Dementia & Memory Loss 2

Question 1

Most common dementia before the age of 60

Answer 1

Frontotemporal dementia

Question 2

1) Taupoathies
2) TDP-43 proteinopathies

Answer 2

Tauopathies
1) tau (microtubule-associated protein tau MAPT) mutations
2) classic Pick disease (with Pick bodies)
3) CBD-type neuropathologic alterations
4) PSP-type neuropathologic alterations

TDP-43 proteinopathies
1) Mutations in the progranulin (PGRN) gene
2) mutations in the TDP-43 gene
3) mutations in the valosin-containing protein (VCP) gene
4) noncoding hexanucleotide repeat expansion on chromosome 9 (C9ORF72)

Question 3

most common underlying pathologies in
1) bvFTD
2) nfaPPA
3) svPPA
4) lvPPA

Answer 3

1) tauopathy or TDP-43 proteinopathy
2) tauopathy
3) TDP-43 proteinopathy
4) AD

Question 4

Percent of patients with FTD who have at least one relative with dementia and most common genetic mutations

Answer 4

Thirty to 50 percent of patients with FTD have at least one relative with dementia.

The most common pathogenic genetic mutations include variants in MAPT, GRN, and the C9orf72 repeat expansion.

Question 5

most common genetic cause of familial FTD and amyotrophic lateral sclerosis (ALS)

Answer 5

C9orf72 is the most common genetic cause of familial FTD and ALS, representing approximately 12 and 25 percent of familial cases, respectively

Question 6

Most striking neuropsychological finding differentiating
patients with FTD from AD is

Answer 6

the preservation of visuospatial abilities early in the disease

Question 7

bvFTD diagnostic criteria

Answer 7

Question 8

Inclusion and exclusion criteria for the diagnosis of PPA

Answer 8

Question 9

Diagnostic features of the nonfluent agrammatic PPA

Answer 9

• αγραμματισμός: ανικανότητα της διατύπωσης των σκέψεων στη σωστή γραμματική και συντακτική μορφή του κοινού προφορικού λόγου

Question 10

Diagnostic criteria for the semantic variant PPA

Answer 10

• surface dyslexia or dysgraphia: words with irregular spellings (eg, yacht, colonel, tissue) are mispronounced or misspelled because the correct pronunciation or spelling relies on semantic knowledge.

Question 11

Diagnostic criteria for logopenic variant PPA

Answer 11

• anomia: διαταραχή στην κατονομασία

Question 12

What distinguishes logopenic from non fluent agrammatic PPA?

Answer 12

• Lack of frank agrammatic errors
• Preservation of articulation and prosody

Question 13

Patients with troubling neurobehavioral symptoms of FTD despite nonpharmacologic interventions management

Answer 13

we suggest a treatment trial of a serotonin reuptake inhibitor (eg, citalopram 10 to 20 mg once daily) or trazodone 25 mg once daily

Other treatment options include atypical antipsychotic agents to be used as a last resort.
Patients with FTD need to be carefully monitored for extrapyramidal side effects, for which they are particularly vulnerable.
If needed, we use a low dose of quetiapine (eg, 12.5 to 25 mg), which has fewer reported extrapyramidal side effects relative to other antipsychotic medications.

Question 14

PSP pathologic findings

Answer 14

Neuronal degeneration, neurofibrillary tangles and tau positive astrocytes in basal ganglia and brainstem structures.

Στους εναπομείναντες νευρώνες των περιοχών που υφίστανται εκφύλιση, ανευρίσκονται ενδοκυτταροπλασματικά έγκλειστα (νευροινιδιακά τολύπια)
Τα νευροινιδιακά τολύπια αποτελούνται από ανώμαλα φωσφορυλιωμένη πρωτείνη Tau η οποία χαρακτηρίζεται από την επικράτηση των ισομορφών Tau που περιέχουν 4 επαναλαμβανόμενες περιοχές.
Επιπλέον, έγκλειστα συσσωματωμάτων πρωτείνης tau βρίσκονται στα αστροκύτταρα (“φουντωτά αστροκύτταρα - tufted, που θεωρούνται τυπικά της νόσου) και στα ολιγοδενδροκύτταρα

The neurofibrillary tangles found in PSP, which contain the
microtubule-associated protein tau, differ from those seen in Alzheimer disease and other neurodegenerative disorders!

Question 15

PSP diagnostic criteria

Answer 15

Clinical Diagnosis of Progressive Supranuclear Palsy:
The Movement Disorder Society Criteria 2017

Question 16

Which component of verbal examination is mostly affected in PSP patients

Answer 16

verbal fluency is particularly impaired in progressive supranuclear palsy, with lexical fluency generally more impaired than semantic fluency

**
Semantic Fluency: Also known as category fluency, in this test, participants are asked to produce words that belong to a specific semantic category, such as animals or fruits. For example, if the category is “animals”, participants might say “dog, cat, lion, tiger, etc.”

Lexical Fluency: Also referred to as phonemic or letter fluency, in this test, participants are asked to produce words that begin with a specified letter, such as ‘p’. For example, if the letter is “p”, participants might say “pen, paper, pear, etc.”.

Question 17

Corticobasal degeneration pathogenesis

Answer 17

Μακροσκοπικά: εστιακή ασύμμετρη ατροφία φλοιού στη μετωποβρεγματική περιοχή και στις ρολάνδειες περιοχές

Μικροσκοπικά: απώλεια νευρώνων και γλοίωση στον φλοιό, καθώς και σε άλλες περιοχές του εγκεφάλου (μέλαινα ουσία, υποθαλάμιο πυρήνα, κερκοφόρο και φακοειδή πυρήνα, θάλαμο και πυρήνες του στελέχους).
Το χαρακτηριστικό ιστολογικό εύρημα είναι η διόγκωση (balloon neurons) και αχρωμασία των νευρώνων στον φλοιό και σε άλλες περιοχές του εγκεφάλου.
Το κυτταρόπλασμα των διογκωμένων νευρώνων είναι γεμάτο από έγκλειστα που αποτελούνται από ανώμαλα φωσφορυλιωμένη πρωτείνη tau

Question 18

clinical research criteria for probable sporadic CBD

Answer 18

https://www.uptodate.com/contents/image?imageKey=NEURO%2F98951&topicKey=NEURO%2F14135&search=corticobasal%20degeneration&rank=1~39&source=see_link

Question 19

phenotypes identified with CBD

Answer 19

● Probable CBS –
Characterized by an asymmetric presentation and at least two of:
Limb rigidity or akinesia
Limb dystonia
Limb myoclonus

plus two of:
Orobuccal or limb apraxia
Cortical sensory deficit
Alien limb phenomena (more than simple levitation)

● Possible CBS –
May be symmetric and characterized by
at least one of:
limb rigidity or akinesia,
limb dystonia, and
limb myoclonus,

plus one of:
orobuccal or limb apraxia
cortical sensory deficit
alien limb phenomena (more than simple levitation)

● Frontal behavioral-spatial syndrome (FBS) – Characterized by two of: executive dysfunction, behavioral or personality changes, and visuospatial deficits

● Nonfluent/agrammatic variant of primary progressive aphasia (naPPA) –
Characterized by effortful, agrammatic speech plus at least one of:
Impaired grammar/sentence comprehension with relatively preserved single-word comprehension
Distorted speech production (apraxia of speech)

● PSP syndrome (PSPS) –
Characterized by three of:

Axial or symmetric limb rigidity or akinesia
Postural instability or falls
Urinary incontinence
Behavioral changes
Supranuclear vertical gaze palsy
Decreased velocity of vertical saccades

Question 20

Common exclusion criteria for both probable sporadic CBD and possible CBD

Answer 20

● Evidence of Lewy body disease, such as classic 4 hertz Parkinson disease resting tremor, excellent and sustained levodopa response, or hallucinations

● Evidence of multiple system atrophy, such as dysautonomia or prominent cerebellar signs

● Evidence of amyotrophic lateral sclerosis, such as the presence of both upper and lower motor neuron signs

● Semantic or logopenic variant of primary progressive aphasia

● Structural lesion suggestive of a focal cause

● Granulin mutation or reduced plasma progranulin levels; TDP-43 mutations; fused in sarcoma (FUS) mutations (ie, genetic variants of frontotemporal dementia and amyotrophic lateral sclerosis)

● Evidence of AD, such as a low ratio of beta amyloid peptide 42 to tau in the cerebrospinal fluid or a positive amyloid PET tracer study

Question 21

Corticobasal degeneration management and prognosis

Answer 21

● There are no neuroprotective treatments for CBD and no medications that provide significant symptomatic benefits. Treatment remains targeted at symptom amelioration but is not consistently effective

● In patients with clinical parkinsonism, we suggest a therapeutic trial of levodopa.
The response can be tested using carbidopa-levodopa up to 25/250 mg administered three times a day for at least two months. With little response, the drug should be tapered off gradually, although some patients may prefer to continue taking it if they notice deterioration of function during the tapering.

● The median survival from onset of symptoms with CBD is 6 to 8 years and ranges from 2 to 13 years

Question 22

Genetic forms of PD with high and low prevalence of dementia

Answer 22

Dementia is common in patients with mutations in the glucocerebrosidase (GBA) gene and some forms of alpha-synuclein (SNCA) associated PD

Dementia is uncommon in patients with parkin (PARK2) mutations

Question 23

PD dementia pathogenesis

Answer 23

The clinicopathologic correlations of patients with PD and dementia suggest that patients fall into one of three categories:
- Lewy body pathology restricted to subcortical areas (typical of PD)
- concomitant PD and AD pathologies
- predominant cortical Lewy bodies

Question 24

Cognitive impairment profile in PD dementia

How long after PD symptoms do cognitive symptoms appear

Answer 24

Cognitive impairment in PD has a heterogeneous cognitive profile that is different from that of Alzheimer disease.
The general pattern is one of
* executive dysfunction
* impaired attention and processing speed
* impaired visuospatial function
* less prominent memory deficits and relatively preserved language function

At least 1 year after PD symptoms

Question 25

Cholinsterase inhibitors in parkinson disease dementia

Answer 25

Most, but not all, studies of cholinesterase inhibitors in PDD have noted a mild to moderate benefit but an increased risk of side effects, including worsened tremor and nausea

Question 26

Genes associated with DLB

Answer 26

ApoE ε4, glucocerebrosidase (GBA)

Question 27

Lewy body dementia diagnostic criteria

Answer 27

Question 28

Lewy body dementia management

Answer 28

● Treatment approach – There are currently no treatments with evidence of disease-modifying effects in DLB.
Treatment is primarily symptomatic and targeted toward specific disease manifestations:

Cognitive or behavioral symptoms –
For patients with bothersome cognitive or behavioral symptoms, we suggest treatment with a cholinesterase inhibitor.
Such medications are widely used and considered the mainstay of treatment in DLB.

Memantine is a reasonable alternative when patients cannot tolerate cholinesterase inhibitors, but it may be more problematic in patients with DLB who have hallucinations or delusions. Memantine may be considered as an adjunct to cholinesterase inhibitors based on its use in Alzheimer disease, but evidence in DLB is scant.

Severe, refractory behavioral symptoms –
Antipsychotic medications are reserved for severe, refractory behavioral symptoms after other measures (including nonpharmacologic treatment and cholinesterase inhibitors) have been tried and other contributors have been excluded.
For such patients, we suggest cautious addition of a low-dose atypical antipsychotic agent (eg, quetiapine 12.5 to 25 mg per day)
Patients and caregivers must be informed of the risks, including increased mortality and the development of severe antipsychotic sensitivity reactions that are characteristic of DLB.

Disabling parkinsonism –
For patients with disabling parkinsonism, we suggest initiation of levodopa therapy.
Low doses and slow upward titration with monitoring for increased psychosis is advised (eg, one-half tablet of carbidopa-levodopa [Sinemet] 25/100 mg three times daily, titrated upward over several weeks as tolerated and according to the response).

REM sleep behavior disorder –
Treatment of REM sleep behavior disorder prioritizes establishing a safe sleeping environment; pharmacotherapy with melatonin or clonazepam can be useful in ameliorating symptoms.

Orthostatic hypotension —

A nonpharmacologic approach should be initiated first; this includes behavioral and lifestyle changes such as standing slowly, raising the head of the bed, increasing fluid and salt intake, and wearing compression stockings or an abdominal binder.
Medications that may exacerbate hypotension should be discontinued where possible.
Medical therapy is indicated when these measures fail and can improve symptoms in most patients with DLB.
While not specifically studied in these patients, fludrocortisone and the alpha-1 receptor agonist midodrine, or a combination of the two, are frequently used to treat symptomatic orthostatic hypotension in DLB. Droxidopa (a prodrug that is metabolized to norepinephrine) may be used as an alternative to midodrine.

Urinary symptoms —
Urinary urgency, frequency, and incontinence are common in DLB. Treatment recommendations are largely based on symptomatic treatment in other settings.
However, antimuscarinic agents (oxybutynin, solifenacin, and trospium) may worsen cognitive function and psychosis, and thus they are relatively contraindicated in DLB.
Mirabegron, a beta-3 adrenoceptor agonist, is preferred as there is low risk for cognitive side effects.

For patients with nocturnal polyuria and sleep fragmentation, desmopressin (oral or intranasal spray) at bedtime may be a viable option to reduce frequent nocturia and is generally well tolerated in patients with conditions related to DLB

Question 29

Normal pressure hydrocephalus pathogenesis

Answer 29

Idiopathic NPH is more common in older adults.
Its pathogenesis is uncertain.

Secondary NPH is most commonly associated with subarachnoid hemorrhage or meningitis, occurs in any age group, and is associated with impaired cerebrospinal fluid resorption.

Question 30

Normal pressure hydrocephalus clinical findings

Answer 30

1) gait disorder
- worsens either subacutely or chronically over weeks, months, or years.
- classically described as “magnetic” (with “freezing” and inability to lift the feet off the floor) and “apraxic” (as if the patient cannot figure out how to move the legs to initiate - has parkinsonian features, with slowness, shuffling, imbalance, and shortened stride length.
In contrast to patients with Parkinson disease, patients with NPH frequently adopt a position offering a wide base of support, often with external rotation of the legs. Also, often the condition is more symmetrical than Parkinson disease.

2) Urinary symptoms
Patients may have minor symptoms, such as increased urinary urgency and frequency.
Alternately, unsuppressed bladder contractions together with decreased voluntary ability to keep the outlet closed can result in incontinence.
There may be incontinence sans gêne, in which the affected individual seems unconcerned about the incontinence.

3) Cognitive symptoms
- usually occur after the onset of gait and urinary dysfunction.
- may range from subtle to severe.
- Typically, dementia is of a subcortical type, involving forgetfulness, inertia, bradyphrenia, apathy, decreased processing speed, and impairment in decision
making, set switching, and other aspects of executive function.
- Patients with memory impairment often demonstrate seemingly poor learning and impaired delayed recall of learned material, with better recognition of learned material with cues (this pattern suggests a primary retrieval deficit
rather than defective encoding of learned material)

Question 31

Approach to the evaluation of a patient with possible normal pressure hydrocephalus

Answer 31

https://www.uptodate.com/contents/image?imageKey=NEURO%2F117418&topicKey=NEURO%2F5069&search=normal%20pressure%20hydrocephalus&rank=1~27&source=see_link

Question 32

disproportionately enlarged subarachnoid space hydrocephalus

Answer 32

“disproportionately enlarged subarachnoid space hydrocephalus” (DESH) has been described as a characteristic feature of NPH.
DESH is characterized by:

●Ventriculomegaly

●Tight high-convexity and medial subarachnoid spaces (easiest to visualize on coronal MRI)

●Disproportionate enlargement of the Sylvian fissures

●Focally dilated or entrapped sulci without adjacent cortical atrophy

Several observational studies have found that DESH is associated with increased likelihood of response to shunting

Question 33

Complications of shunting in normal pressure hydrocephalus

Answer 33

Complications of shunting include “overshunting” with resultant headache, orthostatic symptoms, or development of subdural hematomas or hygromas
these problems can be obviated by checking the valve setting and changing the shunt-valve pressure.
Shunt infections are rare but may require removal of inserted hardware.

Question 34

Huntington disease pathogenesis

Answer 34

Expansion of CAG repeats is thought to produce a toxic “gain of function” (ie, disease develops because the mutant form of the protein gains a new function or has enhanced function that is deleterious to the cell)
Aggregation of mutant huntingtin is a pathologic hallmark of the disease process. However, the precise role of aggregates in the pathogenesis of HD is controversial

The characteristic pathologic change in HD is diffuse, marked atrophy of the neostriatum that may be worse in the caudate than in the putamen

Question 35

Huntington disease genetics

Answer 35

Huntington disease (HD) is caused by expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeats in the HTT gene located on chromosome 4 that encodes the protein huntingtin. The disease is transmitted in an autosomal dominant manner.

*Number of repeats –
Wildtype HTT alleles have 6 to 26 CAG repeat units.
Intermediate alleles have 27 to 35 repeats and rarely cause disease.
The generally accepted threshold for developing HD is 36 repeats, but there is variable penetrance for expression of the HD phenotype with 36 to 39 CAG repeats.
Full penetrance occurs at repeat sizes ≥40

*Genotype-phenotype correlation – Individuals with early-onset HD tend to have a large number of CAG repeats, while those developing HD late in life typically have a low repeat number. Alleles with 40 to 50 CAG repeats are found in most patients with the adult form of HD. In comparison, juvenile HD is typically associated with alleles containing more than 60 CAG repeats.

*Genetic anticipation – Expansion of the CAG repeat number over successive generations may cause an earlier and more severe phenotype, termed “anticipation.”
Επίσπευση
Anticipation is more common following paternal transmission of the disease allele

Approximately 1 percent of patients with a typical HD phenotype test negative for the HTT gene repeat expansion.

Question 36

Huntington disease clinical findings

Answer 36

Symptoms of HD begin insidiously with movement abnormalities and/or with psychiatric and cognitive features.

Chorea is a key feature of HD, and the defining sign at the time of diagnosis.

Psychiatric problems can include irritability, depression, dysphoria, agitation, apathy, anxiety, paranoia, delusions, and hallucinations.
The dementia of HD is characterized by executive dysfunction

With disease progression, motor function slowly deteriorates.
Chorea may eventually be replaced in advanced stages of HD by a parkinsonian akinetic-rigid state.
The slow but relentless deterioration in cognitive and motor function causes significant morbidity and early mortality

Question 37

Huntington disease diagnosis

Answer 37

The diagnosis of HD is based upon the presence of the typical clinical features, a family history of the disease, and confirmatory genetic testing for the disease-causing trinucleotide (cytosine-adenine-guanine [CAG]) repeat expansion in the huntingtin (HTT) gene.

However, there is no apparent family history in up to 8 percent of patients with genetically proven HD.

Question 38

Huntington disease management

Answer 38

https://www.uptodate.com/contents/image?imageKey=NEURO%2F130620&topicKey=NEURO%2F4902&search=huntington%20disease&rank=2~66&source=see_link

Question 39

Which conditions have expanded CAG repeats?

Answer 39

Expanded CAG repeats are found in:
* Huntington disease
* dentatorubral- pallidoluysian atrophy (DRPLA)
* Kennedy disease (bulbospinal muscular atrophy)
* spinocerebellar ataxia types 1, 2, 3, 6, 7, 12, and 17

Question 40

Huntington disease: most common imaging finding

Answer 40

The most striking and best-known feature is that of caudate head atrophy

Question 41

Tetrabenazine 1) Mechanism of action, 2) dosing, 3) monitoring

Answer 41

1) Acts as a reversible inhibitor of the human vesicular monamine transporter type 2 (VMAT-2) and thereby decreases the uptake of monoamines (including dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles and depletes the monoamine stores

2) Oral: 12.5 mg once daily in the morning; may increase to 12.5 mg twice daily after 1 week. May increase daily dosage by 12.5 mg increments at weekly intervals up to 50 mg/day; divide daily doses >37.5 mg into 3 doses (maximum single dose: 25 mg)

3) iver function (baseline and as clinically indicated); orthostatic BP (as clinically indicated); CYP2D6 genotyping for evaluation of metabolizer status (for patients requiring >50 mg/day); EKG (as clinically indicated for QT prolongation); signs/symptoms of suicidal ideation.

Question 42

Tetrabenazine contraindications

Answer 42

Hepatic impairment
active suicidality or untreated or inadequately treated depression
coadministration of monoamine oxidase inhibitors (MAOIs) or use of tetrabenazine within 2 weeks of discontinuation of MAOI therapy
coadministration with reserpine, ≥20 days should pass after discontinuing reserpine before initiating tetrabenazine therapy; coadministration with deutetrabenazine or valbenazine.

Question 43

Major adverse effect of tetrabenazine

Answer 43

can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington disease

Question 44

Midodrine: 1) Mechanism of action, 2) dosing, 3) monitoring

Answer 44

1) alpha1-agonist. This agent increases arteriolar and venous tone resulting in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension.

2) Oral: Initial: 2.5 mg 2 or 3 times daily during daytime hours (eg, every 3 to 4 hours) when patient is upright; titrate as needed based on response and tolerability up to a usual maximum dose of 10 mg 3 times daily. Avoid administering <4 hours before bedtime to minimize risk of supine hypertension

3) BP while supine, sitting, and standing upon awakening; signs or symptoms of bradycardia; renal and hepatic function.

Question 45

Midodrine: 1) adverse effects, 2) contraindications

Answer 45

1)
Bradycardia
Supine hypertension
Dermatologic: Piloerection , pruritus
Genitourinary: Dysuria (including urinary frequency, urinary retention, urinary urgency)
Nervous system: Paresthesia

2)
Severe organic heart disease; acute renal disease; urinary retention; pheochromocytoma; thyrotoxicosis; supine hypertension; poorly controlled hypertension.

Question 46

Rapidly progressive dementia definition

Answer 46

Although the definition of rapid varies in practice, it is
generally accepted that the interval from first symptom to dementia onset is measured in weeks or months, with the majority of patients with RPD progressing from independence to complete (or nearcomplete) dependence within 1 to 2 years

Question 47

Rapidly progressive dementia causes 1

Answer 47

Question 48

Rapidly progressive dementia causes 2

Answer 48

Question 49

Treatable causes of rapidly progressive dementia

Answer 49

• autoimmune/inflammatory conditions (eg, limbic encephalitis)
• CNS infection
• granulomatous disease (e.g. sarcoidosis)
• cerebral amyloid angiopathy with related inflammation
• nutritional/metabolic deficit (eg,Wernicke-Korsakoff syndrome)