Timing Of Cognitive Decline Research Articles

A Bayesian hierarchical change point model with parameter constraints.

Alzheimer's disease is the leading cause of dementia among adults aged 65 or above. Alzheimer's disease is characterized by a change point signaling a sudden and prolonged acceleration in cognitive decline. The timing of this change point is of clinical interest because it can be used to establish optimal treatment regimens and schedules. Here, we present a Bayesian hierarchical change point model with a parameter constraint to characterize the rate and timing of cognitive decline among Alzheimer's disease patients. We allow each patient to have a unique random intercept, random slope before the change point, random change point time, and random slope after the change point. The difference in slope before and after a change point is constrained to be nonpositive, and its parameter space is partitioned into a null region (representing normal aging) and a rejection region (representing accelerated decline). Using the change point time, the estimated slope difference, and the threshold of the null region, we are able to (1) distinguish normal aging patients from those with accelerated cognitive decline, (2) characterize the rate and timing for patients experiencing cognitive decline, and (3) predict personalized risk of progression to dementia due to Alzheimer's disease. We apply the approach to data from the Religious Orders Study, a national cohort study of aging Catholic nuns, priests, and lay brothers.

Onset of Mild Cognitive Impairment in Parkinson Disease.

Characterize the onset and timing of cognitive decline in Parkinson disease (PD) from the first recognizable stage of cognitively symptomatic PD-mild cognitive impairment (PD-MCI) to PD dementia (PDD). Thirty-nine participants progressed from PD to PDD and 25 remained cognitively normal. Bayesian-estimated disease-state models described the onset of an individual's cognitive decline across 12 subtests with a change point. Subtests measuring working memory, visuospatial processing ability, and crystalized memory changed significantly 3 to 5 years before their first nonzero Clinical Dementia Rating and progressively worsened from PD to PD-MCI to PDD. Crystalized memory deficits were the hallmark feature of imminent conversion of cognitive status. Episodic memory tasks were not sensitive to onset of PD-MCI. For cognitively intact PD, all 12 subtests showed modest linear decline without evidence of a change point. Longitudinal disease-state models support a prodromal dementia stage (PD-MCI) marked by early declines in working memory and visuospatial processing beginning 5 years before clinical diagnosis of PDD. Cognitive declines in PD affect motor ability (bradykinesia), working memory, and processing speed (bradyphrenia) resulting in PD-MCI where visuospatial imagery and memory retrieval deficits manifest before eventual development of overt dementia. Tests of episodic memory may not be sufficient to detect and quantify cognitive decline in PD.

Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways

Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways

Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: a voxelwise PiB–PET longitudinal study

Amyloid-β deposition in Alzheimer's disease is thought to start while individuals are still cognitively unimpaired and it is hypothesized that after an early phase of fast accumulation, a plateau is reached by the time of cognitive decline. However, few longitudinal Pittsburgh compound B-positron emission tomography studies have tested this hypothesis, and with conflicting results. The purpose of this work is to further our understanding of the dynamics of amyloid-β deposition in a large longitudinal cohort. A total of 32 patients with Alzheimer's disease, 49 subjects with mild cognitive impairment and 103 healthy controls underwent two Pittsburgh compound B-positron emission tomography scans 18 months apart. For each participant, a parametric map of Pittsburgh compound B-positron emission tomography rate of change was created [(follow-up scan - baseline scan)/follow-up duration] and entered in a voxelwise three-way analysis of covariance, with clinical status (healthy controls, mild cognitive impairment or Alzheimer's disease), disease progression (clinical conversion from healthy controls to mild cognitive impairment or Alzheimer's disease, or from mild cognitive impairment to Alzheimer's disease) and Pittsburgh compound B status (positive versus negative) as independent factors. Only a significant effect of the Pittsburgh compound B status was found: both Pittsburgh compound B-positive and -negative subjects showed a significant increase in amyloid-β deposition, with this increase being significantly higher in Pittsburgh compound B-positive individuals. This finding suggests either that Pittsburgh compound B-negative individuals have slower rates of amyloid-β accumulation than positive, or that the proportion of individuals showing significant increase in amyloid-β deposition, termed 'Pittsburgh compound B accumulators', is higher within the Pittsburgh compound B-positive group than within the Pittsburgh compound B-negative group. The bimodal distribution of the individual rates of neocortical amyloid-β accumulation observed support the existence of 'Pittsburgh compound B non-accumulators' and 'Pittsburgh compound B accumulators' and different clustering analyses led to a consistent threshold to separate these two subgroups (0.014-0.022 standardized uptake value ratio(pons)/year). The voxelwise three-way analysis of covariance was thus recomputed with the 'Pittsburgh compound B accumulators' only and the results were almost unchanged, with the Pittsburgh compound B-positive group showing higher accumulation than the Pittsburgh compound B-negative group. Finally, a significant negative correlation was found between Pittsburgh compound B rate of change and Pittsburgh compound B baseline burden, but only in the Pittsburgh compound B-positive group (r= -0.24; P=0.025). Higher rates of amyloid-β deposition are associated with higher amyloid-β burden suggesting that amyloid-β deposition does not reach a plateau when cognitive impairments manifest but is instead an ongoing process present even at the Alzheimer's disease stage. amyloid-β accumulation also seems to slow down at the latest stages of the process, i.e. in participants with the highest amyloid burden. Furthermore, this study identified the existence of Pittsburgh compound 'accumulators' and 'non-accumulators', notably within the Pittsburgh compound B-negative group, which may be a relevant concept for future studies.

The pattern of cortical atrophy in Parkinson’s disease with mild cognitive impairment according to the timing of cognitive dysfunction

The density of Lewy bodies or the concurrent β-amyloid pathology would act as modulators in the relative timing of dementia during the course of Parkinson's disease. Depending on the temporal relationship between the onset of parkinsonism and that of cognitive impairment, patients with Parkinson's disease with mild cognitive impairment were divided into two groups of earlier (<1 year) and later (≥1 year) cognitive decline, and cortical atrophy patterns and correlation of gray matter and timing of cognitive decline were analyzed using voxel-based morphometry. The morphometric analysis showed that patients with earlier cognitive decline demonstrated greater cortical atrophy in the inferior parietal and orbitofrontal areas than did those with later cognitive decline. Additionally, the anatomical bases of the timing of their cognitive decline differed in terms of correlation patterns. These data suggest that the pathological burden in Parkinson's disease with mild cognitive impairment may be more severe in patients with earlier cognitive decline than in those with later cognitive decline, and that the neural basis corresponding to the timing of cognitive decline may differ in these patients.

Dynamic of Beta-amyloid deposition in healthy elderly, mild cognitive impairment and Alzheimer's disease: a PiB-PET longitudinal study

ß-amyloid (Aß) deposition in Alzheimer's disease (AD) is thought to start while individuals are still cognitively normal with an early phase of fast accumulation and to plateau at the time of cognitive decline. However, only few longitudinal PiB-PET studies have tested this hypothesis with conflicting results. The purpose of this work is to further our understanding of the dynamic of Aß deposition thanks to the use of a large longitudinal neuroimaging cohort. 32 AD patients, 49 mild cognitive impairment (MCI) patients and 103 healthy controls (HC) from the AIBL study8 underwent two PiB-PET scans 18 months apart. For each participant, a parametric map of PiB-PET rate of change was created ((Follow-up scan-Baseline scan)/Follow-up Duration) and entered in a voxelwise 3-way ANCOVA, with clinical status (HC, MCI or AD), clinical outcome (conversion from HC to MCI or AD, or from MCI to AD) and PiB status9 (positive vs. negative) as independent factors. Only a significant effect of the PiB status was found: both PiB+ and PiB- showed a significant increase in Aß deposition, but this increase was significantly higher in PiB+ within a large network. This finding may reflect the fact that PiB- do have slower rates of Aß accumulation, or that they are less numerous to show a significant PiB accumulation. Arguing for the later hypothesis, the distribution of individual rates of neocortical Aß accumulation revealed to be bimodal, and clustering analyses led to a consistent threshold to separate these two subgroups into “PiB non-accumulators” vs. “PiB accumulators”. The voxelwise 3-way ANCOVA was then re-computed with the “PiB accumulators” only and the results were almost unchanged (see Figure). This study highlighted that rates of Aß accumulation increased as the PiB load increased. It thus suggests that Aß deposition does not reach a plateau when cognitive decline occurs but is instead an on-going mechanism over the course of AD. Besides, this is the first study to take into account the fact that Aß accumulation may not increase in all individuals which might offer the possibility to identify the earliest stages of brain Aß accumulation in PiB- accumulators subjects.

Clinical Reasoning: A case of progressive cognitive decline reversed by middle cerebral artery stent placement

A 46-year-old right-handed African American man presented to the emergency department after a 10-minute episode of sudden-onset left-hand weakness and slurred speech. His medical history was significant for a left cerebellar stroke 6 years ago. That event occurred during a physical training exercise and was thought to be secondary to a vertebral artery dissection.1,2 He was placed on aspirin 81 mg daily. The patient had minimal residual deficits, with left face numbness and left hypoacusis. He did not smoke, drink, or use recreational drugs. There was no family history of stroke or vascular disease. On initial examination, the patient was normotensive. His mental status was intact, with a Mini-Mental State Examination (MMSE) score of 30/30. There was no apraxia, aphasia, or visual field deficit. Cranial nerve examination had normal results with the exception of left hypoacusis and left facial numbness over the V1–V3 distribution to pinprick. Funduscopic examination revealed no papilledema or vasculopathy. Motor, sensory, and cerebellar examinations were normal. Deep tendon reflexes were 2+ throughout with bilateral plantar responses. Laboratory testing including a complete blood count, serum chemistry, coagulation panel, and liver function tests were normal. EKG showed normal sinus rhythm and no evidence of left ventricular hypertrophy. MRI showed no evidence of acute intracranial abnormalities; a chronic left cerebellar infarct was seen (figure 1). CT angiography demonstrated severe bilateral middle cerebral artery (MCA) stenosis, worse on the right, as well as an absent left vertebral artery which was confirmed by conventional angiography (figure 2A). Figure 1 Initial imaging Noncontrast head CT (A) on admission demonstrating chronic left cerebellar infarct. Fluid-attenuated inversion recovery (FLAIR) MRI on admission shows no evidence of ischemic changes in the middle cerebral artery territory (B). FLAIR was also negative (C). Figure 2 Initial cerebral angiogram Angiogram on admission (A), at time of cognitive decline (B), and poststent placement (C) …

Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disease resulting in progressive cognitive decline. Amyloid plaque deposits consisting specifically of beta-amyloid peptides that have formed fibrils displaying beta-pleated sheet conformation are associated with activated microglia and astrocytes, are colocalized with C1q and other complement activation products, and appear at the time of cognitive decline in AD. Amyloid precursor protein (APP) transgenic mouse models of AD that lack the ability to activate the classical complement pathway display less neuropathology than do the APPQ+/+ mice, consistent with the hypothesis that complement activation and the resultant inflammation may play a role in the pathogenesis of AD. Further investigation of the presence of complement proteins C3 and C4 in the brain of these mice demonstrate that both C3 and C4 deposition increase with age in APPQ+/+ transgenic mice, as expected with the age-dependent increase in fibrillar beta-amyloid deposition. In addition, while C4 is predominantly localized on the plaques and/or associated with oligodendrocytes in APPQ+/+ mice, little C4 is detected in APPQ-/- brains consistent with a lack of classical complement pathway activation because of the absence of C1q in these mice. In contrast, plaque and cell associated C3 immunoreactivity is seen in both animal models and, surprisingly, is higher in APPQ-/- than in APPQ+/+ mice, providing evidence for alternative pathway activation. The unexpected increase in C3 levels in the APPQ-/- mice coincident with decreased neuropathology provides support for the hypothesis that complement can mediate protective events as well as detrimental events in this disease. Finally, induced expression of C3 in a subset of astrocytes suggests the existence of differential activation states of these cells.

Apolipoprotein 4 Allele and Problems With Orientation Are Associated With a Persistent Decline in Cognition in Community-Dwelling Elderly Persons

A decline in cognitive test scores in elderly persons can signal the beginning of a descent into dementia or may indicate only a short-term cognitive disturbance. It would be clinically useful to distinguish between the two outcomes and to identify characteristics of each. Four hundred thirty-seven community-dwelling elderly persons were given the Mini-Mental State Examination (MMSE) annually for an average of 7 years. A low score between baseline and final MMSE was identified. A low score 3 or more points lower than baseline score indicated cognitive decline. This decline was called persistent if the final MMSE score was also at least 3 points lower than baseline MMSE score; otherwise, the decline was considered transient. Twenty participants (4.6%) experienced a persistent cognitive decline, 67 participants (15.3%) experienced a transient cognitive decline. Presence of the apolipoprotein epsilon4 allele was significantly associated with persistent cognitive decline (age-adjusted odd ratio [OR] = 11.46, p < .0001) but not with transient cognitive decline (age-adjusted OR = 1.53, p = .219). Incorrect answers on the orientation part of the MMSE at the time of cognitive decline was associated with persistent decline compared to transient decline (age-adjusted OR = 3.58, p = .058). Persistent cognitive decline is an infrequent occurrence in community-dwelling elderly persons. Presence of the epsilon4 allele and errors made by the subject on questions of orientation may be useful in determining whether a cognitive decline is likely to be persistent.