Dementias Flashcards
What is Creutzfeldt-Jacob disease?
It is a rapidly progressive neurodegenerative condition associated with brain shrinkage and deterioration. Disease course is more rapid in comparison with the one of Alzheimer’s disease. A brain section these patients will show spongiform pathology.
Etiology —> it is a prion disease caused by the deposition of pathological protein in this case PrP.
Forms —> sporadic 90% of cases no mutations, genetic 10% of cases mutations in PrP gene, iatrogenic associated with brain graft implantation very rare, variant mucca pazza associated with the consumption of products derived by cows suffering from bovine encephalopathy.
Diagnosis —> EEG will show periodic share wave complexes, CSF analysis will show alterations such as total tau and non phosphorylated tau, imaging with DWI and FLAIR shows hyper intense lesions along cortices and caudate and putamen hyper intensity. Cognitive impairment should always be present in order to diagnosis CJD.
It is a rapid disease course as the average survival time is 6 months, cognitive impairment is rarely the only issue of this disease. In a few months patients develop myoclonus, impairment of visual and cerebellar pathways, and other signs.
No treatment.
What are alpha synucleinopathies?
α-SYNUCLEINOPATHIES are neurodegenerative conditions associated with α-Synuclein protein’s alteration/deposition. Parkinson’s disease is the most frequent one, then there are also Dementia with Lewy bodies and Multiple System Atrophy (MSA).
What is dementia with lewy bodies? Epidemiology and pathological hallmarks?
DLB is a common yet underdiagnosed type of dementia as it has a similar onset age of AD. It can be considered as a mix between Parkinson’s and AD as it is characterized by both cognitive and motor impairment
Epidemiology —> some epidemiological studies suggest it is a rare diseased others claim that 23% of AD patients are actually DLB patients.
Pathological hallmarks —> alpha synuclein neuronal inclusions accompanied by neuronal loss. It is common to observe AD pathology in these patients such as amyloidosis and P-TAU protein.
Diagnostic criteria of DLB?
Essential for DLB diagnosis is dementia, defined as a progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Memory impairment may not necessarily occur in the early stages as dementia is due to other cognitive deficits such as executive function, attention and visuospatial deficits.
To better differentiate AD from DBL after the MMSE the patients can be asked to perform the MMSE pentagon copy test. AD patients manage to copy the origin picture but DLB patients even with mild cognitive impairment aren’t able to do so.
Differences between DLB, Parkinson’s and AD?
In case of Dementia with Lewy bodies, alpha-synuclein protein will deposit both in midbrain’s pars compacta (more specifically in substantia nigra as in Parkinson’s disease, in which there is the degeneration of dopaminergic neurons causing bradykinesia, rigidity and tremors) and in cortices (causing cognitive impairment) at the same time.
From the pathological point of view, Parkinson’s disease and DLB are the same disease, but differ in the patterns of pathological spreading. In Parkinson’s disease the cortex is involved later than substantia nigra. Additionally, Parkinson’s disease patients MUST present with bradykinesia at least.
In presence of cognitive impairment and some degrees of Parkinsonism, Dementia with Lewy bodies should be taken in consideration.
Within the cortex there are regions that are more vulnerable in the earlystages of DLB, such as frontal, parietal and occipital lobes. While in Alzheimer’s disease patients, medial temporal lobe and parietal lobe are more involved and this explains why a diseased patient will have episodic memory loss with spatial disorientation at early stages.
If the frontal region is involved, executive dysfunction and attention deficits will be present. If
parietal and occipital lobes are involved, there will be visuospatial deficits. Executive and visuospatial deficits are present together with Parkinsonism in Dementia with Lewy bodies.
Core clinical features of DLB? Supportive clinical features?
- Fluctuating cognition/level of consciousness —> usually a late clinical features but can also happen early in disease course. Caregivers report alternated levels of consciousness during the day due to frontal lobe involvement. Patients tend to be lethargic, drowsy and stare into space.
- Visual hallucinations —> very typical of DLB and occur very early in the disease course. These are due to occipital lobe involvement. Here the patient is aware the hallucinations are not real, the patient can criticize and report these hallucinations. They are usually very well formed and detailed.
- REM sleep disorder —> patients may develop this 2 to 6 years before disease onset. It is common both in DLB and Parkinson’s.
Supportive clinical features include severe autonomic dysfunction such as postural instability, syncope, consitpation, urinary incontinece.
Indicative biomarkers and specific exams used to aid diagnosis?
- Reduced dopamine transported uptake in basal ganglia demonstrated by SPECT or PET.
- Abnormal (low uptake) iodine MIBG myocardial scintigraphy.
- Polysomnographic confirmation of REM sleep without atonia.
DaTSCAN is highly specific for alpha synucleinopathies as it looks for reduced dopamine transported uptake. It cannot distinguish DLB from Parkinson as they display similar conditions.
Myocardial scintigraphy can be used to assess the presence of postganglionic sympathetic cardiac innervation due to alpha synuclein deposition.
FDG PET scan is used to assess the metabolic rate within the cortex, it is used in the DDX between DLB and AD bc the involved cortical regions differ (at least in the early stages). In AD hypo metabolism is present in temporal/parietal regions with occipital spared. In DLB occipital is involved.
Cingulate island sign signals the normal metabolism in the posterior cingulate cortex and reduced metabolism in the adjacent occipital cortex, it is an indicator for DLB.
What is vascular cognitive impairment?
It is a very common type of irreversible dementia. 17% of patients with cognitive impairment have vascular dementia as an etiology and in 10% of cases it can also be associated to other neurodegenerative conditions like AD.
VD progression is step wise and is due to the accumulation of vascular lesions.
Patient features include risk factors for acute cerebrovascular disorders that can be associated to cognitive impairment.
Cognitive impairment characteristic are variable as it depends on the involved region. Since the frontal lobe is the largest region it is also the most frequently involved. Mean features include executive function and attention deficits.
Diagnosis is strengthened by history of stroke and falls, focal neurological signs, neuroimaging positivity for vascular disorders.
Main cerebrovascular disorders associated to cognitive deterioration are large cortical infarction (first cause of VD), multiple lacunae infarcts and extensive white matter lesions.
What is frontotemporal dementia?
It is a clinical condition characterized by a focal atrophy of the frontal lobe and of the anterior portion of the temporal lobe. The occipital and posterior temporal regions are spared. Opposite pattern of AD.
FTD is an umbrella term as it include many different syndrome such as taupathies and TDP43 pathologies. In between these two we have three syndrome : behavioral variant of FTD, semantic variant of PPA, and nonfluent/agrammatic variant of PPA.
Clinical manifestations? Epidemiology and genetics of FTD?
If the frontal lobe is involved we should expect cognitive deficits but also behavioral changes. A neurodegenerative process at this level will be associated to bizzarre behaviors such as stiff jerky posture, uninhibited socially inappropriate behavior, decreased speech, loss of awareness etc.
Epidemiology —> involves younger patients than AD around 60-65 yr. It is rarer than AD but since the patients are younger the social impact is greater.
Genetics —> main two pathologies associated with FTD are tau and TDP43. The semantic variant is mostly associated with TDP43 pathology, the non fluent variant is more frequently associated to taupathy and the behavioral is more challenging, 50/50 scenario. Most frequent mutated gene is C9ORF72.
Behavioral variant of FTD?
Of course behavioral changes are very important in diagnosing this variant and they include : a change from baseline personality, apathy, loss of sympathy, compulsive and ritualistic behaviors, changes in dietary and oral habits, lack of awareness.
Key cognitive features —> frontal region involvement leads to struggle to articulate words and the portal regions to difficulty to remember words. Executive dysfunction is prominent and can be tested with the modified card sorting test.
Diagnostic process —> it is based on characteristic behavioral and cognitive symptoms. In addition there must be a clear picture of neurodegeneration in frontal and temporal regions by MRI of FDG-PET. Classic finding is knife edge atrophy.
The frontal variant of AD cannot be excluded based on prior information therefore CSF analysis is performed.
Semantic variant of PPA?
Main features include naming deficits (anomia) as patients cannot name objects even if they interact with them, single word comprehsion deficit. These are also early symptoms in the disease course.
Late symptoms include loss of knowledge about the meaning of objects. After 2 to 3 years some behavioral deficits may emerge.
Repetition, fluency, speech production, grammar, episodic memory and spatial navigation remain intact.
Diagnosis is given by clinical diagnosis and imaging which must show predominant anterior temporal lobe atrophy or hypofusion/hypometabolism on SPECT or PET.
Non-fluent/agrammtic variant of PPA?
Non-fluent indicates that articulation is impaired, speech is difficult for the patient. Agrammatic indicates dysfunction in grammatical construction of speeech.
The patients generally have no issues understanding single words but may have difficulty understanding complex sentences. Grammatical errors are very inconsistent and vary between patients.
In these patients the frontal lobe brocka’s area is affected.
To diagnose this variant clinical diagnosis is needed in addition to imaging showing either predominant left posterior fronto-insular atrophy on MRI or hypoperfusion/hypermetabolism on SPECT or PET.
Treatment for dementias?
As of today in Italy we don’t have any disease modifying drugs but generally safe symptomatic drugs that stabilize the patient. They include cholinesterase inhibitors and NMDA receptors non competitive antagonists.
Cholinesterase inhibitors include donepezil, rivastigmine, galantamine.
NMDA receptor antagonist include memantine.
