Dementia – Atypical Features Present?

Early onset at age <65: While Alzheimer’s disease is still the most likely diagnosis for an individual with dementia under age 65, it is important to consider other causes of dementia because they become much more prevalent. Examples by categories:
- Neurodegenerative: Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, Parkinson disease dementia, Parkinson plus syndromes
- Vascular contributions to cognitive impairment and dementia (VCID): Vascular dementia, CADASIL, cerebral amyloid angiopathy, primary angiitis of the CNS, secondary CNS vasculitis
- Infectious: Prion diseases, HIV-associated neurocognitive disorder, syphilis, Whipple’s disease, progressive multifocal leukoencephalopathy
- Inflammatory: Multiple sclerosis, paraneoplastic, encephalitis
- Others: Huntington disease, Wilson disease, normal pressure hydrocephalus, alcohol use, chronic traumatic encephalopathy

Non-primary amnestic presentation: Primary amnestic presentations of cognitive impairment are the most common, with changes in memory being the classic presentation of typical Alzheimer’s disease. However, occasionally a patient presents with declines in other cognitive domains and is therefore said to have a non-primary amnestic presentation. A patient with a non-primary amnestic presentation should raise your suspicion for atypical variants of Alzheimer’s disease or non-Alzheimer’s types of dementia

Rapid progression (weeks to months): We often think of prion disease as the most likely etiology of a rapidly progressive dementia, but the differential diagnosis is broad. See table 7-4 in this article (Rapidly Progressive Dementia; Continuum – 2016) if you would like to read more about non-prion causes of rapidly progressive dementia (RPDs). The work-up for RPD is broad, variable, and often conducted by experts.

Hallucinations: Hallucinations can be a feature of several types of dementia, but they are less commonly seen in early Alzheimer’s dementia (if present in Alzheimer’s, they are more likely to occur in later stages).
- The presence of visual hallucinations (VH) may be the best way to differentiate between early dementia with Lewy bodies (DLB) and Alzheimer’s, with VH much more likely in DLB. (What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia?; Brain – 2006)
  - VH are a core clinical feature of DLB.
- Note: VH can be present in Parkinson’s disease in the absence of dementia.
- Remember that Charles Bonnet syndrome (visual hallucinations due to vision loss) may be another cause of VH in older adults in the setting of poor vision, and you must consider other causes of hallucinations, including delirium, psychiatric disease, medication and substance use, etc.
Parkinsonism (resting tremor, bradykinesia, rigidity): The term “parkinsonism” often refers to the clinical syndrome characterized by resting tremor, bradykinesia, and rigidity, of which Parkinson’s disease is one of the causes. If one or more of these signs is present, consider whether a diagnosis of Parkinson’s disease is applicable and whether the patient may benefit from a referral to a neurologist for further characterization of their movement disorder and the associated cognitive changes.
- Resting tremor: tremor noted while extremity is resting
- Bradykinesia: general slowness of movement, often with initiating movements
- Rigidity: resistance to passive movement of a joint in a relaxed position

Falls: Falls are a geriatric syndrome, and often are the result of numerous factors.
- Note: a geriatric syndrome refers to a single entity experienced by a person, such as falls or delirium, that has a multitude of causes.
- Falls are not typical of pure Alzheimer’s disease. However, if falls stand out in the history as temporarily related to the development of cognitive impairment, consider whether the patient’s falls and cognitive impairment could be part of the same process. For example:
  - If there is an asymmetric neurologic exam, consider vascular contributions to cognitive impairment and dementia (VCID)
  - If there is a “magnetic gait” with urinary urge/incontinence, consider normal pressure hydrocephalus (NPH)
  - If there are Parkinsonism features with the falls, consider dementia with Lewy bodies (DLB).
  - If there is ophthalmoplegia and features of akinesia, consider progressive supranuclear palsy (PSP).

History of a stroke and/or other vascular disease: A history of a stroke is associated with cognitive decline. A stroke may be the primary culprit for a patient’s cognitive impairment or it may be one contributor out of several to their cognitive changes.
- Terminology is controversial: Terms used include “vascular dementia”, “vascular contributions to cognitive impairment and dementia”, and “vascular cognitive impairment”. There is significant variation in clinical practice in usage of these terms and criteria for diagnosis. If dementia is temporally related to a significant stroke, use of “vascular dementia” may be appropriate. If the history is unclear regarding a temporal relationship, it may be more appropriate to use “mixed dementia” to describe, for example, the syndrome of a person who has features of Alzheimer’s disease and a significant history of a stroke/vascular disease.
- There are many types of vascular disease associated with cognitive changes:
  - Post-stroke, multi-infarct, hemorrhagic (subdural, subarachnoid, intraparenchymal), cerebral amyloid angiopathy, CADASIL, subcortical vascular dementia (Binswanger’s)

History of head trauma: A significant traumatic brain injury may be the sole culprit for the development of neurocognitive disorder.
- The DSMV diagnosis of “neurocognitive disorder due to traumatic brain injury” requires:
  - Criteria met for major or mild neurocognitive disorder
  - Evidence of TBI with one or more of the following: loss of consciousness, posttraumatic amnesia, disorientation and confusion, neurological signs
  - Presentation of the disorder immediately after the TBI and persistence of the disorder past the acute post-injury period
- If not the sole culprit, a history of a TBI or of repeated head trauma may increase the risk of specific types of dementia such as Alzheimer’s and DLB, among others. Results of studies have been variable in whether there is an association between TBI and dementia.
- Note: Chronic traumatic encephalopathy (CTE) is recognized as a distinct neurodegenerative disorder, related to repeated head traumas, that may result in the development of a distinct form of dementia.
  - Consensus for clinical diagnosis of CTE is lacking, and it is still a neuropathological diagnosis made post-mortem.
  - The clinical syndrome associated with CTE has been termed Traumatic Encephalopathy Syndrome (TES) and diagnostic criteria have been put forth for this syndrome.

Heavy alcohol use: In some studies, heavy alcohol consumption (the definition of which varies significantly) has been associated with all-cause dementia (Alcohol use and dementia: new research directions; Current Opinions in Psychiatry – 2021). However, several studies have shown that low or moderate alcohol consumption is associated with a lower risk of dementia (A Systematic Review of Meta-Analyses that Evaluate Risk Factors for Dementia to Evaluate the Quantity, Quality, and Global Representativeness of Evidence; Journal of Alzheimer’s Disease – 2019).
- Alcohol may just be a contributory factor to various forms of dementia, or it may be the main cause of a dementia.
- Terminology is confusing here when discussing dementia primarily due to alcohol. DSMV recognizes the broad category of “substance/medication induced neurocognitive disorder”, while ICD-10 recognizes both an amnestic syndrome and a “residual and late onset psychotic disorder” with a dementia subtype. The term “alcohol-related dementia” is also used some in the literature and in clinical settings.
- Korsakoff syndrome is still used by many providers to denote the neurocognitive disorder in which amnesia and confabulation are prominent
  - Korsakoff syndrome is often referred to in the setting of heavy alcohol use, however it can be a manifestation of any condition that results in thiamine deficiency.

HIV infection present: If a person has untreated or poorly controlled HIV, they may be at risk for having cognitive changes secondary to HIV. Signs and symptoms include: insidious onset of impairments in memory and concentration as well as psychomotor slowing.
- Terminology: DSMV recognizes “neurocognitive disorder due to HIV infection”, while a major working group uses the terminology “HIV-associated neurocognitive disorders”
  - HIV-associated neurocognitive disorders (HAND) is further subdivided into:
    - HIV-1-associated asymptomatic neurocognitive impairment (ANI)
    - HIV-1-associated mild neurocognitive disorder (MND)
    - HIV-1-associated dementia (HAD)
- Treatment of HIV infection in people who have neurocognitive changes can improve their cognition (Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy).
- However, with treated HIV, a person is more likely to have a different etiology of their dementia than HAND.

Syphilis infection present: Neurosyphilis, a form of syphilis that can occur in people infected with syphilis (particularly if untreated), has been classified into five types, including general paresis (aka dementia paralytica) which is the most common form of neurosyphilis that manifests as dementia. Other types of neurosyphilis include asymptomatic neurosyphilis, meningeal neurosyphilis, meningovascular neurosyphilis, and tabes dorsalis.
- General paresis manifests ~10-30 years after initial infection and can include cognitive impairment, behavioral changes, and neurological changes.