. Fardo, Gregory A. Jicha, Marta S. Mendiondo, Peter T. Nelson, et al. "Mild Cognitive Impairment: Statistical Models of Transition Using Longitudinal Clinical Data." International Journal of Alzheimer's Disease 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/291920.
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Mild cognitive impairment (MCI) refers to the clinical state between normal cognition and probable Alzheimer’s disease (AD), but persons diagnosed with MCI may progress to non-AD forms of dementia, remain MCI until death, or recover to normal cognition. Risk factors for these various clinical changes, which we term “transitions,” may provide targets for therapeutic interventions. Therefore, it is useful to develop new approaches to assess risk factors for these transitions. Markov models have been used to investigate the transient nature of MCI represented by amnestic single-domain and mixed MCI states, where mixed MCI comprised all other MCI subtypes based on cognitive assessments. The purpose of this study is to expand this risk model by including a clinically determined MCI state as an outcome. Analyses show that several common risk factors play different roles in affecting transitions to MCI and dementia. Notably, APOE-4 increases the risk of transition to clinical MCI but does not affect the risk for a final transition to dementia, and baseline hypertension decreases the risk of transition to dementia from clinical MCI.