Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate ...entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD. Their morphological hallmarks - cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies - are similar, but clinical differences at onset suggest some dissimilar profiles. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is provided herein.
The clinical constellations of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and postmortem studies have revealed a more pronounced cortical atrophy, elevated cortical and limbic Lewy body pathologies, higher Aβ and tau loads in cortex and striatum in DLB compared to PDD, and earlier cognitive defects in DLB. Conversely, multitracer PET studies have shown no differences in cortical and striatal cholinergic and dopaminergic deficits. Clinical management of both DLB and PDD includes cholinesterase inhibitors and other pharmacologic and non-drug strategies, yet with only mild symptomatic effects. Currently, no disease-modifying therapies are available.
DLB and PDD are important dementia syndromes that overlap in many clinical features, genetics, neuropathology, and management. They are currently considered as subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), from incidental Lewy body disease and non-demented Parkinson's disease to PDD, DLB, and DLB with Alzheimer's disease at the most severe end. Cognitive impairment in these disorders is induced not only by α-synuclein-related neurodegeneration but by multiple regional pathological scores. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with Alzheimer's disease and other proteinopathies. While we prefer to view DLB and PDD as extremes on a continuum, there remains a pressing need to more clearly differentiate these syndromes and to understand the synucleinopathy processes leading to either one.
The growing body of evidence indicating the heterogeneity of Alzheimer's disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that the development of a ...single magic cure suitable for all cases may not be possible. This calls for a shift in paradigm where targeted treatment is developed for specific AD subpopulations that share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of AD, is expressed in more than half of AD patients and is thus an important possible AD therapeutic target.
This review focuses initially on the pathological effects of apoE4 in AD, as well as on the corresponding cellular and animal models and the suggested cellular and molecular mechanisms which mediate them. The second part of the review focuses on recent apoE4-targeted (from the APOE gene to the apoE protein and its interactors) therapeutic approaches that have been developed in animal models and are ready to be translated to human. Further, the issue of whether the pathological effects of apoE4 are due to loss of protective function or due to gain of toxic function is discussed herein. It is possible that both mechanisms coexist, with certain constituents of the apoE4 molecule and/or its downstream signaling mediating a toxic effect, while others are associated with a loss of protective function.
ApoE4 is a promising AD therapeutic target that remains understudied. Recent studies are now paving the way for effective apoE4-directed AD treatment approaches.
Parkinson disease is a primary degenerative disease of the brain, but parkinsonism can also result from a variety of vascular disorders. Vascular parkinsonism (VP) most frequently presents as lower ...body parkinsonism, a condition that is accompanied by the development of white matter lesions (WMLs) and lacunes in the brain. Patients with lower body parkinsonism exhibit gait impairment and go on to develop urinary incontinence, abnormal pyramidal responses and cognitive decline. However, WMLs and lacunes are also common observations among elderly individuals who do not have parkinsonism, which causes difficulty in determining the pathogenetic mechanisms that lead to VP. In addition, imaging studies suggest that many pathological and clinical features are common to VP and Binswanger disease, a type of small vessel vascular dementia. This Review summarizes current understanding of the clinical characteristics of VP, as well as knowledge gained from neuroimaging and nuclear imaging of the pathological features of VP. The lack of current treatment options, and the emergence of new therapies such as cerebrospinal fluid drainage, are also discussed. Finally, consideration is given to whether the overlap between VP and Binswanger disease means that these two disorders should be considered as part of the same disease entity.
We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after ...stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.
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•CCR5 is differentially upregulated in neurons after stroke•Knockdown of CCR5 induces motor recovery after stroke and improves cognition after TBI•Treatment with an FDA-approved drug, maraviroc induces recovery after stroke and TBI•Human carriers for CCR5delta32 have better outcomes after stroke
Genetic and small molecule-based perturbation of CCR5 promotes functional recovery from stroke and traumatic brain injury.
Poststroke cognitive impairment is a debilitating consequence of stroke. The aim of this study was to assess whether Actovegin confers cognitive benefit in patients who have had an ischemic stroke.
...This was a 12-month, parallel-group, randomized, multicenter, double-blind, placebo-controlled study. Eligible patients were ≥60 years of age with a Montreal Cognitive Assessment test score of ≤25 points. Patients were randomized into 2 groups within 1 week of acute supratentorial ischemic stroke in a 1:1 ratio: Actovegin (a deproteinized hemoderivative of calf blood, 2000 mg/d for ≤20 intravenous infusions followed by 1200 mg/d orally) or placebo for 6 months. Patients were treated in accordance with standard clinical practice for a further 6 months. The primary end point was the change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version at 6 months.
Two-hundred forty-eight patients were randomized to Actovegin and 255 patients to placebo. At month 6, the least squares mean change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version was -6.8 for Actovegin and -4.6 for placebo; the estimated treatment difference was -2.3 (95% confidence interval, -3.9, -0.7;
=0.005). Recurrent ischemic stroke was the most frequently reported serious adverse event, with a nonsignificantly higher number for Actovegin versus placebo.
Actovegin had a beneficial effect on cognitive outcomes in patients with poststroke cognitive impairment. The safety experience was consistent with the known safety and tolerability profile of the drug. These results warrant confirmation in additional robustly designed studies.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01582854.
Is Alzheimer disease a disease? Korczyn, Amos D; Grinberg, Lea T
Nature reviews. Neurology,
04/2024, Letnik:
20, Številka:
4
Journal Article
Recenzirano
Dementia, a prevalent condition among older individuals, has profound societal implications. Extensive research has resulted in no cure for what is perceived as the most common dementing illness: ...Alzheimer disease (AD). AD is defined by specific brain abnormalities - amyloid-β plaques and tau protein neurofibrillary tangles - that are proposed to actively influence the neurodegenerative process. However, conclusive evidence of amyloid-β toxicity is lacking, the mechanisms leading to the accumulation of plaques and tangles are unknown, and removing amyloid-β has not halted neurodegeneration. So, the question remains, are we making progress towards a solution? The complexity of AD is underscored by numerous genetic and environmental risk factors, and diverse clinical presentations, suggesting that AD is more akin to a syndrome than to a traditional disease, with its pathological manifestation representing a convergence of pathogenic pathways. Therefore, a solution requires a multifaceted approach over a single 'silver bullet'. Improved recognition and classification of conditions that converge in plaques and tangle accumulation and their treatment requires the use of multiple strategies simultaneously.
Objectives
The epidemiology, manifestations, and course of Parkinson's disease (PD) may differ in men and women. Assessments of severity of the illness and quality of life (QoL), and the burden on ...their caregivers (CG) may change as the disease advances. We determined gender differences in assessment by patients with PD themselves and by their CGs.
Methods
Married couples in whom one of the partners was a PD patient and his/her spouse served as CG were separately evaluated. The patient completed the PD QoL Questionnaire (PDQ‐39), and the spouse completed the Multidimensional Caregiver Strain Index (MCSI). Comparisons were performed using statistical tests.
Results
We studied 122 patient‐CG pairs consisting of 86 (70.5%) male patients. Female patients reported reduced QoL due to depression and pain. Worsening of QoL in advanced PD was reported only by male patients. Female CGs felt exhaustion and damage to their health resulting from care twice as often as male CG. Social constraint and time limitations were more frequent in female CGs, whereas in male CGs it remained the same. With increasing disease severity female CGs reported that manipulations and excessive demands from their male spouses increased, while male CGs reported the same level in female patients. Male CGs, unexpectedly considered themselves more free as PD advanced in their spouses.
Conclusions
Male and female PD patients and CGs assess differently the severity and burden of the disease. Clinicians and social workers should be aware of these factors in attempting to improve QoL of PD patients and CGs.
Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, ...social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier.
Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline. Disease-modifying strategies should integrate both pharmacological and non-pharmacological multimodal approaches, with pleiotropic effects targeting (1) endothelial and brain-blood barrier dysfunction; (2) neuronal death and axonal loss; (3) cerebral plasticity and compensatory mechanisms; and (4) degenerative-related protein misfolding. Moreover, pharmacological and non-pharmacological treatment in PSCI or VCI requires valid study designs clearly stating the definition of basic methodological issues, such as the instruments that should be used to measure eventual changes, the biomarker-based stratification of participants to be investigated, and statistical tests, as well as the inclusion and exclusion criteria that should be applied.
A consensus emerged to propose the development of a disease-modifying strategy in VCI and PSCI based on pleiotropic pharmacological and non-pharmacological approaches.