The Role of the Anterior Thalamic Nuclei in the Genesis of Memory Disorders in Alzheimer's Disease: An Exploratory Study.

BACKGROUND: Increasing evidence is demonstrating that degeneration of specific thalamic nuclei, in addition to the hippocampus, may occur in Alzheimer's disease (AD) from the prodromal stage (mild cognitive impairment - MCI) and contribute to memory impairment. OBJECTIVE: Here, we evaluated the presence of macro and micro structural alterations at the level of the anterior thalamic nuclei (ATN) and medio-dorsal thalamic nuclei (MDTN) in AD and amnestic MCI (aMCI) and the possible relationship between such changes and the severity of memory impairment. METHODS: For this purpose, a sample of 50 patients with aMCI, 50 with AD, and 50 age- and education-matched healthy controls (HC) were submitted to a 3-T MRI protocol with whole-brain T1-weighted and diffusion tensor imaging and a comprehensive neuropsychological assessment. RESULTS: At macro-structural level, both the ATN and MDTN were found significantly smaller in patients with aMCI and AD when compared to HC subjects. At micro-structural level, instead, diffusion alterations that significantly differentiated aMCI and AD patients from HC subjects were found only in the ATN, but not in the MDTN. Moreover, diffusion values of the ATN were significantly associated with poor episodic memory in the overall patients' group. CONCLUSIONS: These findings represent the first in vivo evidence of a relevant involvement of ATN in the AD-related neurodegeneration and memory profile and strengthen the importance to look beyond the hippocampus when considering neurological conditions characterized by memory decline.

The effectiveness of an immersive virtual reality and telemedicine-based cognitive intervention on prospective memory in Parkinson's disease patients with mild cognitive impairment and healthy aged individuals: design and preliminary baseline results of a placebo-controlled study.

Introduction: Prospective memory (PM) impairments have been extensively documented in individuals with Parkinson's disease associated with mild cognitive impairment (PD-MCI) and in those with healthy aging. Considering how PM failure decreases individuals' quality of life and functional independence in the activities of daily living, training to enhance this ability could be a prior target of intervention. Objective: Here, we aimed to present the study protocol and preliminary results of a novel immersive virtual reality (IVR) and telemedicine-based (TM) cognitive intervention focused on executive abilities (i.e., planning, shifting, and updating) to improve PM functioning in PD-MCI patients and healthy elderly individuals. Methods: Outcome measures, collected before, immediately after and 2 months after the intervention, included: (1) pre-post training changes in objective cognitive functioning, evaluated with tests assessing executive functions and PM; (2) pre-post training changes in subjective perception of memory functioning, psychiatric symptoms, autonomy in daily living and quality of life, evaluated using the appropriate scales; (3) usability, feasibility and users' compliance with the proposed IVR and telemedicine program. The efficacy of this intervention compared to an active control condition is currently being evaluated in a randomized, double-blind controlled trial, which will be conducted on 30 eligible PD-MCI patients and 30 older adults. Results: Preliminary results concerning between-group comparisons of demographic and neuropsychological screening data show a good balance among the intervention groups considered in this study. The results also suggest good levels of usability, feasibility and acceptability, thus supporting the notion that our intervention can be used to promote cognitive functioning, even in people with cognitive decline. Conclusion: Considering the relatively low costs and easy accessibility to this program, it could prove valuable in primary prevention initiatives and early cognitive rehabilitation for dementia risk reduction.

Special issue on "Novel neuropsychological instruments for the prodromal and preclinical diagnosis of Alzheimer's disease".

Dementia is one of the most challenging health and social emergencies today. It affects more than 55 million people worldwide with epidemiological projections of reaching 140 million people in 2050. Diagnosis of Alzheimer's disease (AD), the clinical-pathological entity responsible for 60%-70% of all dementia cases, rests currently on the demonstration of cerebrospinal fluid or neuroimaging biomarkers, as a proxy of AD cortical neuropathology. In this context, the role of neuropsychological assessment, as a rapid and noninvasive tool able to accurately detect the early cognitive alterations and eventually promote the search for specific biological markers of AD, has become a matter of intense investigation and theoretical debate. This special issue includes original studies as well as literature reviews of the most current and promising approaches aimed at addressing the critical question of distinguishing cognitive decline due to preclinical or prodromal AD from decline associated with physiological aging. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Exploring mechanisms that affect retrograde memory for public events in amnestic mild cognitive impairment: A longitudinal update.

Here, we examined mechanisms that affect retrograde memory in amnestic mild cognitive impairment (a-MCI) as a function of longitudinal clinical outcome. 8 a-MCI who converted to Alzheimer's dementia (AD) during the subsequent 3-year follow-up (converter a-MCI) and 10 a-MCI who remained clinically stable during the same period (stable a-MCI) were compared at the baseline evaluation (i.e., when they were diagnosed as a-MCI) using a remote memory questionnaire for public events that allows disentangling the differential contribution of storage and retrieval mechanisms to performance accuracy. Results suggest that deficits in remote memory are primarily explained by impaired retrieval abilities in stable a-MCI and by impaired storage in converter-to-AD a-MCI. This distinction between retrograde amnesia due to defective trace utilisation in stable a-MCI and trace storage in converter a-MCI is consistent with the temporal unfolding of declining anterograde memory over the course of disease progression to AD.

The diagnostic usefulness of experimental memory tasks for detecting subjective cognitive decline: Preliminary results in an Italian sample.

OBJECTIVE: Subjective cognitive decline (SCD) was recently proposed as an early risk factor for future mild cognitive impairment and Alzheimer's disease (AD). In this study, we investigated the sensitivity of novel neuropsychological testing paradigms (which have been proposed as potentially challenging tools for the identification of preclinical AD) in capturing the subtle cognitive changes leading to SCD but not objectively detected by traditional tests. METHOD: The performances of 18 patients with SCD and 15 healthy individuals with no worries of cognitive decline (healthy controls [HC]) was compared on demanding tasks that investigated, respectively, associative memory, memory binding, spatial pattern separation processes and semantic memory. The diagnostic utility of these tests in capturing the subtle cognitive changes associated with SCD and possible relationships with SCD-related worries were investigated. RESULTS: No significance between-group difference was found on the standard neuropsychological tests. Conversely, the performance of patients with SCD and HC differed significantly on specific indexes derived from experimental tasks assessing face-name associative memory and spatial pattern separation. Moreover, these measures correctly classified group membership with good overall accuracy (between 79% and 82%) and were significantly associated with self-perceived memory functioning. CONCLUSIONS: Our preliminary findings suggest that specific measures derived from demanding cognitive paradigms could be sensitive neuropsychological indexes for detecting the subtle cognitive impairment associated with SCD. These observations could be useful for further refining cognitive assessment aimed at early detection of AD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Forgetting rate for the familiarity and recollection components of recognition in amnestic mild cognitive impairment: A longitudinal study.

Here we aimed to investigate the rate of forgetting of the familiarity and recollection components of recognition in patients at the onset of medial temporal lobe (MTL) pathology and destined to convert to Alzheimer's disease (AD). For this purpose, we conducted a longitudinal study of 13 patients who were diagnosed with amnestic mild cognitive impairment (a-MCI) at the first assessment and followed-up for 3 years. During this time, five patients converted to AD and eight remained in a stable condition of cognitive impairment. A group of 15 healthy subjects were enrolled as the control group (HC). In order to separately quantify the contribution of recollection and familiarity to recognition memory performance, the experimental sample was submitted to a modified version of Huppert and Piercy's procedure that included a Remember/Know paradigm. Data demonstrated that both stable and converter a-MCI patients forgot memory traces relative to the familiarity components of recognition at the same rate as HC. Conversely, converter a-MCI patients showed accelerated long-term forgetting specifically for the recollection component of recognition compared to stable a-MCI and HC. This is the first empirical demonstration that familiarity and recollection components of declarative memory are subject to different rates of forgetting in a-MCI patients as a function of their longitudinal clinical outcome. Our finding of accelerated long-term forgetting of the recollection component of recognition disclosed by converter a-MCI patients suggests that atrophy in the MTL not only interferes with the storage aspects but also disrupts the consolidation of memory traces.

Accelerated long-term forgetting in neurodegenerative disorders: A systematic review of the literature.

Accelerated Long-term Forgetting (ALF) is a memory deficit characterised by normal retention up to relatively short intervals (e.g., minutes, hours) with increased forgetting over longer periods (e.g., days, weeks). ALF is often underestimated due to a lack of common memory assessments beyond 30-60 min. The purpose of this review was to provide an overview of ALF occurrence in neurodegenerative disorders, evaluating whether it can be considered a cognitive deficit useful for diagnosing and monitoring patients. We included 19 experimental studies that investigated ALF in neurodegenerative disorders. Most papers were focused on Alzheimer's disease (AD) dementia and related forms of cognitive decline (Mild Cognitive Impairment, Subjective Cognitive decline, Pre-symptomatic subjects at risk of AD dementia). The major finding of the present work concerns the presence of ALF in very early forms of cognitive decline related to AD. These findings, supporting the hypothesis that ALF is a subtle and undetected hallmark of pre-clinical AD, highlights the importance of investigating forgetting over a longer period and devising standardised measures to be included in clinical practice.

Memory for public events in amnestic mild cognitive impairment: The role of hippocampus and ventro-medial prefrontal cortex.

BACKGROUND: Current theories assume that retrograde memory deficits for semantic information in amnestic mild cognitive impairment (aMCI) are temporally graded and partially sparing most remote memories. Moreover, these models assume a prevalent role of the hippocampus in early phases of memory consolidation and of the prefrontal mesial neocortical areas in permanent consolidation of traces. PURPOSE: To explore the relationship between hippocampus and memory accuracy for the most recent public events and between the ventro-medial prefrontal cortex (vmPFC) and memory accuracy irrespective of the memory age, we investigated in aMCI patients the retrograde memory for public events and its relationship with grey matter volume reductions in the hippocampus and vmPFC. METHODS: 18 aMCI patients and 13 healthy subjects (HS) underwent a modified version of the Famous Events questionnaire (FEq) to assess their memory performance for public events. Patients underwent 3T-MRI scanning to assess correlations between FEq's scores and grey matter volumes. RESULTS: aMCI showed significantly reduced performances on FEq compared to HS in the recollection of most recent events, while no significant difference was observed for more remote memories, thus demonstrating a temporal gradient. Moreover, hippocampal volumes predicted accuracy scores for most recent, but not older, public events. Finally, an area in the subcallosal portion of the vmPFC, corresponding to BA32, predicted accuracy scores on FEq irrespective of the period examined. CONCLUSIONS: Pathological changes in a neural circuit linking hippocampal to medial prefrontal cortical regions are responsible for impaired recollection of retrograde memories in aMCI.

Verbal and spatial memory spans in mild cognitive impairment.

OBJECTIVES: Working memory (WM) for verbal and visual material may be affected early in individuals with mild cognitive impairment (MCI). Verbal and visuospatial span tasks, that is neuropsychological procedures commonly used for the clinical assessment of WM, have been scarcely investigated in these patients. Therefore, this study was aimed at evaluating whether performance on tests of verbal and visual-spatial span (which rely to different extents on distinct components of the WM system) is differently sensitive to the presence of MCI and, in particular, of a preclinical AD condition in patients with MCI. MATERIALS & METHODS: 99 patients with amnesic MCI were given the Digit Span Forward (DSF) and Digit Span Backward (DSB) tests and the Corsi span task (CS) at baseline and were followed up for two years. 32 MCI patients converted to Alzheimer's disease (MCIc), but 67 patients did not deteriorate to meet the criteria for AD (MCIs). RESULTS: Results showed that although performance on DSF did not differ between groups, performance on DSB and CS and ratio indexes indicative of a performance decline passing from DSF to DSB and from DSF to CS significantly discriminated between a group of matched healthy controls and the overall group of MCI patients. Moreover, the ratio indexes significantly discriminated between MCIc and MCIs individuals. CONCLUSIONS: These data are consistent with the hypothesis that individuals with MCI, particularly those destined to convert to AD, are affected by reduced central executive resources even though the phonological loop is still functioning normally.

A Lack of Practice Effects on Memory Tasks Predicts Conversion to Alzheimer Disease in Patients With Amnestic Mild Cognitive Impairment.

The aim of the current study was to test the accuracy of practice effects, that is, improvement in test performance due to repeated neuropsychological evaluations, in identifying patients with amnestic mild cognitive impairment (a-MCI) at greater risk of conversion to Alzheimer disease (AD). For this purpose, we conducted a longitudinal study of 54 patients diagnosed with a-MCI at the first assessment and followed-up for 4 years. During this time, 18 patients converted to AD. Baseline and 6- to 12-month follow-up performances on a large set of neuropsychological tests were analyzed to determine their diagnostic ability to predict later conversion to dementia. Results demonstrate that a lack of practice effects on episodic memory tests is an accurate prognostic indicator of late conversion to AD in a-MCI patients. In fact, even though the performance of both groups was substantially comparable at the baseline evaluation, stable a-MCI patients greatly improved their memory performance at retest after 6 to 12 months; instead, scores of converter a-MCI remained stable or decreased passing from baseline to follow-up. Standardized z-change scores on memory tasks, which were computed as a reliable measure of performance change, classified group membership with very good overall accuracy, which was higher than the classification of converter and stable a-MCIs provided by baseline or follow-up scores. We hypothesize that the lack of practice effects on memory tasks mirrors the early involvement of medial temporal lobe areas in converter a-MCI that are fundamental for the consolidation of new memory traces.

Forgetting Rates on the Recency Portion of a Word List Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease.

Amnestic mild cognitive impairment has a greater risk of progressing to Alzheimer's disease (AD). Consistent with AD patients' distinctive deficit in consolidating new memory traces, in a recent study we demonstrated that the forgetting rate on the recency portion of a word list differentiates AD from other forms of dementia. In line with this finding, the aim of this study was to investigate whether increased recency forgetting could be a reliable index for predicting amnestic mild cognitive impairment (MCI) patients' conversion to AD. For this purpose, we compared accuracy in immediate and delayed recall from different portions of a word list in a group of patients with amnestic MCI who converted (C-MCI) or did not convert (S-MCI) to AD during a three-year follow-up period and in a group of normal controls. The results of the present study show that the forgetting from the recency portion of the list (operationalized as a ratio between immediate and delayed recall) was significantly larger in C-MCI than in S-MCI patients. Consistently, the hierarchical logistic regression analyses demonstrated that the recency ratio is a strong predictor of group membership. Similar to what occurs in full-blown AD patients, the results of our study suggest that the increased forgetting rate from the recency portion of the list in C-MCI patients is due to severely reduced efficiency in converting transitory short-term memory representations into stable long-term memory traces. This is consistent with prominent involvement of neuropathological changes in the cortical areas of the medial-temporal lobes and suggests that the recency ratio is a cognitive marker able to identify MCI patients who have a greater likelihood of progressing to AD.

The role of hippocampus in the retrieval of autobiographical memories in patients with amnestic Mild Cognitive Impairment due to Alzheimer's disease.

The role of the hippocampus and neocortical areas in the retrieval of past memories in pre-dementia Alzheimer's disease (AD) patients was investigated. The aim was to assess whether the hippocampus has a temporary role in memory trace formation, according to the Cortical Reallocation Theory (CRT), or whether it continuously updates and enriches memories, according to the Multiple Trace Theory. According to the former theory, hippocampal damage should affect more recent memories, whereas the association cortex is expected to affect memories of the entire lifespan. In the second case, damage to either the hippocampus or the association cortices should affect memories of the entire lifespan. Seventeen patients with amnestic Mild Cognitive Impairment due to AD were submitted to autobiographical (i.e., episodic and semantic personal) memory assessment. Patients underwent MRI for the acquisition of T1-weighted brain volumes. Voxel-based morphometry was used to assess correlations between grey matter (GM) volumes and autobiographical memory. Correlation analyses revealed a strict association between GM volumes in the hippocampus and patients' ability to retrieve the most recent but not the oldest autobiographical memories in both aspects, episodic and semantic. Moreover, patients' GM volumes in the pre-frontal and temporal polar areas were associated with recollection of episodic and semantic events, respectively. Finally, GM volumes in the precuneus and occipital cortex were associated with retrieval of the most recent episodic events. These findings indicate that the hippocampus has a specific time-dependent role; thus, they support the CRT.

Lost or unavailable? Exploring mechanisms that affect retrograde memory in mild cognitive impairment and Alzheimer's disease patients.

Retrograde amnesia has been largely documented in patients with amnestic mild cognitive impairment (a-MCI) and Alzheimer's disease (AD). However, it is still not clear whether ineffectiveness in recalling past acquired information reflects loss of individual memory traces or failure to access specific stored traces. We aimed to disentangle the differential contribution of storage and retrieval processes to the pattern of retrograde amnesia in these patients. This issue was investigated in 18 a-MCI and 19 AD patients who were compared to 20 healthy controls. A novel questionnaire about public events was used; it consisted of two procedures (i.e., a free recall test and a true/false recognition test). Crucial differences emerged in the way the two groups of patients performed the experimental tasks. In fact, although both a-MCI and AD patients showed a similar pattern of impairment on the free recall test, a-MCI patients were able to normalise their performance on the recognition test, thus overcoming their deficits at the time of recall. Conversely, AD patients showed both reduced free recall ability and diminished sensitivity to benefit from recognition in recalling public events. Our findings suggest that the memory processes underlying RA were different for a-MCI and AD. Deficits in remote memory are prevalently explained by impaired retrieval abilities in a-MCI and by impaired storage in AD. This distinction between retrograde amnesia due to defective trace utilisation in a-MCI and trace storage in AD is consistent with the temporal unfolding of declining anterograde memory over the course of disease progression to AD.

Predicting progression to Alzheimer's disease in subjects with amnestic mild cognitive impairment using performance on recall and recognition tests.

The research of reliable procedures for predicting cognitive decline or stability in persons with amnestic mild cognitive impairment (a-MCI) is a major goal for the early identification of subjects in the prodromal stages of dementia. The aim of this study was to evaluate whether different memory performances on two procedures commonly used for the neuropsychological assessment of episodic memory (i.e., free recall and recognition) might be a key in predicting a-MCI patients' subsequent progression to Alzheimer's disease (AD). For this purpose, 80 patients diagnosed with a-MCI at the first assessment and followed-up for at least 3 years were included. During this time, 41 subjects remained in a stable condition of cognitive impairment or improved (stable-MCI) and 39 patients converted to AD dementia (converter-MCI). Sixty-two age- and education-matched healthy individuals were also recruited as healthy controls (HC). Baseline memory performance on the free recall (5th immediate and 15-min delayed) and yes/no recognition (the sensitivity measure d') of a 15-word list were analyzed. Results showed that stable-MCIs forgot significantly more information from immediate to delayed recall of the word list than HC, but exhibited a pronounced improvement of memory performance in the recognition test format. On the contrary, converter-MCIs showed diminished sensitivity in benefiting from cues for recognizing studied words. Word list recognition correctly classified group membership with good overall accuracy, which was higher compared to the classification of converter and stable a-MCIs provided by free recall; therefore, it could be a useful diagnostic tool for predicting progression to AD dementia from the prodromal stage.

Forgetting Rate on the Recency Portion of a Word List Differentiates Mild to Moderate Alzheimer's Disease from Other Forms of Dementi.

Patients with Alzheimer's disease (AD) demonstrate a disproportionately larger forgetting rate in episodic memory tasks. Previous studies documented that, in comparison with healthy controls, the increased forgetting manifested by AD patients in word list recall tasks is confined to the recency portion of the list with normal forgetting rates on the primacy and mid-list portions. In this study we compared the primacy, mid-list, and recency ratios, obtained by dividing the immediate and delayed recall of words in position 1-4, 5-11, and 12-15 of a 15-word list, in different groups of demented patients, i.e., AD, frontal variant of frontotemporal dementia (fvFTD), Lewy body disease (LBD), subcortical ischemic vascular dementia (SIVD), and a group of normal controls (NC). The aim was to investigate whether the above reported forgetting pattern would differentiate AD performance from that of other dementia groups. Results of the statistical analysis showed that only the recency ratio differentiated AD from patients in the other dementia groups. Consistently, hierarchical logistic regression analyses demonstrated that the recency ratio discriminated between AD patients and individuals affected by other forms of dementia. In particular, the discrimination power was high in differentiating AD from fvFTD patients but was less accurate in differentiating AD from LBD and SIVD patients. We assume that the increased forgetting in AD patients is due to a deficit in memory consolidation mechanisms (specific to AD) that prevent the terminal items in a list from being transferred from a temporary short-term memory store to a stable long-term memory store.

Different deficit patterns on word lists and short stories predict conversion to Alzheimer's disease in patients with amnestic mild cognitive impairment.

Episodic memory impairment is the most common and initial cognitive symptom of AD related to the early involvement of the medial temporal lobe (MTL). In this study, we compared performance on tasks routinely used in the neuropsychological assessment of episodic memory to evaluate which test is more sensitive in predicting subsequent progression to AD in patients with amnestic mild cognitive impairment (a-MCI). For this purpose, we conducted a longitudinal study in 61 patients diagnosed as a-MCI at baseline and followed for 3 years. Baseline memory performance on the word list and short story tests was analyzed to determine the diagnostic ability of the tests to predict subsequent conversion to AD. Results showed that stable a-MCI patients performed worse on word list than on story recall, whereas patients who later converted to AD tended to have similar poor memory performance on both tasks. Furthermore, a pronounced memory decay passing from immediate to delayed recall on the short story test was significantly associated with both higher risk and faster mean time of conversion to AD. We hypothesized that this pattern of results is a consequence of the early involvement in converter a-MCI of MTL areas which are fundamental in the consolidation of new memory traces.

Retrograde Amnesia for Episodic and Semantic Memories in Amnestic Mild Cognitive Impairment.

Retrograde amnesia (RA), which includes loss of memory for past personal events (autobiographical RA) and for acquired knowledge (semantic RA), has been largely documented in patients with amnestic mild cognitive impairment (aMCI). However, previous studies have produced controversial results particularly concerning the temporal extent of memory impairment. Here we investigated whether, with the onset of hippocampal pathology, age of memory acquisition and retrieval frequency play different roles in modulating the progressive loss of semantic and episodic contents of retrograde memory respectively. For this purpose, aMCI patients and healthy controls were tested for the ability to recall semantic and autobiographical information related to famous public events as a function of both age of acquisition and retrieval frequency. In aMCI patients, we found that the impairment in recollecting past personal incidents was modulated by the combined action of memory age and retrieval frequency, because older and more frequently retrieved episodes are less susceptible to loss than more recent and less frequently retrieved ones. On the other side, we found that the loss of semantic information depended only on memory age, because the remoteness of the trace allows for better preservation of the memory. Our results provide evidence that the loss of the two components of retrograde memory is regulated by different mechanisms. This supports the view that diverse neural mechanisms are involved in episodic and semantic memory trace storage and retrieval, as postulated by the Multiple Trace Theory.

Does retrieval frequency account for the pattern of autobiographical memory loss in early Alzheimer's disease patients?

Episodic autobiographical memory (ABM) has been found to be impaired from the early stage of Alzheimer's disease (AD). Previous works have focused on how ABM decreases over the lifespan, but no study has deeply investigated whether the extent of episodic autobiographical amnesia is mediated by the retrieval frequency of the episodic trace itself. The aim of the present study was to determine whether the frequency of trace retrieval has an effect on the quality of autobiographical incidents recall and whether the extent of this contribution changes over time. For this purpose, the episodic component of ABM was assessed in patients in the early stage of AD through a questionnaire which allowed evaluating memory of past personal incidents as a function of both their age of acquisition and retrieval frequency. We found that both AD patients and healthy controls took advantage of greater retrieval frequency across all time segments, because of their better memory performance on frequently retrieved episodes than less frequently retrieved ones. Although in the AD group the retrieval frequency effect (i.e., higher scores on the episodes rated as more frequently retrieved) was found in all time segments, the extent of its beneficial effect on memory performance was temporally-graded and inversely related to the time course. Our findings provide new evidence that the combined action of both age of memory and retrieval frequency could provide a valuable framework for predicting patterns of ABM loss, at least in early AD patients. In line with the Multiple Trace Theory, we speculated that retrieval frequency protects episodic trace recall against hippocampal damage by reinforcing the neural representation of personal context-rich memories, which consequently are easier to access and recall. Furthermore, the age of memory should change the amplitude of this beneficial effect as a function of the remoteness of the trace.